anti-pd-l1 antibodies and uses of these

专利摘要:
ANTIBODIES ANTI-PD-L1, ITS PRODUCTION PROCESS, ISOLATED NUCLEIC ACID, VECTOR, HOST CELL, KIT, AND PHARMACEUTICAL COMPOSITION.The present patent application relates to anti-PD-L1 antibodies or antigen-binding fragments thereof, nucleic acid encoding them, therapeutic compositions thereof and their use to increase T cell function to up-regulate immune responses cell-mediated and for the treatment of dysfunctional T-cell disorders, such as tumor immunity, for the treatment of cancer.
公开号:BR112014012819A2
申请号:R112014012819-7
申请日:2012-11-21
公开日:2020-10-20
发明作者:Horacio G. Nastri；Christel Iffland；Olivier Leger；Qi An；Mark Cartwright；Sean D. McKenna；Vanita D. Sood；Gang Hao
申请人:Merck Patent Gmbh；
IPC主号:

专利说明:

[001] [001] The present patent application relates to anti-PD-L1 antibodies or antigen-binding fragments thereof, nucleic acid encoding them, their therapeutic compositions and their use to enhance T cell function for regulate upward cell-mediated immune responses and for the treatment of dysfunctional T-cell disorders, such as tumor immunity, for treatment and cancer. Background to the invention Lymphocyte development and activation
[002] [002] Two main types of lymphocytes in humans are T (derived from the thymus) and B (derived from bone marrow). These cells are derived from hematopoietic stem cells in the bone marrow and fetal liver that have compromised the lymphoid development pathway. The origin of these stem cells follows divergent pathways to mature into B lymphocytes or T lymphocytes. The development of human B lymphocytes takes place entirely within the bone marrow. T cells, on the other hand, develop from immature precursors that leave the marrow and travel through the bloodstream to the thymus, where they proliferate and differentiate into mature T lymphocytes.
[003] [003] Mature lymphocytes that emerge from the thymus or bone marrow are in a quiescent state, or “at rest”, that is, they are mitotically inactive. When dispersed in the bloodstream, these “naive” or “virgin” lymphocytes travel in various secondary or peripheral lymphoid organs, such as the spleen, lymph nodes or tonsils. Most virgin lymphocytes have an inherently short life expectancy and die within a few days after leaving the spinal cord or thymus. However, if such a cell receives signals that indicate the presence of an antigen, they can activate and undergo successive cycles of cell division. Some resulting progeny cells then revert to the resting state to become memory lymphocytes - B and T cells that are essentially adapted for the next encounter with the stimulating allergen. Another progeny of activated virgin lymphocytes are effector cells, which survive for only a few days, but perform specific defensive activities. Lymphocyte activation refers to an ordered series of events that a resting lymphocyte undergoes as it is stimulated to divide and produce progeny, some of which become effector cells. A complete response includes both the induction of cell proliferation (mitogenesis) and the expression of immune functions. Lymphocytes are activated when specific ligands bind to receptors on their surfaces. The ligands are different for T cells and B cells, but the resulting intracellular physiological mechanisms are similar.
[004] [004] Some foreign antigens can induce lymphocyte activation, especially large polymeric antigens that bind surface immunoglobulins in B cells or other glycoproteins in T cells. However, most antigens are not polymeric and even directly bound to B cells in large numbers fail to result in activation. These most common antigens activate B cells when they are co-stimulated with nearby helper T lymphocytes activated. Such stimulation can occur from lymphokines secreted by the T cell, but is transmitted more efficiently by direct contact of the B cell with T cell surface proteins that interact with certain B cell surface receptors to generate a secondary signal. T cells
[005] [005] T lymphocytes do not express immunoglobulins, but instead detect the presence of foreign substances by means of surface proteins called T cell receptors (TCR). These receptors recognize antigens by direct contact or by influencing the activity of other immune cells. In conjunction with macrophages, T cells are the primary cell type involved in cell-mediated immunity.
[006] [006] Unlike B cells, T cells can detect foreign substances only in specific contexts. In particular, T lymphocytes will recognize a foreign protein only if it first cleaves into small peptides, which are then displayed on the surface of a second host cell, called an antigen presenting cell (APC). Many types of host cells can present antigens under some conditions, but certain types are more specifically adapted for this purpose and are particularly important in controlling T cell activity, including macrophages and other B cells. The antigen presentation depends in part on proteins specific, called major histocompatibility complex (MHC) proteins, on the surface of presenting cells. Thus, to stimulate cell-mediated immunity, foreign peptides must be presented to T cells in combination with MHC peptides, and this combination must be recognized by a T cell receptor.
[007] [007] There are two significant subsets of T cell: cytotoxic T lymphocytes (Tc cells or CTLs) and helper T cells (TH cells), which can be roughly identified based on the cell surface expression of the CD8 and CD4 marker. Tc cells are important in viral defense and can kill viruses directly by recognizing certain viral peptides expressed on the cell surface. TH cells promote proliferation, maturation and immune function of other cell types, for example, lymphokine secretion to control activities of B cells, macrophages and cytotoxic T cells.
[008] [008] An important negative co-stimulatory signal that regulates T cell activation is provided by the programmed death receptor 1 (PD-1) (CD279) and its PD-L1 ligand binding partners (B7-H1, CD274) and PD- L2 (B7-DC, CD273). The negative regulatory role of PD-1 has been revealed by PD-1 knockouts (Pdcdl - / -), which are prone to autoimmunity. Nishimura et al, Immunity JJ: 141-51 (1999); Nishimura et al, Science 291: 319-22 (2001). PD-1 is related to CD28 and CTLA-4, but without the proximal membrane cysteine that allows homodimerization. The cytoplasmic domain of PD-1 contains a tyrosine-based immunoreceptor inhibition motif (ITIM, V / 1xYxxL / V). PD-1 only binds to PD-L1 and PD-L2. Freeman et al, J. Exp. Med. 192: 1-9 (2000); Dong et al, Nature Med. 5: 1365-1369 (1999); Latchman et al, Nature Immunol 2: 261-268 (2001); Tseng et al, J. Exp. Med. 193: 839-846 (2001).
[009] [009] PD-1 can be expressed in T cells, B cells, natural killer T cells, activated monocytes and dendritic cells (DC). PD-1 is expressed by activated human CD4 + and CD8 + T cells, but not by unstimulated and B cells and myeloid cells. This is in contrast to the more restricted expression of CD28 and CTLA-4. Nishimura et al, Int. Immunol. 8: 773-80 (1996); Boettler et al, J. Virol. 80: 3532-40 (2006). There are at least 4 PD-1 variants that have been cloned from activated human T cells, including transcripts without (i) exon 2, (ii) exon 3, (iii) exons 2 and 3 or (iv) exons 2 to 4. Nielsen et al, Cell. Immunol. 235: 109-16 (2005). With the exception of PD-I∆ex3, all variants are expressed at similar levels as PD-1 in resting peripheral blood mononuclear cells (PBMCs). The expression of all variants is significantly induced after activation of human T cells with anti-CD3 and anti-CD28. PD-1Aex3 variants without a transmembrane domain, and resemble soluble CTLA-4, which plays an important role in autoimmunity. Ueda et al, Nature 423: 506-11 (2003).
[0010] [0010] PD-1 signaling typically has a greater effect on cytokine production than on cell proliferation, with significant effects on IFN-y, TNF-α and IL-2 production. PD-1-mediated inhibitory signaling also depends on the intensity of TCR signaling, with greater inhibition delivered at low levels of TCR stimulation. This reduction can be overcome by co-stimulation by CD28 [Freeman et al, J. Exp. Med. 192: 1027-34 (2000)] or the presence of IL-2 [Carter et al, Eur. J. Immunol. 32: 634-43 (2002)]. There is evidence that signaling by PD-L1 and PD-L2 can be bidirectional. That is, in addition to TCR modification or BCR signaling, signaling can also be returned to cells that express PD-L1 and PD-L2. Although treatment of dendritic cells with a naturally human anti-PD-L2 antibody isolated from a patient with Waldenstrom macroglobulinemia has not been discovered to regulate upward co-stimulating MHC II or B7 molecules, such cells actually produced greater amounts of pro-cytokines inflammatory, particularly TNF-α and IL-6, and stimulated T cell proliferation. Nguyen et al, J. Exp. Med. 196: 1393-98 (2002). Treatment of mice with this antibody also (1) increased resistance to transplanted bl6 melanoma and quickly induced tumor-specific CTL. Radhakrishnan et al, J. Immunol. 170: 1830-38 (2003); Radhakrishnan et al, Cancer Res. 64: 4965-72 (2004); Heckman et al, Eur. J. Immunol. 37: 1827-35 (2007); (2) blocked the development of inflammatory airway disease in a mouse model of allergic asthma. Radhakrishnan et al, J. Immunol. 173: 1360-65 (2004); Radhakrishnan et al, J. Allergy Clin. Immunol. UJy. 668-74 (2005).
[0011] [0011] New evidence for reverse signaling in dendritic cells (“DC”) results from bone marrow-derived CD studies cultured with soluble PD-1 (EC domain of PD-1 fused to the Ig constant region - “s-PD -1"). Kuipers et al, Eur. J. Immunol. 36: 2472-82 (2006). This sPD-1 inhibited DC activation and increased the production of IL-10, in a reversible manner by the administration of anti-PD-1. In addition, several studies show a PD-L1 or PD-L2 receptor that is independent of PD-1. B7.1 has already been identified as a PD-L1 liaison partner. Butte et al, Immunity 27: 111-22 (2007). Chemical interconnection studies suggest that PD-L1 and B7.1 may interact through their IgV-like domains. B7.1: PD-L1 interactions can induce an inhibitory signal in T cells.
[0012] [0012] The binding of PD-L1 in CD4 + T cells by B7.1 or the binding of B7.1 in CD4 + T cells by PD-L1 delivers an inhibitory signal. T cells without CD28 and CTLA-4 show reduced proliferation and cytokine production when stimulated by beads coated with anti-CD3 plus B7.1. In T cells without all B7.1 receptors (i.e., CD28, CTLA-4 and PD-L1), T cell proliferation and cytokine production were no longer inhibited by beads coated with anti-CD3 plus B7. 1. This indicates that B7.1 acts specifically for PD-L1 in the T cell in the absence of CD28 and CTLA-
[0013] [0013] The direct interaction between B7.1 and PD-L1 suggests that the current understanding of co-stimulation is incomplete, and reinforces the significance for the expression of these molecules in T cells. PD-L1 - / - T cell studies indicate that PD -L1 in T cells can down regulate T cell cytokine production. Latchman et al, Proc. Natl. Acad. Sci. USA 101: 10691-96 (2004). As both PD-L1 and B7.1 are expressed in T cells, B cells, DC and macrophages, there is potential for directional interactions between B7.1 and PD-L1 in these cell types. Additionally, PD-L1 in non-hematopoietic cells can interact with B7.1 as well as PD-1 in T cells, leading to the question of whether PD-L1 is involved in its regulation. One possible explanation for the inhibitory effect of the B7.1: PD-L1 interaction is that the PD-L1 T cell can capture or secrete APC B7.1 away from the interaction with CD28.
[0014] [0014] As a result, antagonism of PD-L1 signaling, including blocking PD-L1 from interacting with PD-1, B7.1 or both, thereby preventing PD-L1 from sending a negative co-stimulatory signal to T cells and other antigen presenting cells are likely to increase immunity in response to infection (for example, acute and chronic) and tumor immunity. In addition, the anti-PD-L1 antibodies of the present invention can be combined with antagonists of other components of PD-1: PD-L1 signaling, for example, anti-PD-1 and anti-PD-L2 antibody antagonist.
[0015] [0015] In particular, inhibition of PD-L1 signaling has been proposed as a means of enhancing T cell immunity for the treatment of cancer (eg tumor immunity) and infection, including both acute and chronic infection (eg , persistent).
[0016] [0016] Inhibitors that block the PD-L1: PD-1 interaction are known, i.a., from W02001014557, W02002086083, W02007005874, W02010036959, W02010077634 and W02011066389. However, as an optimal therapeutic product targeting this target has yet to be commercialized, a significant unmet medical need exists. Description of the invention
[0017] [0017] It is an object of the present invention to provide anti-PD-L1 antibodies, including coding nucleic acids and compositions containing such antibodies, and their use to enhance T cell function to up-regulate cell-mediated immune responses and to the treatment of dysfunctional T cell disorders, such as tumor immunity. Surprisingly, it has been found that anti-PD-L1 antibodies according to the present invention, which have antibody dependent cell mediated cytotoxicity (ADCC) activity, directly act on tumor cells carrying PD-L1 inducing their lysis without showing any toxicity significant. In addition, antibodies not only block the interaction between human PD-L1 and human PD-1, but also the interactions between the respective proteins of the mouse and the cinomolgus monkey.
[0018] [0018] In one embodiment, the invention provides an isolated heavy chain variable region polypeptide comprising a sequence of HVR-H1, HVR-H2 and HVR-H3, wherein:
[0019] [0019] (a) the sequence of HVR-H1 is X1YX2MX3 (SEQ ID NO: 1);
[0020] [0020] (b) the HVR-H2 sequence is SIYPSGGX4TFYADX5VKG (SEQ ID NO: 2);
[0021] [0021] (c) the HVR-H3 sequence is IKLGTVTTVX6Y (SEQ ID NO: 3);
[0022] [0022] even where: X1 is K, R, T, Q, G, A, W, M, I or S; X2 is V, R, K, L, M or I; X3 is H, T, N, Q, A, V, Y, W, F or M; X4 is F or I; X5 is S or T; X6 is E or D.
[0023] [0023] In a preferred embodiment X1 is M, I or S; X2 is R, K, L, M or I; X3 is F or M; X4 is F or I; X5 is S or T; X6 is E or D.
[0024] [0024] In a more preferred mode, X1 is M, I or S; X2 is L, M or I; X3 is F or M; X4 is I; X5 is S or T; X6 is D.
[0025] [0025] In an even more preferred mode, X1 is S; X2 is I; X3 is M; X4 is I; X5 is T; X6 is D.
[0026] [0026] In another aspect, the polypeptide also comprises framework sequences of the heavy chain of the variable region juxtaposed between the HVRs according to the formula: (HC-FR1) - (HVR-H1) - (HC-FR2) - (HVR -H2) - (HC-FR3) - (HVR-H3) - (HC-FR4).
[0027] [0027] In yet another aspect, framework sequences are derived from human framework consensus sequences or human germline framework sequences.
[0028] [0028] In an additional aspect, at least one of the framework sequences is as follows:
[0029] [0029] HC-FR1 is EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 4);
[0030] [0030] HC-FR2 is WVRQAPGKGLEWVS (SEQ ID NO: 5);
[0031] [0031] HC-FR3 is RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 6);
[0032] [0032] HC-FR4 is WGQGTLVTVSS (SEQ ID NO: 7).
[0033] [0033] In a still further aspect, the heavy chain polypeptide is further combined with a variable region light chain comprising an HVR-L1, HVR-L2 and HVR-L3, in which:
[0034] [0034] (a) the HVR-L1 sequence is TGTX7X8DVGX9YNYVS (SEQ ID NO: 8);
[0035] [0035] (b) the HVR-L2 sequence is X10VX11X12RPS (SEQ ID NO: 9);
[0036] [0036] (c) the HVR-L3 sequence is SSX13TX14X15 X16X17RV (SEQ
[0037] [0037] even where: X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is I, N or S; X12 is D, H or N; X13 is F or Y; X14 is N or S; X15 is R, T or S; X16 is G or S; X17 is I or T.
[0038] [0038] In a preferred mode, X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is N or S; X12 is N; X13 is F or Y; X14 is S; X15 is S; X16 is G or S; X17 is T.
[0039] [0039] In a more preferred mode, X7 is S; X8 is S; X9 is G; X10 is D; X11 is S; X12 is N; X13 is Y; X14 is S; X15 is S; X16 is S; X17 is T.
[0040] [0040] In a still additional aspect, the light chain also comprises sequences of the variable region light chain juxtaposed between the HVRs according to the formula: (LC-FR1) - (HVR-L1) - (LC-FR2) - (HVR-L2) - (LC-FR3) - (HVR-L3) - (LC-FR4).
[0041] [0041] In a still further aspect, the light chain framework sequences are derived from human framework consensus sequences or human germline framework sequences.
[0042] [0042] In a still further aspect, the light chain framework sequences are lambda light chain sequences.
[0043] [0043] In a still further aspect, at least one of the framework sequence is as follows:
[0044] [0044] LC-FR1 is QSALTQPASVSGSPGQSITISC (SEQ ID NO: 11);
[0045] [0045] LC-FR2 is WYQQHPGKAPKLMIY (SEQ ID NO: 12);
[0046] [0046] LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC (SEQ ID NO: 13);
[0047] [0047] LC-FR4 is FGTGTKVTVL (SEQ ID NO: 14).
[0048] [0048] In another embodiment, the invention provides an isolated anti-PD-L1 antibody or antigen-binding fragment comprising a sequence of the variable region of the heavy chain and one of the light chain, wherein:
[0049] [0049] (a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further: (i) the HVR-H1 sequence is X1YX2MX3 (SEQ ID NO: 1); (ii) the HVR-H2 sequence is SIYPSGGX4TFYADX5VKG (SEQ ID NO: 2); (iii) the HVR-H3 sequence is IKLGTVTTVX6Y, e (SEQ ID NO: 3);
[0050] [0050] (b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further: (iv) the HVR-L1 sequence is TGTX7X8DVGX9YNYVS (SEQ ID NO: 8); (v) the HVR-L2 sequence is X10VX11X12RPS (SEQ ID NO: 9); (vi) the HVR-L3 sequence is SSX13TX14X15X16X17RV (SEQ ID NO: 10); where: X1 is K, R, T, Q, G, A, W, M, I or S; X2 is V, R, K, L, M or I; X3 is H, T, N, Q, A, V, Y, W, F or M; X4 is F or I; X5 is S or T; X6 is E or D; X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is I, N or S; X12 is D, H or N; X13 is F or Y; X14 is N or S; X15 is R, T or S; X16 is G or S; X17 is I or T.
[0051] [0051] In a preferred embodiment, X1 is M, I or S; X2 is R, K, L, M or I; X3 is F or M; X4 is F or I; X5 is S or T; X6 is E or D; X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is N or S; X12 is N; X13 is F or Y; X14 is S; X15 is S; X16 is G or S; X17 is T.
[0052] [0052] In a more preferred mode, X1 is M, I or S; X2 is L, M or I; X3 is F or M; X4 is I; X5 is S or T; X8 is D; X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is N or S; X12 is N; X13 is F or Y; X14 is S; X15 is S; X16 is G or S; X17 is T.
[0053] [0053] In an even more preferred mode, X1 is S; X2 is I; X3 is M; X4 is I; X5 is T; X6 is D; X7 is S; X8 is S; X9 is G; X10 is D; X11 is S; X12 is N; X13 is Y; X14 is S; X15 is S; X16 is S; X17 is T.
[0054] [0054] In an additional aspect, the variable region of the heavy chain comprises one or more framework sequences juxtaposed between the HVRs such as: (HC-FR1) - (HVR-H1) - (HC-FR2) - (HVR-H2) - (HC-FR3) - (HVR-H3) - (HC-FR4), and the variable regions of the light chain comprise one or more framework sequences juxtaposed between the HVRs such as: (LC-FR1) - (HVR-L1) - (LC-FR2) - (HVR-L2) - (LC-FR3) - (HVR-L3) - (LC-FR4).
[0055] [0055] In a still further aspect, the framework sequences are derived from consensus human framework sequences or human germline sequences.
[0056] [0056] In a still further aspect, one or more of the heavy chain framework sequences are as follows:
[0057] [0057] HC-FR1 is EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 4);
[0058] [0058] HC-FR2 is WVRQAPGKGLEWVS (SEQ ID NO: 5);
[0059] [0059] HC-FR3 is RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 6);
[0060] [0060] HC-FR4 is WGQGTLVTVSS (SEQ ID NO: 7).
[0061] [0061] In a still further aspect, the light chain framework sequences are lambda light chain sequences.
[0062] [0062] In an even further aspect, one or more of the light chain framework sequences are as follows:
[0063] [0063] LC-FR1 is QSALTQPASVSGSPGQSITISC (SEQ ID NO: 11);
[0064] [0064] LC-FR2 is WYQQHPGKAPKLMIY (SEQ ID NO: 12);
[0065] [0065] LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC; (SEQ ID NO: 13);
[0066] [0066] LC-FR4 is FGTGTKVTVL (SEQ ID NO: 14).
[0067] [0067] In a still further aspect, the polypeptide of the heavy chain variable region, antibody or antibody fragment further comprises at least one CH1 domain.
[0068] [0068] In a more specific aspect, the polypeptide of the heavy chain variable region, antibody or antibody fragment further comprises a CH1, a CH2 and a CH3 domain.
[0069] [0069] In a still further aspect, the variable region of the light chain, antibody or antibody fragment further comprises a CL domain.
[0070] [0070] In a still further aspect, the antibody further comprises a CH1 domain, a CH2, a CH3 and a CL.
[0071] [0071] In a specific yet further aspect, the antibody further comprises a human or murine constant region.
[0072] [0072] In a still further aspect, the human constant region is selected from the group consisting of lgG1, lgG2, lgG2, lgG3, lgG4.
[0073] [0073] In a specific yet further aspect, the human or murine constant region is IgG1.
[0074] [0074] In yet another embodiment, the invention provides an anti-PD-L1 antibody comprising a sequence of the variable region of the heavy chain and one of the light chain, in which:
[0075] [0075] (a) the heavy chain comprises an HVR-H1, HVR-H2 and an HVR-H3, having at least 80% total sequence identity to SYIMM (SEQ ID NO: 15), SIYPSGGITFYADTVKG (SEQ ID NO: 16) and IKLGTVTTVDY (SEQ ID NO: 17), respectively, and
[0076] [0076] (b) the light chain comprises an HVR-L1, HVR-L2 and an HVR-L3, having at least 80% total sequence identity to TGTSSDVGGYNYVS (SEQ ID NO: 18), DVSNRPS (SEQ ID NO: 19) and SSYTSSSTRV (SEQ ID NO: 20), respectively.
[0077] [0077] In a specific aspect, the sequence identity is 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99% or 100%.
[0078] [0078] In yet another embodiment, the invention provides an anti-PD-L1 antibody comprising a sequence of the variable region of the heavy chain and one of the light chain, in which:
[0079] [0079] (a) the heavy chain comprises an HVR-H1, HVR-H2 and an HVR-H3, having a total sequence identity of at least 80% to MYMMM (SEQ ID NO: 21), SIYPSGGITFYADSVKG (SEQ ID NO: 22) and
[0080] [0080] (b) the light chain comprises an HVR-L1, HVR-L2 and an HVR-L3, having at least 80% total sequence identity to TGTSSDVGAYNYVS (SEQ ID NO: 23), DVSNRPS (SEQ ID NO: 19) and SSYTSSSTRV (SEQ ID NO: 20), respectively.
[0081] [0081] In a specific aspect, the sequence identity is 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99% or 100%.
[0082] [0082] In an even further aspect, in the antibody or antibody fragment according to the invention, when compared to the sequences of HVR-H1 (SEQ ID NO: 15), HVR-H2 (SEQ ID NO: 16) and HVR -H3 (SEQ ID NO: 17), at least those amino acids that remain unchanged are highlighted by underlining as follows:
[0083] [0083] (a) in HVR-H1 SYIMM (SEQ ID NO: 15),
[0084] [0084] (b) in SlYPSGGITFYADTVKG HVR-H2 (SEQ ID NO: 16),
[0085] [0085] (c) in HVR-H3 IKLGTVTTVDY (SEQ ID NO: 17);
[0086] [0086] and also when, when compared with the sequences of HVR-L1 (SEQ ID NO: 18), HVR-L2 (SEQ ID NO: 19) and HVR-L3 (SEQ ID NO: 20) at least those amino acids which remain unchanged are highlighted by underlining as follows:
[0087] [0087] (a) HVR-L1 TGTSSDVGGYNYVS (SEQ ID NO: 18)
[0088] [0088] (b) HVR-L2 DVSNRPS (SEQ ID NO: 19)
[0089] [0089] (c) HVR-L3 SSYTSSSTRV (SEQ ID NO: 20).
[0090] [0090] In another aspect, the variable region of the heavy chain comprises one or more framework sequences juxtaposed between the HVRs such as: (HC-FR1) - (HVR-H1) - (HC-FR2) - (HVR-H2) - (HC-FR3) - (HVR-H3) - (HC-FR4), and the variable regions of the light chain comprise one or more framework sequences juxtaposed between the HVRs such as: (LC-FR1) - (HVR-L1) - (LC-FR2) - (HVR-l_2) - (LC-FR3) - (HVR-L3) - (LC-FR4).
[0091] [0091] In yet another aspect, the framework sequences are derived from human germline sequences.
[0092] [0092] In an additional aspect, one or more of the heavy chain framework sequences are as follows:
[0093] [0093] HC-FR1 is EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 4);
[0094] [0094] HC-FR2 is WVRQAPGKGLEWVS (SEQ ID NO: 5);
[0095] [0095] HC-FR3 is RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 6);
[0096] [0096] HC-FR4 is WGQGTLVTVSS (SEQ ID NO: 7).
[0097] [0097] In a still further aspect, the light chain framework sequences are derived from a lambda light chain sequence.
[0098] [0098] In a still further aspect, one or more of the light chain framework sequences are as follows:
[0099] [0099] LC-FR1 is QSALTQPASVSGSPGQSITISC (SEQ ID NO: 11);
[00100] [00100] LC-FR2 is WYQQHPGKAPKLMIY (SEQ ID NO: 12);
[00101] [00101] LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC (SEQ ID NO: 13);
[00102] [00102] LC-FR4 is FGTGTKVTVL (SEQ ID NO: 14).
[00103] [00103] In a specific yet further aspect, the antibody further comprises a human or murine constant region.
[00104] [00104] In a still further aspect, the human constant region is selected from the group consisting of lgG1, lgG2, lgG2, lgG3, lgG4.
[00105] [00105] In a still further embodiment, the invention provides an isolated anti-PD-L1 antibody comprising a sequence of the variable region of the heavy chain and one of the light chain, in which:
[00106] [00106] (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLE
[00107] [00107] (b) the light chain sequence has at least 85% sequence identity to the light chain sequence:
[00108] [00108] QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQ
[00109] [00109] In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 %, 99% or 100%. In a still further embodiment, the invention provides an isolated anti-PD-L1 antibody comprising a sequence of the variable region of the heavy chain and one of the light chain, in which:
[00110] [00110] (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence:
[00111] [00111] EVQLLESGGGLVQPGGSLRLSCAASGFTFSMYMMMWVR
[00112] [00112] (b) the light chain sequence has at least 85% sequence identity to the light chain sequence:
[00113] [00113] QSALTQPASVSGSPGQSITISCTGTSSDVGAYNYVSWYQ
[00114] [00114] In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 %, 99% or 100%.
[00115] [00115] In another embodiment, the antibody binds to human, mouse, or cynomolgus monkey PD-L1. In a specific aspect, the antibody is able to block the interaction between human, mouse or cynomolgus monkey PD-L1 and the respective human, mouse or cynomolgus monkey PD-1 receptors.
[00116] [00116] In another embodiment, the antibody binds to human PD-L1 with a Kd of 5x10-9 M or less, preferably with a Kd of 2x10-9 M or less, and even more preferably with Kd of 1x10-9 M or less.
[00117] [00117] In yet another embodiment, the invention relates to an isolated anti-PD-L1 antibody or antigen-binding fragment thereof that binds to a functional epitope comprising residues Y56 and D61 of human PD-L1 (SEQ ID No. 28).
[00118] [00118] In a specific aspect, the functional epitope further comprises human PD-L1 E58, E60, Q66, R113 and M115 (SEQ ID NO: 28).
[00119] [00119] In a more specific aspect, the antibody binds to a conformational epitope, comprising residues 54-66 and 112-122 of human PD-L1 (SEQ ID NO: 28).
[00120] [00120] In an additional embodiment, the invention relates to an anti-PD-L1 antibody or antigen-binding fragment thereof, which cross-competes for binding to PD-L1 with an antibody according to the invention as described herein order.
[00121] [00121] In a further embodiment, the invention provides compositions comprising any of the anti-PD-L1 antibodies described above in combination with at least one pharmaceutically acceptable carrier.
[00122] [00122] In an additional embodiment, the invention provides an isolated nucleic acid that encodes a polypeptide, or a sequence of the light or heavy chain variable region of an anti-PD-L1 antibody or antigen binding fragment thereof, as described in this application.
[00123] [00123] In an additional embodiment, the invention provides an isolated nucleic acid that encodes a sequence of the variable region of the light chain or one of the heavy chain of an anti-PD-L1 antibody, where:
[00124] [00124] (a) the heavy chain comprises a sequence of HVR-H1, HVR-H2 and an HVR-H3 having at least 80% sequence identity to SYIMM (SEQ ID NO: 15), SIYPSGGITFYADTVKG (SEQ ID NO: 16) and IKLGTVTTVDY (SEQ ID NO: 17), respectively, or
[00125] [00125] (b) the light chain comprises a sequence of HVR-L1, HVR-L2 and an HVR-L3 having at least 80% sequence identity to TGTSSDVGGYNYVS (SEQ ID NO: 18), DVSNRPS (SEQ ID NO: 19) and SSYTSSSTRV (SEQ ID NO: 20), respectively.
[00126] [00126] In a specific aspect, the sequence identity is 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99% or 100%.
[00127] [00127] In an additional aspect, the nucleic acid is SEQ ID NO: 30 for the heavy chain and SEQ ID NO: 31 for the light chain.
[00128] [00128] In another aspect, the nucleic acid further comprises a vector suitable for the expression of the nucleic acid encoding any of the anti-PD-L1 antibodies previously described.
[00129] [00129] In a further specific aspect, the vector further comprises a host cell suitable for expression of the nucleic acid.
[00130] [00130] In a further specific aspect, the host cell is a eukaryotic cell or a prokaryotic cell.
[00131] [00131] In an additional specific aspect, the eukaryotic cell is a mammalian cell, like the Chinese Hamster Ovary (CHO).
[00132] [00132] In a further embodiment, the invention provides a process for producing an anti-PD-L1 antibody or antigen binding fragment thereof, comprising culturing a host cell containing the nucleic acid encoding any of the anti-PD antibodies PD-L1 previously described or antigen binding fragment in a form suitable for expression, under conditions suitable to produce such an antibody or fragment, and recovery of the antibody or fragment.
[00133] [00133] In an additional embodiment, the invention provides a kit of parts comprising a container confining a therapeutically effective amount of a composition described in this application and a package insert indicating the use for the treatment of a dysfunctional T cell disorder.
[00134] [00134] In an additional embodiment, the invention provides a kit of parts comprising any of the anti-PD-L1 compositions described above in combination with at least one additional therapeutic agent or vaccine, such as a chemotherapeutic agent.
[00135] [00135] In one aspect, at least one chemotherapeutic agent is gemcitabine, cyclophosphamide, fluorouracil or oxiplatin.
[00136] [00136] In another aspect, the vaccine is Stimuvax.
[00137] [00137] In a further embodiment, the invention provides a method of enhancing T cell function comprising administering an effective amount of any of the anti-PD-L1 antibodies or compositions described above.
[00138] [00138] In one aspect, the anti-PD-L1 antibody or composition gives rise to dysfunctional non-dysfunctional T cells.
[00139] [00139] In another aspect, the antibody or composition treats or prevents a symptom of persistent infection, such as viral infection, for example, by human immunodeficiency virus (HIV), herpes virus, Eppstein-Barr virus or human papilloma virus.
[00140] [00140] In a further embodiment, the invention provides a method of treating a dysfunctional T cell disorder comprising administering a therapeutically effective amount of any of the anti-PD-L1 antibodies or compositions described above.
[00141] [00141] In a specific aspect, dysfunctional T cell disorder is tumor immunity.
[00142] [00142] In an additional aspect, the method further comprises treatment with a vaccine.
[00143] [00143] In an additional aspect, the antibody or composition for PD-L1 is combined with a treatment regimen further comprising a traditional therapy selected from the group consisting of: surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, therapy hormonal, inhibition of angiogenesis and palliative care.
[00144] [00144] In an additional specific aspect, tumor immunity results from a cancer selected from the group consisting of: breast, lung, colon, ovary, melanoma, bladder, kidney, liver, salivary, stomach, gliomas, thyroid, thymic, epithelial, head and neck cancers, gastric, and pancreatic cancer.
[00145] [00145] Another aspect of the invention relates to the use of antibody-dependent cell-mediated cytotoxicity (ADCC) of an antibody or anti-PD-L1 composition described in this application in the treatment of cancer.
[00146] [00146] Therefore, the invention pertains to the method of treating cancer comprising administering to an individual in need thereof an effective amount of an anti-PD-L1 antibody that induces antibody dependent cell mediated cytotoxicity (ADCC).
[00147] [00147] In a preferred embodiment, the anti-PD-L1 antibody constant region is IgG1.
[00148] [00148] In another preferred modality, cancer is selected from the group consisting of: breast, lung, colon, ovarian, melanoma, bladder, kidney, liver, salivary, stomach, gliomas, thyroid, thymic, epithelial, head cancers and neck, gastric and pancreatic cancer.
[00149] [00149] Equivalent to the aforementioned methods of increasing T cell function, treating a dysfunctional T cell disorder, or treating cancer, the invention likewise relates to the use of an anti-PD-L1 antibody or composition as described above and below for the production of a drug to increase T cell function, treating a dysfunctional T cell disorder or treating cancer;
[00150] [00150] or for an anti-PD-L1 antibody or composition for use in enhancing T cell function or treating a dysfunctional T cell disorder or cancer.
[00151] [00151] Still in an additional embodiment, the invention is directed to engineered antibodies or engineered antibody fragments, which are fused directly or through a molecule binding to therapeutic agents, such as cytokines (for example, IL-2, IL-12, TNFa, IFNa, IFNb), or growth factors; that engineered antibodies or engineered antibody fragments can also be used in tumor therapy and diseases related to the immune system. Antibody fusion proteins, especially immunocytokines, are well known in the art. The fusion partner can be linked to the N-terminal of the antibody or antibody fragment or, preferably, to its C-terminal. Definitions
[00152] [00152] "Dysfunction" in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation. The term includes the common elements of both exhaustion and anergy in which antigen recognition can occur, but the following immune response is ineffective in controlling infection or tumor growth.
[00153] [00153] "Increase the function of the T cell" means to induce, provoke or stimulate a T cell to have a sustained or amplified biological function, or to renew or reactivate exhausted or inactive T cells. Examples of increased T cell function include: increased CD8 + T cell interferon γ secretion, increased proliferation, increased antigen responsiveness (eg, clearance of viruses or pathogens) relative to such levels prior to intervention. In one embodiment, the level of the increase is at least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The way to measure this increase is known to one of ordinary skill in the art.
[00154] [00154] A "dysfunctional T cell disorder" is a disorder or condition of T cells characterized by reduced responsiveness to antigenic stimulation. In a particular embodiment, a dysfunctional T cell disorder is a disorder that is specifically associated with inappropriate increased signaling by PD-1. In another embodiment, a dysfunctional T cell disorder is one in which T cells are anergic or have a reduced ability to secrete cytokines, to proliferate or perform cytolytic activity. In a specific aspect, reduced responsiveness results in ineffective control of a pathogen or tumor that expresses an immunogen. Examples of dysfunctional T cell disorders characterized by T cell dysfunction include acute unresolved infection, chronic infection and tumor immunity.
[00155] [00155] "Tumor immunity" refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such avoidance is mitigated, and tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.
[00156] [00156] The term "vaccine" as used in this application includes any non-pathogenic immunogen that, when inoculated into a host, induces protective immunity against a specific pathogen.
[00157] [00157] The term "antibody" includes monoclonal antibodies (including full length antibodies that have an immunoglobulin Fc region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies, diabodies, and single chain molecules, as well as antibody fragments (e.g., Fab, F (ab ') 2, and Fv)}. The term "immunoglobulin" (Ig) is used interchangeably with "the antibody" in this application. The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. An IgM antibody consists of 5 of the basic heterotetrameric units along with an additional polypeptide called a J chain and contains 10 antigen binding sites, while IgA antibodies comprise 2 to 5 of the 4 basic chain units that can polymerize to form polyvalent junctions in combination with the J chain. In the case of IgGs, the 4-chain unit is usually approximately 150,000 daltons. Each L chain is linked to an H chain by a covalent disulfide bond, while two H chains are linked together by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also have regularly spaced intrachain disulfide bridges. Each H chain has a variable domain (VH) at the N-terminal followed by three constant domains (CH) for each of the α and γ chains and four CH domains for the µ and ε isotypes. Each L chain has a variable domain (VL) at the N-terminal followed by a constant domain at its other end. The VL is aligned with VH and CL is aligned with the first heavy chain constant domain (CH1). Particular amino acid residues are believed to form an interface between light and heavy chain variable domains. Pairing a VH and VL together forms a single antigen-binding site. For the structure and properties of different classes of antibodies, see, for example, Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT , 1994, page 71 and Chapter 6. The L chain of any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of its constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, designating α, δ, ε, γ and µ heavy chains, respectively. Classes γ and α are further divided into subclasses based on relatively minor differences in the CH sequence and function, for example, humans express the following subclasses: lgG1, lgG2A, lgG2B, lgG3, lgG4, lgA1 and lgK1.
[00158] [00158] An "isolated" antibody is one that has been identified, separated and / or recovered from a component of its production environment (for example, natural or recombinant). Preferably, the isolated polypeptide is without association with all other components of its production environment. Contaminating components in your production environment, such as that resulting from recombinant transfected cells, are materials that would typically interfere with research, diagnostic or therapeutic uses of the antibody, and may include enzymes, hormones and other protein or non-protein solutes. In preferred embodiments, the polypeptide will be purified: (1) to more than 95% by weight of the antibody as determined, for example, by the Lowry method, and in some embodiments, to more than 99% by weight; (1) to a degree sufficient to obtain at least 15 N-terminal residues or internal amino acid sequence by using a rotating cup sequencer, or (3) homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver marker. The isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's environment will not be present. Ordinarily, however, an isolated polypeptide or antibody will be prepared by at least one purification step.
[00159] [00159] The "variable region" or "variable domain" of an antibody refers to the amino terminal domains of the heavy or light chain of the antibody. The heavy and light chain variable domains can be referred to as "VH" and "VL" respectively. These domains are generally the majority of the variable parts of the antibody (relative to other antibodies in the same class) and contain the antigen binding sites.
[00160] [00160] The term "variable" refers to the fact that certain segments of the variable domains differ extensively in the sequence between antibodies. The V domain mediates binding to the antigen and defines the specificity of a particular antibody by its particular antigen. However, the variability is not evenly distributed across the entire breadth of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) in both the light and variable domains of the heavy chain. The most highly conserved portions of variable domains are called framework regions (FR). The variable domains of heavy and light native chains each comprise four FR regions, basically adopting a beta leaf configuration, connected by three HVRs, which form loop connections, and in some cases be part of the beta leaf structure. The HVRs in each chain are held together in close proximity by the FR regions and, with the HVRs in another chain, contribute to the formation of the antibody-binding site to the antigen (see Kabat et al, Sequences of Immunological Interest, Fifth Edition, Institute National Health, Bethesda, MD (1991)). The constant domains are not directly involved in binding the antibody to an antigen, but exhibit various effector functions, such as the participation of the antibody in antibody-dependent cellular toxicity.
[00161] [00161] The term "monoclonal antibody" as used in this application refers to an antibody obtained from a population of substantially homogeneous antibodies, that is, the individual antibodies comprising the population are identical except for possible mutations that naturally occur and / or modifications post-translation (for example, isomerizations, amidations) that may be present in smaller quantities. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant in the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are synthesized by the culture of hybridomas, not contaminated by other immunoglobulins. The "monoclonal" modifier indicates the character of the antibody as obtained from a substantially homogeneous population of antibodies and should not be interpreted as a requirement for the production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention can be produced by a variety of techniques, including, for example, the hybridoma method (for example, Kohler and Milstein., Nature, 256: 495-97 (1975) ; Hongo et al, Hybridoma, 14 (3): 253-260 (1995), Harlow et al, Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al, in: Monoclonal Antibodies and T-Cell Hybridomas 563 - 681 (Elsevier, NY, 1981)), recombinant DNA methods (see, for example, US Patent No. 4,816,567), phage display technologies (see, for example, Clackson et al, Nature, 352: 624 - 628 (1991); Marks et al, J. Mol Biol. 222: 581-597 (1992); Sidhu et al, J. Mol Biol. 338 (2): 299-310 (2004) ); Lee et al, J. Mol Biol. 340 (5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. ScL USA 101 (34): 12467-12472 (2004); and Lee et al, J. Immunol. Methods 284 (1-2): 119-132 (2004), and technologies to produce human antibodies or not ilars to humans in animals that have parts or all of the human immunoglobulin loci or genes that encode human immunoglobulin sequences (see, for example, WO 1998/24893; WO 1996/34096; WO 1996/33735; WO 1991/10741; Jakobovits et al, Proc. Natl. Acad. ScL USA 90: 2551 (1993); Jakobovits et al, Nature 362: 255-258 (1993); Bruggemann et al, Year in Immunol. 7:33 (1993); U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and
[00162] [00162] An "antibody fragment" comprises a portion of an intact antibody, preferably binding to the antigen and / or the variable region of the intact antibody. Examples of antibody fragments include Fab, Fab ', F (ab') 2 and Fv fragments; diabodies; linear antibodies (see U.S. Patent 5,641,870, Example 2; Zapata et al, Protein Eng. 8HO): 1057-1062 [1995]); single chain antibody molecules and multispecific antibodies were formed from antibody fragments. Papain digestion of antibodies produced two identical antigen-binding fragments, called "Fab" fragments and a residual "Fc" fragment, a designation that reflects the ability to readily crystallize. The Fab fragment consists of an entire L chain next to the variable region domain of the H chain (VH) and the first constant domain of a heavy chain (CH1). Each Fab fragment is monovalent with respect to antigen binding, that is, it has a unique antigen binding site. Pepsin treatment of an antibody produces a large single F (ab ') 2 fragment that roughly corresponds to two disulfide-linked Fab fragments having different antigen binding activity and is still capable of interlinking the antigen. Fab 'fragments differ from Fab fragments having some additional residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation in this application of Fab 'in which the cysteine residue (s) of the constant domains carry a free thiol group. F (ab ') 2 antibody fragments were originally produced as pairs of Fab' fragments having hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
[00163] [00163] The Fc fragment comprises the terminal carboxy portions of both H chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, a region that is also recognized by Fc receptors (FcR)
[00164] [00164] "Fv" is the minimum antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer from a variable region domain of the heavy chain and one from the light chain in strict, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops from each H and L chain) that contribute to the antigen-binding amino acid residues and confer specificity to the antigen-binding antibody. However, even a single variable domain (or half of Fv comprising only three antigen-specific HVRs) has the ability to recognize and bind to the antigen, albeit at a lower affinity than the entire binding site. "Single chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments comprising VH and VL antibody domains connected in a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the VL and VH domains that allows the sFv to form the desired antigen-binding structure. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, volume 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994). "Functional fragments" of the antibodies of the invention comprise a portion of an intact antibody, generally including binding to the antigen or the variable region of the intact antibody or the Fc region of an antibody that conserves or has modified FcR binding capacity. Examples of antibody fragments include linear antibody molecules, single chain antibody and multispecific antibodies formed from antibody fragments.
[00165] [00165] The term "diabody" refers to the small antibody fragments prepared by the construction of sFv fragments (see the preceding paragraph) with short ligands (approximately 5-10) residues) between the VH and VL domains such that the inter-match but no intrachain V domains are achieved, thereby resulting in a bivalent fragment, that is, a fragment having two antigen binding sites. Bispecific diabody bodies are the heterodimers of two "transversal" sFv fragments in which the VH and VL domains of the two antibodies are present in different polypeptide chains. Diabodies are described in more detail, for example, in EP 404,097; WO 93/11161; Hollinger et al, Proc. Natl. Acad. ScL USA 90; 6444-6448 (1993).
[00166] [00166] The term "nanobodies" refers to single domain antibodies which are antibody fragments consisting of a single monomeric variable antibody domain. As a whole antibody, they are able to selectively bind to a specific antigen. With a molecular weight of only 12-15 kDa, single domain antibodies are much smaller than ordinary antibodies (150-160 kDa). The first single domain antibodies were generated from heavy chain antibodies found in camelids. Gibbs, W. Wayt (August 2005). "Nanobodies". Scientific American Magazine.
[00167] [00167] The monoclonal antibodies in this application specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular class or subclass of antibody, while the rest of the chain (s) is (are) identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another class or subclass of antibody, as well as fragments of such antibodies, as long as they exhibit biological activity desired (US Patent No. 4,816,567; Morrison et al, Proc. Natl. Acad. ScL USA, 81: 6851-6855 (1984)).
[00168] [00168] "Humanized" forms of non-human antibodies (for example, murine) are chimeric antibodies that contain the minimal sequence derived from non-human immunoglobulin. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR (defined below) from the recipient are replaced by residues from an HVR from a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate that has the desired specificity, affinity and / or ability. In some examples, framework residues ("FR") of human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibodies can comprise residues that are not found in the recipient antibody or the donor antibody. These modifications can be made to further refine the performance of the antibody, such as binding affinity. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions are those of a human immunoglobulin sequence, although FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FR is typically no more than 6 in the H chain, and in the L chain, no more than 3. The humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, for example, Jones et al, Nature 321: 522-525 (1986); Riechmann et al, Nature 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992). See also, for example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1: 105-115 (1998); Harris, Biochem. Soc. Transactions 23: 1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5: 428-433 (1994); and U.S. Pat. U.S. Nos. 6,982,321 and 7,087,409.
[00169] [00169] A "human antibody" is an antibody that has an amino acid sequence that corresponds to that of an antibody produced by a human being and / or was made using any of the techniques for producing human antibodies as described in this application. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol, 227: 381 (1991); Marks et al, J. Mol. Biol, 222: 581 (1991). Also available for the preparation of human monoclonal antibodies are the methods described in Cole et al, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al, J. Immunol, 147 (1): 86-95 (1991). Also see van Dijk and van de Winkel, Curr. Opin. Pharmacol, 5: 368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to the antigen challenge, but whose endogenous loci have been deactivated, for example, immunized xenocams (see, for example, U.S. Pat.
[00170] [00170] The term "hypervariable region," "HVR," or "HV," when used in this application, refers to regions of an antibody variable domain that are hypervariable in the sequence and / or form structurally defined loops. Antibodies generally comprise six HVRs; three in VH (H1, H2, H3), and three in VL (L1, L2, L3). In native antibodies, H3 and L3 exhibit most of the diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine antibody specificity. See, for example, Xu et al, Immunity 13: 37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248: 1-25 (Lo, ed., Humana Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consisting of a heavy chain are only functional and stable in the absence of the light chain. See, for example, Hamers-Casterman et al., Nature 363: 446-448 (1993); Sheriff et al, Nature Struct. Biol. 3: 733-736 (1996).
[00171] [00171] Several HVR designs are in use and are included in this application. The Kabat Complementarity Determination Regions (CDRs) are based on sequence variability and are most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)). Chothia refers instead to the position of the structural loops (Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987)). AbM HVRs represent a compromise between Kabat's HVRs and Chothia's structural loops, and are used by the Oxford Molecular AbM antibody modeling program.
[00172] [00172] The "contact" HVRs are based on an analysis of the complex crystalline structures available. The residues of each of these HVRs are noted below.
[00173] [00173] Handle Kabat AbM Chothia Contact
[00174] [00174] L1 L24-L34 L24-L34 L26-L32 L30-L36
[00175] [00175] L2 L50-L56 L50-L56 L50-L52 L46-L55
[00176] [00176] L3 L89-L97 L89-L97 L91-L96 L89-L96
[00177] [00177] H1 H31-H35B H26-H35B H26-H32 H30-H35B (Kabat numbering)
[00178] [00178] H1 H31-H35 H26-H35 H26-H32 H30-H35 (Chothia numbering)
[00179] [00179] H2 H50-H65 H50-H58 H53-H55 H47-H58
[00180] [00180] H3 H95-H102 H95-H102 H96-H101 H93-H101
[00181] [00181] HVRs can comprise "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in VL and 26 -35 (H1), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in VH. Variable domain residues are numbered according to Kabat et al., Supra, for each of these definitions.
[00182] [00182] The term "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat," and variations thereof, refers to the numbering system used for variable domains of the heavy chain or variable domains of antibody chain light chain in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence can contain fewer or additional amino acids that correspond to a reduction or insertion in an FR or HVR of the variable domain. For example, a variable domain of the heavy chain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (for example, residues 82a, 82b, and 82c, etc. according to Kabat) after the FR residue of the heavy chain 82. Kabat numbering of residues can be determined for an antibody given by aligning regions of antibody sequence homology with the "standard" numbered Kabat sequence.
[00183] [00183] "Arcabouço" or "FR" residues are those residues of variable domain in addition to the HVR residues as in this defined order. A "human consensus framework" or "human accepting framework" is a framework that represents the amino acid residues that most commonly occur in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subset of variable domain sequences. Generally, the sequence subgroup is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for VL, the subgroup may be the subgroup kappa I, kappa II, kappa III or kappa IV as in Kabat et al, supra. Additionally, for VH, the subgroup can be subgroup I, subgroup II or subgroup III as in Kabat et al., Supra. Alternatively, a human consensus framework can be derived from those mentioned above in which particular residues, such as when a human framework residue is selected based on its homology to the donor framework by aligning the donor framework sequence with a collection of various human framework sequences. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework can comprise the same amino acid sequence as this one, or it may contain pre-existing amino acid sequence modifications. In some embodiments, the number of pre-existing amino acid modifications is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less.
[00184] [00184] An "amino acid modification" at a specified position, for example, in the Fc region, refers to the replacement or deletion of the specified residue or the insertion of at least one amino acid residue adjacent to the specified residue. Insertion “adjacent” to a specified residue means insertion within one to two residues of it. The insertion can be N- or C- terminal to the specified residue. The preferred amino acid modification in this application is a substitution.
[00185] [00185] An "affinity-matured" antibody is one with one or more changes in one or more of its HVRs that results in an improvement in the antibody's affinity for the antigen, compared to a parental antibody that does not have that change (s) ( sions). In one embodiment, an affinity-matured antibody has nanomolar or even picomolar affinities for the target antigen. Affinity-matured antibodies are produced by procedures known in the art. For example, Marks et al, Bio / Technology 10: 779-783 (1992) describes affinity maturation by mixing VL and VH domain. Random mutagenesis of HVR and / or framework residues is described by, for example: Barbas et al. Proc Nat. Acad. ScL USA 91: 3809-3813 (1994); Schieret al. Gene 169: 147-155 (1995); YαXon et al. J. Immunol. 155: 1994-2004 (1995); Jackson et al, J. Immunol. 154 (7): 3310-9 (1995); and Hawkins et al, J. Mol. Biol. 226: 889-896 (1992).
[00186] [00186] As used in this application, the term "specifically binds to" or is "specific to" refers to measurable and reproducible interactions such as binding between a target and an antibody, which is the determinant of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules. For example, an antibody that specifically binds to a target (which may be an epitope) is an antibody that binds to that target with greater affinity, avidity, more readily, and / or with a longer duration than it binds to other targets. In one embodiment, the extent of binding of an antibody to an unrelated target is less than approximately
[00187] [00187] "Antibody dependent cell mediated cytotoxicity" or ADCC refers to a form of cytotoxicity in which secreted Ig bound to Fc receptors (FcRs) present in certain cytotoxic cells (for example, natural killer cells (NK), neutrophils and macrophages) allows these cytotoxic effector cells to specifically bind to a target cell carrying the antigen and subsequently eliminate the target cell with cytotoxins. Antibodies "arm" cytotoxic cells and are required to eliminate the target cell by this mechanism. Primary cells to mediate ADCC, NK cells, express FcyRIII only, whereas monocytes express FcγRI, FcγRII and FcγRIII. Fc expression in hematopoietic cells is summarized in Table 3 on page 464 by Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991). To assess the ADCC activity of a molecule of interest, an in vitro ADCC assay, such as the one described in U.S. Patent No. 5,500,362 or 5,821,337 can be performed. Useful effector cells from such assays include natural killer cells (NK) and peripheral blood mononuclear cells (PBMC). Alternatively, or in addition, the ADCC activity of the molecule of interest can be assessed in vivo, for example, in an animal model such as that described in Clynes et al, PNAS USA 95: 652-656 (1998). Unless otherwise indicated in this application, the numbering of residues on an immunoglobulin heavy chain is that of the EU index as in Kabat et al, supra. The “EU index as in Kabat” refers to the EU residue numbering of the human IgG1 antibody. In many cancers, tumor cells express high levels of PD-L1 on their surface. By binding to PD-L1 in tumor cells and binding with its fragment of the crystalline part (Fc) to gamma Fc- (FCGR) receptors in leukocytes, anti-PD-L1 antibodies with the ADCC potential can cause ADCC that can lead to the death of these tumor cells.
[00188] [00188] The term "Fc region" in this application is used to define a C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the Fc region of the human IgG heavy chain is normally defined to stretch from an amino acid residue at the Cys226 position, or from Pro230, to the carboxyl terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) from the Fc region can be removed, for example, during the production or purification of the antibody, or by recombinant engineering of the nucleic acid encoding an antibody heavy chain . Consequently, an intact antibody composition can comprise antibody populations with all K447 residues removed, antibody populations without K447 residues removed and antibody populations having a mixture of antibodies with and without the K447 residue. Native sequence Fc regions suitable for use in the antibodies of the invention include human IgG1, IgG2 (IgG2A, IgG2B), IgG3 and IgG4. "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. Preferred FcR is a native sequence human FcR. In addition, preferred FcR is one that binds to an IgG antibody (a gamma receptor) and includes receptors of the subclasses FcγRI, FcγRII and FcγRIII, including allelic variants and alternatively plaited forms of these receptors, FcγRII receptors include FcγRIIA (a “receptor of activation ”) and FcγRIIB (an“ inhibitor receptor ”), which have similar amino acid sequences that differ mainly in their cytoplasmic domains. Activation of the FcγRIIA receptor contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibition of the FcyRIIB receptor contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain, (see M. Daeron, Annu. Rev. Immunol. 15: 203-234 (1997). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel et al, Immunomethods 4: 25-34 (1994); and de Haas et al, J. Lab. Clin. Med. 126: 330-41 (1995) Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" in this application.
[00189] [00189] The term "Fc receptor" or "FcR" also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus. Guyer et al, J. Immunol. 117: 587 (1976) and Kim et al., J. Immunol. 24: 249 (1994). Methods for measuring binding to FcRn are known (see, for example, Ghetie and Ward, Immunol. Today 18: (12): 592-8 (1997); Ghetie et al, Nature Biotechnology 15 (7): 637-40 ( 1997); Hinton et al, J. Biol. Chem. TJI (8): 6213-6 (2004); WO 2004/92219 (Hinton et al). Binding to FcRn in vivo and the serum half-life of binding polypeptides high-affinity human FcRn can be analyzed, for example, in transgenic mice or transfected human cell lines expressing human FcRn, or in primates to which polypeptides that have a variant Fc region are administered. WO 2004/42072 (Presta) describes antibody variants that have improved or decreased binding to FcRs. Also see, for example, Shields et al, J. Biol. Chem. 9 (2): 6591-6604 (2001).
[00190] [00190] "Effector cells" are leukocytes that express one or more FcRs and perform effector functions. In one aspect, effector cells at least express FcyRIII and perform the ADCC effector function. Examples of human leukocytes that mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer cells (NK), monocytes, cytotoxic T cells and neutrophils. Effector cells can be isolated from a native source, for example, blood. Effector cells are usually lymphocytes associated with the effector phase and function to produce cytokines (helper T cells), eliminating cells in infected with pathogens (cytotoxic T cells) or secreting antibodies (differentiated B cells).
[00191] [00191] "Binding affinity" generally refers to the strength of the sum total of non-covalent interactions between a single binding site on a molecule (for example, an antibody) and its binding partner (for example, an antigen) . Unless otherwise stated, as used in this application, "binding affinity", "binding to", "binding to" or "binding to" refers to the intrinsic binding affinity that reflects interaction 1 : 1 between members of a binding pair (for example, antibody and antigen Fab fragment). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described in this application. Low-affinity antibodies generally bind to the antigen slowly and tend to dissociate readily, while high-affinity antibodies generally bind to the antigen more quickly and tend to stay on longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for the purposes of the present invention. Specific illustrative and exemplary modalities for measuring binding affinity, i.e. binding strength, are described below.
[00192] [00192] The "KD" or "KD value" according to this invention is in a mode measured by a radiolabeled antigen (RIA) binding assay performed with the Fab version of the antibody and antigen molecule as described by the following assay that measures the binding affinity of the Fabs solution to the antigen by balancing Fab with a minimum concentration of antigen marked with (125l) in the presence of a series of titers of the unlabeled antigen, then capturing the antigen bound with an antibody-coated plate antifab (Chen, et al, (1999) J. Mol Biol 293: 865-881). To establish the conditions of the assay, the microtiter plates (Dynex) are covered overnight with 5 µg / ml of an anti-capture antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and then blocked with 2% (w / v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23 ° C). In a non-adsorbent plate (Nunc No.269620), 100 pM or 26 pM of antigen with [125 l] are mixed with serial Fab dilutions of interest (compatible with evaluation of an anti-VEGF antibody, Fab-12, in Presta et al, (1997) Cancer Res. 57: 4593-4599). The Fab of interest is then incubated overnight; however, incubation can continue for a longer period (for example, 65 hours) ensuring that equilibrium is achieved. After that, the mixtures are transferred to the capture plate for incubation at room temperature for one hour. The solution is then removed and the plate washed eight times with 0.1% Tween-20 in PBS. When the plates have dried, 150 µl / well of scintillant (Scint-Micro 20; Packard) is added, and the plates are counted with a Topcount gamma counter (Packard) for ten minutes. The concentrations of each Fab that provide less than or equal to 20% of the maximum binding are chosen for use in competitive binding assays.
[00193] [00193] A "membership fee" or "kon" according to this invention can also be determined as described above using a BIACORE®-2000 or BIACORE®-3000 system (BIAcore, Inc., Piscataway, NJ) at 25 ° C with CM5 chips with antigen i mobilized in approximately 10 response units (UK). Briefly, carboxymethylated dextran (CM5, BIAcore Inc.) biosensor chips are activated with N-ethyl-N '- (3-propyl dimethylamino) - carbodiimide (ECD) and N-hydroxysuccinimide (NHS) hydrochloride according to the instructions in the provider. The antigen is diluted with mM sodium acetate, pH 4.8, in 5 mg / ml (~ 0.2 mM) before injection at a flow rate of 5 ml / min. to achieve approximately 10 response units (RU) of the coupled protein. After injection of the antigen, 1 M ethanolamine is added to block unreacted groups. For kinetic measurements, double serial dilutions of Fab (0.78 nM to 500 nM) are injected into PBS with 0.05% Tween 20 (PBST) at 25 ° C at a flow rate of approximately 25ul / min. Association rates (kon) and dissociation rates (koff) are calculated using a simple individual Langmuir linkage model (version 3.2 of the BIAcore Evaluation Program) while simultaneously adjusting association and dissociation sensorgrams. The equilibrium dissociation constant (KD) was calculated as the koff / kon ratio. See, for example, Chen, Y., et al, (1999) J. Mol Biol 293: 865-881. However, if the association rate exceeds 106 M-1 s-1 by the surface plasmon resonance assay above, then the association rate is preferably determined using a fluorescent extinction technique that measures the increase or decrease in the intensity of the emission of fluorescence (excitation = 295 nm; emission = 340 nm, pass band 16 nm) at 25 ° C of an antigen antigen 20 nM (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of the antigen as measured in a spectrometer, such as a flow stop equipped spectrophotometer (Aviv Instrumentss) or an SLM-Aminco 8000 series spectrophotometer (Thermo Spectronic) with a stirred cuvette.
[00194] [00194] The term "functional epitope", as used in this application, refers to amino acid residues of an antigen that contribute energetically to the binding of an antibody, that is, formation of an "energetic epitope". Mutation of any of the energetically contributing antigen residues to alanine will disrupt antibody binding such that the relative KD ratio (mutant PD-L1 KD / wild PD-L1 KD) of the antibody will be greater than 4 (see Example 3.x (b)).
[00195] [00195] The term "conformational epitope" as used in this application refers to amino acid residues from the PD-L1 antigen that assemble on the surface when the polypeptide chain folds to form the native protein, and show a significantly reduced rate of HD exchange due to Fab binding, as described in the experimental section. The conformation epitope contains, but is not limited to, the functional epitope.
[00196] [00196] The phrase "substantially reduced," or "substantially different," as used in this application, denotes a sufficiently high degree of difference between two numerical values (usually one associated with a molecule and the other associated with a reference / comparator molecule) such that a person skilled in the art would think that the difference between the two values was of statistical significance within the context of the biological characteristic measured by said values (for example, KD values). The difference between said two values, for example, is greater than approximately 10%, greater than approximately 20%, greater than approximately 30%, greater than approximately 40% and / or greater than approximately 50% as a function of the molecule value reference / comparator.
[00197] [00197] The term "substantially similar" or "substantially the same," as used in this application, denotes a sufficiently high degree of similarity between two numerical values (for example, one associated with an antibody of the invention and another associated with an antibody of reference / comparator), such that a person skilled in the art would think that the difference between the two values was of little or no biological and / or statistical significance within the context of the biological characteristic measured by said values (for example, KD values). The difference between the two said values is, for example, less than approximately 50%, less than approximately 40%, less than approximately 30%, less than approximately 20%, and / or less than approximately 10% as a function of the value of reference / comparator.
[00198] [00198] "Percentage (%) amino acid sequence identity" and "homology" with respect to a sequence of peptides, polypeptides or antibodies are defined as the percentage of amino acid residues in a candidate sequence that is identical to the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and inserting gaps, if necessary, to achieve maximum percent sequence identity, and do not consider any conservative substitution as part of the sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be achieved in a number of ways that are within the skill of the art, for example, using the publicly available computer program such as BLAST, BLAST-2 or
[00199] [00199] A "blocking" antibody or an "antagonist" antibody is one that inhibits or reduces a biological activity of the antigen to which it binds. In some embodiments, blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen. The anti-PD-L1 antibodies of the invention block the interaction between PD-L1 and its PD-1 receptor, and thus PD-1 signaling to restore a functional T cell response from a state related to dysfunction to the stimulation of antigen. The activation antibody or "agonist" is one that increases or initiates signaling through the antigen to which it binds. In some embodiments, agonist antibodies elicit or activate signaling without the presence of the natural ligand.
[00200] [00200] The terms "cross competition", "cross competition", "cross block", "cross block" and "cross block" are used interchangeably in this application to mean the ability of an antibody or fragment thereof to interfere with binding directly or indirectly by allosteric modulation of the anti-PD-L1 antibodies of the invention to the target human PD-L1. The extent to which an antibody or fragment thereof is capable of interfering with the other's binding to the target, and therefore it can be said that cross-blocking or cross-competition according to the invention, can be determined using assays competition link. A particularly suitable quantitative cross-competition assay uses either a FACS-based or an AlphaScreen-based approach to measure competition between a labeled antibody or fragment thereof (for example, labeled with
[00201] [00201] An "isolated" nucleic acid molecule encoding the antibodies in this application is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it ordinarily associates in the environment in which it was produced . Preferably, the isolated nucleic acid is without association with all components associated with the production environment. The isolated nucleic acid molecules that encode the polypeptides and antibodies in this application are in a form except in the form or setting in which it is found in nature. The isolated nucleic acid molecules, therefore, are distinguished from the nucleic acid encoding the polypeptides and antibodies in this application naturally occurring in cells.
[00202] [00202] The term "control sequences" refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. Control sequences that are suitable for prokaryotes, for example, include a promoter sequence, optionally an operator and a ribosome binding site. Eukaryotic cells are known to use promoters, polyadenylation signals and enhancers. The nucleic acid is "operationally linked" when it is placed in a functional relationship with another nucleic acid sequence. For example, DNA from a pre-sequence or secretory leader is operably linked to DNA from a polypeptide if it is expressed as a pre-protein that participates in the secretion of the polypeptide; a promoter or enhancer is operationally linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operationally linked to a coding sequence if it is positioned to facilitate translation. Generally, “operationally linked” means that the DNA sequences that are linked are contiguous, and, in the case of a secretarial leader, contiguous and in the reading phase. However, enhancers do not have to be contiguous. The binding is carried out by binding at suitable restriction sites. If such sites do not exist, synthetic oligonucleotide adapters or ligands are used as conventional. A "stable" formulation is one in which the protein in which it essentially retains its physical and chemical stability and integrity after storage. Various analytical techniques for measuring protein stability are available in the art and are reviewed at Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, New York, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993). Stability can be measured at a selected temperature from a selected period of time. For quick tracking, the formulation can be kept at 40 ° C for 2 weeks to 1 month, in which the stability time is measured. Where the formulation must be stored at 2-8 ° C, generally the formulation must be stable at 30 ° C or 40 ° C for at least 1 month and / or storage at 2-8 ° C for at least 2 years. When the formulation must be stored at 30 ° C, generally the formulation must be stable for at least 2 years at 30 ° C and / or stable at 40 ° C for at least 6 months. For example, the extension of aggregation during storage can be used as an indicator of protein stability. Thus, a "stable" formulation can be one in which less than approximately 10% and preferably less than approximately 5% of the protein are present as an aggregate in the formulation. In other embodiments, any increase in aggregate formation during storage of the formulation can be determined.
[00203] [00203] A "reconstituted" formulation is one that has been prepared by dissolving a lyophilized protein or antibody formulation in a diluent such that the protein is dispersed throughout. The reconstituted formulation is suitable for administration (for example, subcutaneous administration) to a patient to be treated with the protein of interest and, in certain embodiments of the invention, can be that which is suitable for parenteral or intravenous administration.
[00204] [00204] An "isotonic" formulation is one that has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure of approximately 250 to 350 mOsm. The term “hypotonic” describes a formulation with an osmotic pressure below that of human blood. Accordingly, the term “hypertonic” is used to describe a formulation with an osmotic pressure above that of human blood. Isotonicity can be measured using an osmometer like vapor pressure or freezing water, for example, the formulations of the present invention are hypertonic as a result of the addition of salt and / or buffer. "Vehicles", as used in this application, include pharmaceutically acceptable vehicles, excipients or stabilizers that are non-toxic to the cell or mammal that is exposed to them at the dosages and concentrations employed. Often, the physiologically acceptable carrier is an aqueous solution in buffered pH. Examples of physiologically acceptable vehicles include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight polypeptide (less than approximately 10 residues); proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers like polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugar alcohols like mannitol or sorbitol; salt-forming counterions such as sodium; and / or non-ionic surfactants such as TWEEN ™, polyethylene glycol (PEG) and PLURONICS ™.
[00205] [00205] A "pharmaceutically acceptable acid" includes inorganic and organic acids that are non-toxic in concentration and in the manner in which they are formulated. For example, suitable inorganic acids include hydrochloric, perchloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfonic, sulfuric, sulfanilic, phosphoric, carbonic, etc. Suitable organic acids include straight and branched chain alkyl, aromatic, cyclic, cycloaliphatic, arylaliphatic, heterocyclic, saturated, unsaturated, mono, di and tricarboxylic,
[00206] [00206] "Pharmaceutically acceptable bases" include inorganic and organic bases that are non-toxic in concentration and in the manner in which they are formulated. For example, suitable bases include those formed from inorganic base-forming metals such as lithium, sodium, potassium, magnesium, calcium, ammonium, iron, zinc, copper, manganese, aluminum, N-methylglucamine, morpholine, piperidine and non-toxic organic bases including, primary, secondary and tertiary amines, substituted amines, cyclic amines and basic ion exchange resins, [for example, N (R ') 4+ (where R' is independently H or C1-4 alkyl, for example, ammonium, Tris)], for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimetamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucamine, glucamine, glucamine , purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimetamine, dicyclohexylamine, choline and caffeine. Additional pharmaceutically acceptable acids and bases usable with the present invention include those that are derived from amino acids, for example, histidine, glycine, phenylalanine, aspartic acid, glutamic acid, lysine and asparagine.
[00207] [00207] "Pharmaceutically acceptable buffers" and salts include those derived from both acid addition and basic addition salts of the acids and bases indicated above. Specific buffers and / or salts include histidine, succinate and acetate.
[00208] [00208] A "pharmaceutically acceptable sugar" is a molecule that, when combined with a protein of interest, significantly prevents or reduces the chemical and / or physical instability of the protein after storage. When the formulation is intended to be lyophilized and then reconstituted, "pharmaceutically acceptable sugars" can also be known as a "lyoprotectant". Exemplary sugars and their corresponding sugar alcohols include: an amino acid such as monosodium glutamate or histidine; methylamine as betaine; a lyotropic salt such as magnesium sulfate; a polyol such as trihydric or higher molecular weight sugar alcohols, for example, glycerin, dextran, erythritol, glycerol, arabitol, xylitol, sorbitol and mannitol; propylene glycol; polyethylene glycol; PLURONICS®; and combinations of these. Additional exemplary lyoprotectants include glycerin and gelatin, and the sugars melibiosis, melezitosis, raffinose, manotriosis and stachyose. Examples of reducing sugars include glucose, maltose, lactose, maltulose, iso-maltulose and lactulose. Examples of non-reducing sugars include non-reducing glycosides of polyhydroxy compounds selected from sugar alcohols and other straight chain polyalcohols. Preferred sugar alcohols are monoglycosides, especially those compounds obtained by reducing disaccharides such as lactose, maltose, lactulose and maltulose. The glycosidic side group can be glycosidic or galactosidic. Additional examples of sugar alcohols are glucitol, maltitol, lactitol and iso-maltulose. Preferred pharmaceutically acceptable sugars are non-reducing sugars, trehalose or sucrose. Pharmaceutically acceptable sugars are added to the formulation in an "amount of protection" (eg, pre-lyophilization) which means that the protein essentially maintains its physical and chemical stability and integrity during storage (for example, after reconstitution and storage).
[00209] [00209] The "diluent" of interest in this application is one that is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation, such as a reconstituted formulation after lyophilization. Exemplary diluents include sterile water, bacteriostatic water for injection (BWFI), a pH buffered solution (for example, phosphate buffered saline), sterile saline, Ringer's solution or dextrose solution. In an alternative embodiment, diluents may include aqueous solutions of salts and / or buffers.
[00210] [00210] A "preservative" is a compound that can be added to the formulations in this application to reduce bacterial activity. The addition of a preservative, for example, can facilitate the production of a multipurpose formulation (multiple dose). Examples of potential preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long chain compounds), and benzethonium chloride. Other types of preservatives include aromatic alcohols such as phenol, butyl and benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and w-cresol. The most preferred preservative in this application is benzyl alcohol.
[00211] [00211] ‘Treatment’ refers to clinical intervention designed to alter the natural course of the individual or cell being treated, and can be performed for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing the occurrence or relapse of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, and improved remission or prognosis. In some embodiments, the antibodies of the invention are used to delay the development of a disease or disorder. An individual is successfully "treated", for example, using the apoptotic anti-PD-L1 antibodies of the invention if one or more symptoms associated with a dysfunctional T cell disorder are mitigated.
[00212] [00212] An "effective amount" refers to at least an effective amount, in dosages and for periods of time necessary, to achieve the desired or indicated effect, including a therapeutic or prophylactic result. For example, an effective amount of the anti-PD-L1 antibodies of the present invention is at least the minimum concentration that results in inhibition of PD-L1 signaling, by PD-1 in T cells or by B7.1 in other APCs or both .
[00213] [00213] A "therapeutically effective amount" is at least the minimum concentration required to effect a measurable improvement or prevention of a particular disorder. A therapeutically effective amount in this application can vary according to factors such as the patient's disease state, age, sex, and weight and the ability of the antibody to elicit a desired response in the individual. A therapeutically effective amount is also that in which any negative or toxic effect of the antibody is outweighed by the therapeutically beneficial effects. For example, a therapeutically effective amount of the anti-PD-L1 antibodies of the present invention is at least the minimum concentration that results in the inhibition of at least one symptom of a dysfunctional T-cell disorder.
[00214] [00214] A "prophylactically effective amount" refers to an effective amount, in the dosages and for periods of time necessary, to achieve the desired prophylactic result. For example, a prophylactically effective amount of the anti-PD-L1 antibodies of the present invention is at least the minimum concentration that prevents or mitigates the development of at least one symptom of a dysfunctional T-cell disorder.
[00215] [00215] "Mammal" for treatment purposes refers to any animal classified as a mammal, including humans, domestic and farmed animals, and zoo, sports or pets, such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. Preferably, the mammal is the human being.
[00216] [00216] The term “'pharmaceutical formulation” refers to a preparation that is in such a way as to allow the biological activity of the active ingredient to be effective, and that it does not contain any additional components that are unacceptably toxic to an individual to whom the formulation would be administered. Such formulations are sterile.
[00217] [00217] A "sterile" formulation is aseptic or free from all living microorganisms and their spores.
[00218] [00218] The term "approximately" as used in this application refers to the usual error range of the respective value readily known to the expert in this technical field.
[00219] [00219] An "autoimmune disorder" is a disease or disorder originating from and directed against an individual's own tissues or organs or a co-segregation or manifestation of this or condition resulting from it.
[00220] [00220] The term "cytotoxic agent", as used in this application, refers to a substance that inhibits or prevents the function of cells and / or causes the destruction of cells. The term includes radioactive isotopes (e.g. At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32 and radioactive isotopes of Lu), and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal or fragments thereof.
[00221] [00221] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylene melamine, triethylene phosphoramide, triethylene thiophosphoramide and trimethylolomelamine; acetogenins (especially bulatacin and buflatacinone); delta-9-tetrahydrocannabinol (dronabinol); beta-lapachone; lapachol; colchicines; betulinic acid; camptothecin (including the synthetic analogue of topotecan (CPT-11 (irinotecan), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); briostatin; pemetrexed; calistatin; CC-1065 (including its synthetic analogues adozelesin, carzelesine; and bizelesin; podofillínico; teniposide; cryptoficina (particularly criptoficina 1 and criptoficina 8); dolastatina; duocarmicina (including the synthetic analogs, KW-2189 and CB1-TM1); eleuterobina; pancratistatina; TLK-286; CDP323, an oral alpha-4 integrin inhibitor ; a sarcodictin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, colophosphamide, estramustine, ifosfamide, meclorethamine, meclorethamine oxide hydrochloride, melphalan, novembichine, phenesterine, prednimustine, trophosphoramine, mustard, urine, mustardine, mustard; lomustine, nimustine, and ranimnustine; antibiotics such as enediin antibiotics (eg, calicheamicin, especially c aliqueamicin gamma ll and calicheamicin omega ll (see, for example, Nicolaou et al, Angew.
[00222] [00222] Other therapeutic agents that can be used in combination with the anti-PD-L1 antibodies of the invention are bisphosphonates such as clodronate, NE-58095, oledronic acid / zoledronate, alendronate, pamidronate, tiludronate, or risedronate; as well as troxacitabine (a nucleoside cytosine 1,3-dioxolane analog); antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in aberrant cell proliferation, such as, for example, PKC-alpha, Raf, H-Ras and epidermal growth factor receptor (EGF-R); vaccines such as Stimuvax vaccine, Theratope vaccine and gene therapy vaccines, for example, Alovectin vaccine, Leuvectin vaccine and Vaxid vaccine; topoisomerase 1 inhibitor; an antiestrogen like fulvestrant; a Kit inhibitor like imatinib or EXEL-0862 (a tyrosine kinase inhibitor); EGFR inhibitor like erlotinib or cetuximab; an anti-VEGF inhibitor like bevacizumab; arinotecan; rmRH; lapatinib and lapatinib ditosylate (a small molecule inhibitor of dual tyrosine kinase ErbB-2 and EGFR also known as GW572016); 17AAG (geldanamycin derivative which is a heat shock protein (Hsp) poison 90), and salts, pharmaceutically acceptable acids or derivatives of any of the above.
[00223] [00223] "Stimuvax" is a BLP25 liposome cancer vaccine designed to induce an immune response to cancer cells that express MUC1, a protein antigen widely expressed in common cancers. MUC1 is overexpressed in many cancers like lung cancer, breast cancer, prostate cancer and colorectal cancer. Stimuvax is thought to act by stimulating the body's immune system to identify and destroy cancer cells that express MUC1. Brief description of the Figures
[00224] [00224] Figure 1 shows that A09-246-2 efficiently blocks 125 I-PD-L1 that binds to immobilized PD-1-Fc. Inactive mutant: Mutant VL-A31G, D52E, R99Y from A09-188-1. A09-246-2 (1): Expressed in HEK 293 cells. A09-246-2 (2): Expressed in CHO-S cells, lot No.1. A09-246-2 (3): Expressed in CHO-S cells, lot No.2.
[00225] [00225] Figure 2 shows the sequence of the extracellular domain (fused to a 6 amino acid His marker, SEQ ID NO: 29) of PD-L1. Peptides that can be identified by MS are indicated by gray bars. Those who showed protection from HD exchange in the presence of Fab are represented by black bars. Peptides that cannot be analyzed are highlighted by underlining and highlighting in italics in the sequence.
[00226] [00226] Figure 3 shows the epitope of A09-246-2 in PD-L1. The PD-L1 skeleton is shown in a band representation. Amino acids that, when mutated to alanine, destabilize the A09-246-2 - PD-L1 bond by more than 0.7 kcal / mol are shown as stems.
[00227] [00227] Figure 4 shows that A09-246-2 efficiently increases the T cell activities represented by IL-2 production as shown by the human SEA PBMC assay.
[00228] [00228] Figures 5-16 show that A09-246-2 increases ADCC in different tumor lines (stimulated and unstimulated) and allotypes.
[00229] [00229] Experimental section
[00230] [00230] The working examples presented below are intended to illustrate the particular embodiments of the invention and are not intended to limit the scope of the specification or the claims in any way. 1 Antibody Selection and Improvement
[00231] [00231] Antibodies were selected from Fab phage display libraries. The selection included two different arms, one using biotinylated human PD-L1 in the different selection cycles and the other alternating human and mouse PD-L1 as the target in different cycles . 3840 clones were screened by ELISA to identify 170 individual PD-L1 ligands. Based on the inhibition of binding to the PD-1 ligand, 48 hits were selected and expressed on a medium scale for further characterization.
[00232] [00232] The selected hits were reformatted and expressed as IgGs. Hit optimization candidates were selected based on the power to block the binding of PD-1 to PD-L1 and the binding capacity of both human and mouse versions of PD-L1. Binding to PD-L1 was originally determined by ELISA and then quantified by Biacore and binding to cells expressing PD-L1 by FACS. Four candidates adjusted the predestined profile, including A09-188-1 which contained a lambda light chain.
[00233] [00233] A09-188-1 was chosen for affinity maturation and sequence optimization. The goals of affinity maturation were increased affinity for the human target, cross-reactivity to the murine target and improved manufacturability. Heavy chain mutations in HVR’s were introduced by codon-based randomization. This diversity of the heavy chain was combined with the diversity of the light chain introduced by mixing the light chain to generate the affinity maturation library. In addition, heavy and light chain FR and HVR residues have been mutated to increase antibody stability and introduce amino acids found in the germline, such as the 193V heavy chain FR mutation.
[00234] [00234] This produced the HVR sequences given below. It can be shown that at least residues X1-X17 are variable in terms of target binding and have preferential meanings as in this application described.
[00235] [00235] HVR-H1 sequence is X1YX2MX3 (SEQ ID NO: 1);
[00236] [00236] HVR-H2 sequence is SIYPSGGX4TFYADX5VKG (SEQ ID NO: 2);
[00237] [00237] HVR-H3 sequence is IKLGTVTTVX6Y (SEQ ID NO: 3);
[00238] [00238] where: X1 is K, R, T, Q, G, A, W, M, I or S; X2 is V, R, K, L, M or I; X3 is H, T, N, Q, A, V, Y, W, F or M; X4 is F or I; X5 is S or T; X6 is E or D
[00239] [00239] HVR-L1 sequence is TGTX7X8DVGX9YNYVS (SEQ ID NO: 8);
[00240] [00240] HVR-L2 sequence is X10VX11X12RPS (SEQ ID NO: 9);
[00241] [00241] HVR-L3 sequence is SSX13TX14X15X16RV (SEQ ID NO: 10);
[00242] [00242] where: X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is I, N or S; X12 is D, H or N; X13 is F or Y; X14 is N or S; X15 is R, T or S; X16 is G or S; X17 is I or T.
[00243] [00243] Antibody A09-246-2 corresponding to SEQ ID NO: 32 (heavy chain) and SEQ ID NO: 33 (light chain), was expressed from CHO-S cells transfected with the KOL isotype DNA sequence and EU version optimized by sequence, respectively. Cell cultures were conducted in batches in a 250L single use Bioreactor (SUB) (Table 2-2). The cells were grown in ProCHO5 growth media supplemented with 4 mM L-Glutamine + 25 pg / ml puromycin at 37 ° C. Cultures were fed with 15% Efficient Feed B and 1.0 mM valproic acid 3 days after inoculation.
[00244] [00244] The conditioned media of raw material from the bioreactor runs were clarified using the 1.1 m2 Millistak + Pod DOHC (Millipore MD0HC10FS1) and 0.11 m2 Millistak + Pod A1HC (Millipore MA1HC01FS1) filters, followed by filtration terminal with the Sartopore 2 filter (Sartorius 5445307H8-SS).
[00245] [00245] The purification process consisted of two chromatography steps; (a) Protein A MabSelect to capture the antibody from the clarified collection and (b) refining step in Type II Hydroxyapatite to remove aggregate product from the rest, host cell proteins and DNA, and product related impurities. An intermediate Q filtration step was inserted between the 2 chromatography steps to further reduce the DNA. SDS-PAGE and SE-HPLC size exclusion chromatography were used to analyze samples within the process during purification. The protein content of the samples in the Mabselect process was performed using the HPLC method on Protein A while UV / Vis spectroscopy was used for all other steps in the process.
[00246] [00246] Post-Mabselect eluates were subjected to 30 min of viral inactivation at low pH (pH 3.7) and subsequently neutralized to pH 7.0 before the next purification step.
[00247] [00247] The final refining step was with Type II hydroxyapatite chromatography. The conductivity of the Sartobind Q filtrate was adjusted to <3 mS / cm with water and pH reduced to 6.5 with acetic acid before loading the sample.
[00248] [00248] The bound anti-PD-L1 product was eluted with a gradient from the NaCI step. The aggregated product-related impurities were eluted with the Strip Buffer.
[00249] [00249] Anti-PDL1 purified from the hydroxyapatite refining step were concentrated and then diafiltered in their respective buffers according to the Table below. The volume products were then sterile filtered through 0.2 µ filter units and further diluted with the formulation buffer to their final concentrations. The formulated bulk substance was further tested for endotoxin and verified by SE-HPLC. Formulation UF / DF A09-246-2 Initial Sample (mg) 1279% Recovery 100 Final concentration 10.2 Purity (% momomer) 99 Buffer formulation 10 mM sodium acetate 140 mM sodium chloride, Tween 20 a 0.05% (v / v), pH 6.0
[00250] [00250] The following target administration and formulation profile have been established:
[00251] [00251] Route of administration: IV infusion
[00252] [00252] Human dose range: 1-15 mg / kg
[00253] [00253] Concentration: 10 mg / ml
[00254] [00254] Storage conditions: liquid or frozen
[00255] [00255] Shelf life: more than 12 m
[00256] [00256] The following liquid formulation has been selected:
[00257] [00257] A09-246-2 10.0 mg / mL
[00258] [00258] 10 mM acetate
[00259] [00259] Mannitol 5.1% (w / v)
[00260] [00260] 1.4 mM methionine
[00261] [00261] Tween 20 0.05% (w / v)
[00262] [00262] adjusted to pH 5.5
[00263] [00263] The formulation contains antioxidative excipients and has been shown to be sufficiently stable under the following stress conditions:
[00264] [00264] - Light stress
[00265] [00265] - Shear stress
[00266] [00266] - Freeze-thaw cycles
[00267] [00267] - Oxidation stress
[00268] [00268] Stability was assessed at 2-8 ° C and 25 ° C up to 26 and 13 weeks, respectively. The formulation was found to be sufficiently stable at 2-8 ° C until the last time point of 26 weeks. Also, a vacuum frozen formulation was made with excellent stability at 25 ° C for up to 26 weeks
[00269] [00269] The affinity and selectivity of binding were determined by Biacore assays. The affinity of the main candidate antibody for human and non-human orthologists is summarized in the table below. The binding affinity of the anti PD-L1 antibody A09-246-2 according to this invention of human, mouse and monkey cinomolgus proteins was statistically similar but highly reduced for dog, rat and rabbit proteins that exhibited a dissociation profile very fast. PD-L1 ka kd (1 / s) KD (M) KD (nM) +/- (1 / Ms) STDEV Human 2.72E + 05 1.83E-04 6.73E-10 0.7 0.09 Monkey 2.49E + 05 2.79E-04 1.12E-09 1.1 0.02 Mouse 1.77E + 05 1.64E-04 9.26E-10 0.9 0.04 Dog 2.38E + 06 1.07E-02 4.50E-09 4.5 0.4 Mouse 3.54E + 05 2.20E-02 6.68E-08 66.8 8.8
[00270] [00270] The kinetic profiles for A09-188-1 and additional mutants thereof are shown in the table below: Accid ID Anti-PD-L1 KD t1 / 2 KD Relative Antibody (nM) (min) A09-188-1 Antibody having a 5.29 13.2 1.00 heavy chain according to SEQ ID NO: 34, and a light chain according to SEQ ID NO: 35 A09-188-1 * A09- heavy chain combination variants 204-1 VH-M31I, M33I, M35F, S63T, I93V 0.10 578.2 0.02 A09-211-1 VH-M311, M33L, M35F, S63T, I93V 0.59 109.4 0.11 A09- 212-1 VH-M33I, M35F, S63T, I93V 0.22 254.4 0.04 A09-213-1 VH-M311, M35F, S63T, I93V 2.51 27.7 0.47 A09-214-1 VH -M311, M33I, S63T, I93V 0.40 179.1 0.08 A09-215-1 VH-M33L, M35F, S63T, I93V 1.28 50.6 0.24 A09-216-1 VH-M311, M33L , S63T, I93V 0.91 77.8 0.17 A09-219-1 VH-M31S, M33I, M35F, S63T, I93V 0.18 278.5 0.03 A09-220-1 VH-M31S, M33L, M35F , S63T, I93V 0.78 68.3 0.15 A09-221-1 VH-M31S, M33I, S63T, I93V 0.44 126.7 0.08 A09-222-1 VH-M31S, M33L, S63T, I93V 1.24 47.1 0.23 A09-223-1 VH-M31S, M35F, S63T, I93V 3.62 13.5 0.68 Variant of the light chain of A09-188-1 * A09-202-1 VL-A31G 4.15 18.8 0.78 Combination variants of the heavy and light chain of A09-188-1 *
[00271] [00271] (*) Amino acid positions counted from the N-terminal of the heavy and light chains, respectively
[00272] [00272] Selectivity was determined by assessing binding to members of the B7 family including hu-PD-L1-huFc, hu-PDL-2-huFc, hu- B7.1-huFc, hu-B7.2-huFc, huB7- H2-huFc and huB7-H3-huFc by Biacore.
[00273] [00273] Every anti-huPD-L1 MAb tested including A09-246-2 reacted specifically only with the huPD-L1 protein and not with any other B7 Family protein.
[00274] [00274] The ability of A09-246-2 and a control antibody to compete with binding of radiolabelled PD-L1 to immobilized PD-1 was determined by the competitive radioactive displacement assay. Figure 1 shows competition curves representative of the test antibodies. The results demonstrated that A09-246-2 efficiently blocks the interaction of PD-1 and PD-L1 with an IC50 of 0.071 ± 0.008 nM (0.01 ± 0.001 µg / ml).
[00275] [00275] The following test protocol was used:
[00276] [00276] Add 60 ml / well of PBS, containing 1 mg / ml of human PD-1 Fc (R&D Systems, 1086-PD; lyophilized PD-1 dissolved with PBS in 200 mg / ml) to white Costar plates (Corning 3922 ). Incubate overnight at 4 ° C.
[00277] [00277] Rinse the wells once with PBS.
[00278] [00278] Block the wells with 120 ml of 0.5% BSA (Sigma A-3059) dissolved in the binding buffer, for 1 h at room temperature (RT).
[00279] [00279] Rinse 1x wells with binding buffer.
[00280] [00280] Add 50 ml of the test sample to the wells (antibody, supernatant). Antibodies diluted to 20 nM in the assay buffer and serially diluted 9x in a 1: 4 dilution. The samples are diluted to final concentration 2x, before addition to the wells (usually starting at 10 nM - 1x concentration).
[00281] [00281] Non-specific binding: add 50 ml of PD-L1 / Fc (R&D Systems, 156-B7) in a final concentration of 250 nM in place of the test sample in excess of 500 times for the labeled PD-L1. The total wells receive the same volume as the assay buffer. 125
[00282] [00282] Add 50 ml of 0.5 nM I-PD-L1 (label adapted in Perkin Elmer, batch number CIS32211, 250 nM, 2400 Ci / mmol) to each of the wells. Diluted to 2x the final concentration in assay buffer - final concentration = 0.25 nM.
[00283] [00283] Shake the plate for 2-2.5 h at 37 ° C.
[00284] [00284] Wash the wells 5 times with the cold binding buffer.
[00285] [00285] Add 100 ml of Microscint 20 (Packard 6013641) to each well. Incubate for at least one hour at RT. 125
[00286] [00286] Count the Luminescence in Topcount (protocol l- Microscint).
[00287] [00287] Binding buffer: 50 mM Hepes, pH 7.5, 130 mM NaCI, 5.1 mM KCI, 1.3 mM MgSO4 Assay buffer: binding buffer + 0.5% BSA
[00288] [00288] The ability of A09-246-2 to block the binding of soluble B7.1 to PD-L1 on the cell surface was measured by FACS. The results indicated that A09-246-2 efficiently blocks the interaction of B7.1 and PD-L1 with an IC50 of 0.2 ± 0.004nM (0.03 ± 0.0006 µg / ml).
[00289] [00289] The extracellular domain of the PD-L1 antigen (SEQ ID NO: 29) was incubated in heavy water solution (D2O) to allow the amide protons in the protein skeleton to exchange the deuteriums of the solvent, in the presence or absence of Excessive anti-PD-L1 Fab or non-specific Fab. The samples were digested with protease and analyzed by liquid chromatography - mass spectrometry (LC-MS) to determine the level of deuteration in each peptide.
[00290] [00290] The Fab corresponding to A09-246-2 was used instead of complete IgG in order to simplify the analysis of mass spectrometry by decreasing the number of peptides generated by protease digestion. Despite this, some regions remained unidentifiable and analyzed (portions of the sequence underlined in italics in Figure 2), however these regions represent a small fraction of the sequence, and most reside in the second immunoglobulin domain, far from the region containing the epitope . Residues 32-39 in domain I of the extracellular domain were also resistant to identification by mass spectrometry and encompass the site of an N-linked glycosylation; as A09-246-2 is known to bind to an aglycosylated version of PD-L1 produced in E. coli, the inability to analyze this peptide for HD exchange rates was not of interest.
[00291] [00291] It was observed that several antigen peptides had a significantly reduced rate of deuterium proton exchange in the presence of Fab than in their absence, suggesting that at least some residues of these peptides are in direct contact with Fab and constitute a conformational epitope (Figure 2). Although the two peptides showing solvent protection are far from the primary sequence (underlined in bold in Figure 2, they are proximal to the three-dimensional structure of PD-L1 and each constitutes a single bond seam on the antigen surface (see Figure 3).
[00292] [00292] In short, the HD exchange identified two peptides
[00293] [00293] residues 36-48 in Figure 2 (extracellular domain plus His marker, SEQ ID NO: 29), corresponding to residues 54-66 of the complete sequence (SEQ ID NO: 28)
[00294] [00294] residues 94-104 in Figure 2 (SEQ ID NO: 29), corresponding to residues 112 - 122 SEQ ID NO: 28
[00295] [00295] which form a conformational epitope on PD-L1 and which contains the functional epitope of A09-246-2.
[00296] [00296] b) Mutagenesis
[00297] [00297] To obtain a more accurate level mapping of the epitope residue and to complement HD exchange data, molecular modeling and manual inspection of the PD-L1 crystalline structure (Lin, DY-W. Et al. PNAS105, 3011 -6 (2008; 3BIK PDB record) was used to select residues exposed to the solvent in and around the epitope identified by HD exchange. The selected residues were mutated either by alanine (large to small) or the other potentially more disturbing amino acid ( small to large).
[00298] [00298] In total, 48 point mutants were designed, expressed and purified from HEK cells and tested for binding to A09-246-2 using surface plasmon resonance (SPR). The binding stress areas or residues that contribute most to the binding energy (Wells. J.A., PNAS 93, 1-6, 1996), have been identified as those that do not satisfy a threshold signal in 100 nM antigen. In addition, the affinity of the wild-type antibody and each mutant was determined and used to calculate the contribution of each epitope residue to the binding energy.
[00299] [00299] The results are summarized in the table below, where 48 point PD-L1 mutants were compared with wild PD-L1 antigen for antibody binding. SPR (Biacore) was used to perform a kinetics study allowing the determination of the kinetic rate constants (ka and kd). Briefly, goat anti-human polyclonal antibody was chemically coupled to a CM5 chip. A11-128 was later injected and captured by the polyclonal. The buffer was used to remove unbound antibody until the base UK stabilized. The antigen (wild-type or mutant PD-L1) was then injected at a fixed concentration for 3 minutes and the association was recorded. The buffer was injected for an additional 3 minutes and dissociation was observed. The antigens were injected in concentrations of 100 nM, 50 nM, 25 nM, 12.5 nM and 6.25 nM (except mutants Y56 and D61, which were injected in 1 µM, 500 nM, 250 nM, 125 nM and 62 , 5 nM). Between each cycle, the chip was regenerated with the low pH buffer and fresh A09-246-2 was captured before injecting the next antigen concentration. Rate constants were determined by iterative adjustment of the data to a 1: 1 link model by an algorithm that minimizes Chi-square. The dissociation equilibrium constant (KD) was calculated as the ratio of the kinetic constants and change in Gibbs free energy of the mutant binding relative to the wild PD-L1 (∆∆Gmut) was derived from the ratio of the wild and mutant KDs. The free energy modifications are highlighted according to the destabilization of the antibody-antigen bond; “**”: destabilization> 3 kcal / mol (bonding stress areas); "*":> 0.7 kcal / mol. The Y56 mutants had an affinity so low that KD can be exactly measured and the minimum KD is given instead. For D61A no connection can be found. According to this analysis, the amino acids marked with "**" or "*" are part of the functional epitope. The temperature midpoint of the fluorescently monitored thermal denaturation is given for both wild and mutant proteins. ND; Not determined; BP: Biphasic. The qualitative appearance of wild and mutant proteins in size exclusion chromatography (SEC) is also given. M: monodisperse and the same elution volume as the wild; M / T: peak at the same elution volume as the wild, but with an additional tail. For KD and T1 / 2, the mean and standard deviation is given where n> 1. KD (nM) T1 / 2 (° C) (kcal / mol) AAGmut mutation
[00300] [00300] It was important to confirm that the lack of binding to A09-246-2 of the point mutants Y56A, Y56K and D61A which were in fact due to the loss of hotspot residues and not to the global unfolding of the antigen. The structural integrity of the mutated proteins was confirmed using the fluorescence monitored thermal split assay in which the protein is incubated with a dye that is quenched in the aqueous solution but fluoresces when bound by exposed hydrophobic residues. When the temperature increases, the thermal denaturation of the protein exposes the main hydrophobic residues and this can be monitored by an increase in the fluorescence of the dye. Mutants of Y56 or D61, all exhibit a two-state transition similar to wild PD-L1, indicating a folded structure at room temperature. The data were adjusted to equation 1 (adapted from Bullock, AN et al. Thermodynamic stability of wild-type and mutant p53 core domain. PNAS 94,14338-14342 (1997)) to determine the temperature at the inflection point of the curve (T1 /two). Equation 1:
[00301] [00301] The Y56 and D61 mutants exhibited minimal destabilization of the antigen indicated by the small reduction in T1 / 2 of the fluorescence-monitored unfolding (table above). This confirms that Y56 and D61 are true link voltage areas of A09-246-2. The structural integrity of most of the other mutant proteins was also confirmed by this method (table above). The observation that most mutant proteins behaved similarly to the wild in analytical size exclusion chromatography (last column in the table above) provides additional support for the native structure of mutant antigen proteins.
[00302] [00302] The binding of A09-246-2 to PD-L1 on the surface of tumor cells as well as in primary human cells and experimental animals was confirmed by a FACS assay. A09-246-2 demonstrated reactivity to human PD-L1 in the seven human tumor lines tested (A431, epithelial carcinoma cell line; A549, lung adenocarcinoma epithelial cells; BxPC3, pancreatic cancer cells; HCT116, colorectal carcinoma; M24, strains melanoma cells; PC3mm2, prostate cancer cell line; U-87 MG, glioblastoma-astrocytoma) of which PD-L1 was regulated upwards by interferon treatment to allow detection. As primary PBMC has low levels of PD-L1 expression that is difficult to detect, human PBMC or dog, rabbit and rat PBMC were all subjected to PHA stimulation for 2 days. A09-246-2 demonstrated reactivity to PD-L1 in primary human and animal cells.
[00303] [00303] The dose-dependent ability of A09-246-2 to the target on the cell surface has been confirmed by FACS. A09-246-2 binds efficiently to human PD-L1 expressed on the HEK cell surface with an EC50 of 0.3 ± 0.02 nM (0.04 ± 0.003 µg / ml); for cinomolgus monkey expressed on the HEK cell surface with an EC50 of 0.94 ± 0.015 nM (0.14 ± 0.002 ng / ml); Mouse PD-L1 expressed on the HEK293 cell surface with an EC50 of 0.34 ± 0.08 nM (0.05 ± 0.012 µg / ml) and mouse PD-L1 expressed on the EL4 cell surface with an EC50 of 0, 91 ± 0.21 nM (0.13 ± 0.03 µg / ml). The trials qualitatively described the dose-dependent binding characteristics of anti-PD-L1.
[00304] [00304] Currently there is no scientific evidence that the occupation of PD-L1 with its ligands converts PD-L1 stimulatory signaling into cells expressing PD-L1, so the tests developed employed T cell activation in the procedures. The ability of the anti-PD-L1 antibody to increase T cell immunoresponses was measured in vitro in cell assays using murine T cells or human PBMC. OT-1 assay
[00305] [00305] Antigen-specific CD8 T cells were generated by stimulation of splenocytes from transgenic mice OT-1 with the Ova SIINFEKL peptide and cryopreserved. EL4 cells overexpressing mPD-L1 were used as antigen presenting cells. Serial dilutions of tested compounds were incubated with thawed OT-1 T cells and APC loaded with SIINFEKL for 48 hours. IFN-γ in the supernatant was measured using mlFN-γ ELISA. Anti-PD-L1 (A09-246-2) efficiently increased the T cell activities represented by IFN-γ production with an EC50 of 0.28 ± 0.1 nM (0.04 ± 0.015 ng / ml)
[00306] [00306] b) SEA test
[00307] [00307] During the development of the human PBMC assay, it could be demonstrated that only anti-PD-L1 treatment did not cause the production of IL-2 or IFN-y in the absence of T cell activation and did not increase the production of IL- 2 in the presence of optimal activation as well. The ability of anti-PD-L1 to increase IL-2 production by T cells that respond to antigen overactivation was evaluated. The superantigen such as Staphylococcal Enterotoxin A (SEA) is capable of interconnecting the T cell receptor (TCR) and MHC class II to activate CD4 T cells. The dose-dependent activity of A09-246-2 to increase T cell functions was assessed after such activation. Serial dilutions of A09-246-2 were incubated with human PBMC in the presence of SEA for 96 hours. Human IL-2 in the supernatant was measured using ELISA for human IL-2. The results indicated that anti-PD-L1 efficiently increased T cell activities represented by IL-2 production with an EC50 of 0.08 ± 0.03 nM (0.012 ± 0.005 µg / ml)
[00308] [00308] ADCC was measured using two different human tumor lines A431 and A549 as target cells and human PBMC as effector cells. In some cases, tests were performed using target cells after stimulation with Interferon gamma to increase expression of PD-L1. The anti-EGFR antibody, cetuximab, was used as a positive ADCC control. Since the 158V allotype of the Fcyllla receptor exhibits a higher affinity for human IgG1 and increases ADCC, the observed results were correlated with the donor allotype.
[00309] [00309] The ADCC activity of A09-246-2 was comparable to that mediated with the anti-EGFR antibody cetuximab, inducing approximately 50% of the maximum lysis in both cell lines. INF-y treatment did not alter the response of A431 cells from all the different allotypes tested (V / V, V / F and F / F). A significant difference (almost twice) between stimulated and unstimulated cells was observed when A549 cells were used for PBMC from V / V and V / F donors. No ADCC was observed when PBMC from F / F donors were analyzed with A549 cells.
[00310] [00310] In the studies presented in this application, the effectiveness of antibody blocking for PD-L1 (Ab) against various murine tumor models was investigated. Inhibition of the PD-1 / PD-L1 interaction is proposed to exert a therapeutic effect by restoring CD8 + T cell antitumor responses, thus all preclinical efficacy studies have been conducted in murine syngeneic tumor models in which the host immune system it is completely intact. To meet the need for a substitute antibody, the antibody used in the studies was specifically selected for cross-reactivity to murine PD-L1. However, since the antibody is fully human, neutralization of immunogenicity is brought about in mice, which limits the effective dosing window to a period of seven days. Despite this significant dosage limitation, the selected antibody demonstrated significant activity as a monotherapy and in various combination therapy settings. The anti-tumor activity of the anti-PD-L1 antibody demonstrated a dose-dependent tendency when given as a monotherapy against MC38 tumors.
[00311] [00311] Immunohistochemical analysis of PD-L1 expression within responsive and unresponsive tumor models revealed a strong connection between the level of PD-L1 expression and the level of antitumor efficacy. To confirm the proposed mechanism of action (MOA), a study was conducted in mice carrying the MC38 tumor that were systemically depleted of CD8 + T cells. In animals depleted of CD8 + T cells, the effectiveness of anti-PD-L1 therapy has been completely nullified, confirming that the effector function of cytotoxic T lymphocyte (CTL) is responsible for inhibiting tumor growth. To assess the potential for combining anti-PD-L1 therapy, combination partners were selected because they are known to elicit anti-tumor T cell responses or otherwise increase the effects of immunotherapy. In combination with fractional radiotherapy against MC38 tumors, the anti-PD-L1 antibody showed strong synergistic activity, with healing potential. The combination with a single low dose of cyclophosphamide resulted in increased anti-tumor effects in the model
[00312] [00312] Mechanistic data derived from these studies demonstrated that anti-PD-L1 therapy is constantly associated with increased percentages of CD8 + T cells, effector memory T cells and CD8 + PD-1 + T cells in the spleens and tumors of mice treated.
[00313] [00313] In this study, mice were inoculated subcutaneously on the right flank with 1x106 MC38 colon carcinoma cells. When the tumors reached an average volume of ~ 50 mm3, the mice were classified into treatment groups (N = 14) (defined as study day 0). The groups were administered A09-246-2 intravenously at dose levels of 100, 200,400 or 800 pg on days 0, 3, and 6. A control group was treated with 200 pg of an inactive isotype antibody. Tumors were measured twice weekly for the duration of the study. All treatment groups demonstrated significant efficacy (P <0.050) when compared to the isotype control group. Although the 800 pg dose group did not show increased efficacy over the 400 pg group, a significant trend towards a dose dependent effect was observed. In a second dose response study that followed the same design, a general trend towards dose-dependent activity was again observed. However, the 800 pg dose group in which the particular study showed significantly lower antitumor activity than the 400 pg dose group. The lack of increased efficacy at doses above 400 pg may indicate a plateau of efficacy as a result of the target saturation, or a stronger immunogenic effect may occur at higher doses, resulting in lower drug exposure. In addition, these studies explored the efficacy of anti-PD-L1 in combination with pretreatment with a low, immunomodulatory dose of cyclophosphamide (CPA). It was observed that the combination of CPA significantly improved the efficacy of low doses of anti-PD-L1 (100 pg), and this effect was associated with increased frequencies of CD8 + T cells specific for the tumor antigen p15E as determined by ELISPOT. The immunophenotyping data from these studies revealed that anti-PD-L1 therapy was associated with significantly increased percentages of various subsets of spleen CD8 + T cells: total CD8 + T cells, CD8 + T cells specific for the p15E tumor antigen, CD8 + PD T cells -1+ and CD8 + T cells of effector memory (TEM) and CD8 + T of central memory (TCM). Increased intratumor accumulation of CD8 + T cells and CD8 + TEM cells was also observed. This observation supports that anti-PD-L1 therapy as an effective strategy to control CD8 + T cell antitumor responses.
[00314] [00314] To create the disseminated leukemia model, C4198-GFP leukemia cells (2x104) were injected iv into C57BL / 6 mice on day 0. The mice were then randomized into treatment groups (N = 5) that received a 400 pg dose of anti-PD-L1 Ab (A09-246-2) or an equivalent dose of an inactive isotype antibody on days 1, 4, and 7 by ip injection The primary parameter of this study was survival based on the onset of clinical signs, indicative of metastatic spread, which guaranteed euthanasia. At the end of the study (day 76), 20% of mice (1/5) were still alive in the isotype antibody treated group, and 80% (4/5) survivors remained in the A09-246-2 treated group.
[00315] [00315] Three separate studies were conducted to investigate the combination of anti-PD-L1 MAb (A09-246-2) and Gemcitabine (GEM). The studies were designed to explore the positioning of anti-PD-L1 therapy within the chemotherapy “vacation” period of a 21-day or 28-day GEM cycle. Orthotopic models involve the inoculation of tumor cells in the original organ, resulting in a closed recap of the disease progression as occurs in the human scenario. To create a model of pancreatic adenocarcinoma, PANC02 cells (1x106) were injected into the pancreas of female C57BL / 6 mice. Five days later, the mice were randomized into treatment groups. GEM was dosed at 150 mg / kg in all studies and A09-246-2 was dosed at 400 pg per mouse. In two studies, a 28-day GEM cycle was modeled (administration on days 5.19, 26), with a vacation period of 14 days during which A09-246-2 was given on days 8, 11.14. In a third study, a 21-day GEM cycle was modeled (administration on 5.12, 26, 33), with a 14-day vacation period during which A09-246-2 was given on 13.16 , 19. Monotherapy with GEM or anti-PD-L1 failed to extend the survival time in this model. However, in the three studies, the combination of GEM and A09-246-2 significantly extended the mean survival time (P <0.02). Immunophenotyping revealed several effects in groups receiving A09-246-2, either as a monotherapy or in combination with GEM, was compatible with the proposed anti-PD-L1 MOA including increased percentages of TEM CD8 + in spleens, an increased proportion of splenic TEM CD8 + cells to Treg, and increased percentages of splenic CD8 + PD-1 + T cells. In addition, immunophenotyping of tumor infiltrating lymphocytes (TIL) showed significantly increased percentages of T IL CD8 + in the combination group.
[00316] [00316] It is known that low dose CPA increases anti-tumor immune responses through the inhibition of immunosuppressive regulatory T cells. The potential for low-dose CPA pretreatment has been investigated to increase the efficacy of anti-PD-L1 Ab (A09 - 246-2) in the MC38 subcutaneous tumor model. The mice were inoculated subcutaneously on the right flank with 1x106 MC38 colon carcinoma cells. When the tumors reached an average volume of ~ 50 mm3, the mice were classified into treatment groups (N = 14) on day 0. The combination group received 100 pg of A09-246-2 by iv injection on days 0, 3 , and 6, with or without pretreatment with a dose of 100 mg / kg of CPA delivered iv on
[00317] [00317] The blocking ability of PD-L1 to restore antitumor T cell responses provides a strong rationale for combining with cancer vaccines. Stimuvax is a vaccine against the human MUC1 antigen, which is commonly overexpressed by solid tumors. Transgenic mice for human MUC1 protein (MUCI.tg mice) are immunologically tolerant to the antigen, and, when inoculated with murine tumors that also express human MUC1, provide a relevant model of the clinical vaccination environment. In the clinic, cyclophosphamide (CPA) pretreatment is used in combination with Stimuvax as a strategy to transiently deplete immunosuppressive Treg cells that may inhibit the vaccine response.
[00318] [00318] In this study, MUCI.tg mice were inoculated subcutaneously in the right rear flank with 1x106 MC38 / MUC1 colon carcinoma cells. Five days after tumor cell inoculation, the mice were randomized into treatment groups (N = 10) on day -3. On day -3, a dose of 100 mg / kg of CPA was administered by i.v. Vaccination was started on day 0 and was repeated weekly. Ab Anti-PD-L1 (A09-246-2) was dosed by i.p. on days 0, 3, and 6. Tumors were measured twice weekly. The combination of CPA / Stimuvax and A09- 246-2 showed significantly increased inhibition (p <0.050) of tumor growth when compared to treatment with CPA / Stimuvax. In a second study, 1x106 PANC02 / MUC1 cells were inoculated into the pancreas of MUCI.tg mice. Four days later, the mice were randomized into groups (N = 8) and treatment was started. The same treatment schedule was applied as for the first study. The combination of CPA / Stimuvax and anti-PD-L1 (A09-246-2) significantly increased the mean survival time (MST) when compared to treatment with CPA / Stimuvax (MST 43.5 days versus 70 days, P = 0.0001). FACS immunophenotyping showed a significant trend towards increased percentages of TEM CD8 + and TCM CD8 + in the combination group.
[00319] [00319] Radiotherapy (TA) has been shown to increase the immunogenicity of tumor cells, by increased expression of MHC class I and diversification of the intracellular peptide cluster. To test the anti-PD-L1 antibody treatment in combination with radiotherapy, MC38 colon carcinoma cells (1x105) were inoculated intramuscularly into the right quadriceps of female C57BL / 6 mice. When the tumors reached an average volume of 150 mm3, the mice were classified into treatment groups (N = 8) on day 0. The legs carrying the tumor were isolated and treated with 360 cGy of gamma radiation from a source of cesium 137 in days 0,1,2, 3, and 4 (total dose of 1800 cGy). Ab Anti-PD-L1 (A09-246-2) was dosed iv at 400 pg on days 3, 6 and 9. The combination of A09-246-2 and radiotherapy resulted in a high rate of tumor regressions, ultimately taking 6 / 10 complete answers (CR). The mice with CR were redefined by inoculating MC38 tumor cells, and 3/6 mice remained tumor free seventy-four days after redefining, indicating that effective immune memory was generated by combination therapy. Conversely, a control group treated with an isotype control antibody in combination with radiation showed significant tumor growth inhibition, but did not induce regressions.
[00320] [00320] A repeat of the TA and anti-PD-L1 combination study (A09-246-2) was performed, with the inclusion of a second combination therapy group in which the mice were systemically depleted of CD8 + T cells. Additional immunological readings measured in this study included FACS-based splenocyte immunophenotyping, in vivo proliferation analysis and ELISPOT assay. Again, the combination demonstrated the synergistic efficacy that induced an initial phase of regression or stasis in all tumors. However, complete regression was only observed in 1/8 mice, with another mouse experiencing a prolonged period of tumor stasis. The depletion of CD8 + T cells completely disrupted the combination synergy, confirming that the mechanism involves the stimulation of CD8 + T cell antitumor responses. This observation was further supported by increased frequencies of CD8 + T cells reactive to the p15E tumor antigen. FACS immunophenotyping revealed increased percentages of CD8 + T cell proliferation in spleens and increased splenic percentages of TEM CD8 + and TCM CD8 +.
[00321] [00321] FOLFOX is a combination chemotherapy regimen, consisting of folinic acid, 5-fluorouracil (5-FU), and oxiplatin (OX), used to treat stage III colorectal cancer. The potential to combine anti-PD-L1 with the main components of FOLFOX
[00322] [00322] FACS-based immunophenotyping conducted in these studies revealed increases in several immunological markers compatible with a CD8 + T cell-controlled MOA, including increased splenic levels of CD8 + T cells specific for the tumor antigen p15E, an increase in the splenic proportion of TEM cells to regulatory T (Treg), and increased splenic percentages of CD8 + PD-1 + T cells. In addition, it was observed that the percentage of infiltrating natural killer (NK) cells in the tumor and CD8 + T cells increased significantly in the combination group.
[00323] [00323] Four groups of 2 male and 2 female cinomolgus monkeys were treated with human anti-PD-L1 (A09-246-2) at dose levels of 0 (vehicle), 20, 60 and 140 mg / kg by intravenous infusion weekly of the total of 5 administrations.
[00324] [00324] The TK assessment indicates that all animals were exposed to the test material during the study. Exposure levels increased approximately proportionally to the dose increase in both the 1st and 4th doses, without any relevant accumulation or gender dependence at any dose. The anti-drug antibody was detected in 2/4 and 1/4 monkeys in 20 and levels of 140 mg / kg respectively. There was no premature death of the animals in the study. No treatment-related changes were observed in the 20 and 60 mg / kg dosage groups of all parameters assessed in the study.
[00325] [00325] At the high dose level of 140 mg / kg, treatment-related findings include a slight reduction in lymphocytes in the hematology test, a slight reduction in lymphocyte count together with a reduction in NK cell count on day 30 of the study. There were no significant histological changes in major organs / tissues except vessel inflammation / necrosis and moderate perivascular hemorrhage observed at the local injection site at 140 mg / kg. There was no clear trend or change observed in the multicytokine analysis at this dose level. Based on the results from this study, the No Observable Adverse Effect Level (NOAEL) was identified as 140 mg / kg.
[00326] [00326] Conclusion: A09-246-2 was tolerated in the cinomolgus monkey at dose levels up to 140 mg / kg after receiving a total of 5 consecutive weekly doses. Injection site reactions with moderate severity of subcutaneous / perivascular and vascular degenerative inflammatory changes were observed at 140 mg / kg.

权利要求:
Claims (1)
[1]
1. Polypeptide of variable region of the isolated heavy chain, characterized by the fact that it comprises a sequence of HVR-H1, HVR-H2 and HVR-H3, being that: (a) the sequence of HVR-H1 is X1YX2MX3 (SEQ ID NO: 1); (b) the HVR-H2 sequence is SIYPSGGX4TFYADX5VKG (SEQ ID NO: 2); (c) the HVR-H3 sequence is IKLGTVTTVX6Y (SEQ ID NO: 3); yet where: X1 is K, R, T, Q, G, A, W, M, I or S; X2 is V, R, K, L, M or I; X3 is H, T, N, Q, A, V, Y, W, F or M; X4 is F or I; X5 is S or T; Xe is E or D.
2. Polypeptide, according to claim 1, characterized by the fact that X1 is M, I or S; X2 is R, K, L, M or I; X3 is F or M; X4 is F or I; X5 is S or T; X6 is E or D.
3. Polypeptide, according to claim 1, characterized by the fact that X1 is M, I or S; X2 is L, M or I; X3 is F or M; X4 is I; X5 is S or T; X6 is D.
4. Polypeptide according to claim 1, characterized by the fact that X1 is S; X2 is I; X3 is M; X4 is I; X5 is T; X6 is D.
5. Polypeptide according to any one of claims 1 to 4, characterized by the fact that it also comprises sequences of the variable region of the heavy chain HC-FR1, HC-FR2, HC-FR3 and HC-FR4 , juxtaposed between the HVRs, thus forming the formula sequence: (HC-FR1) - (HVR-H1) - (HC-FR2) - (HVR-H2) - (HC-FR3) - (HVR-H3) - (HC-FR4).
6. Polypeptide according to claim 5, characterized by the fact that one or more of the framework sequences are as follows: HC-FR1 is EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID
No.: 4); HC-FR2 is WVRQAPGKGLEWVS (SEQ ID NO: 5); HC-FR3 is RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 6); HC-FR4 is WGQGTLVTVSS (SEQ ID NO: 7).
7. Polypeptide according to claim 6, characterized by the fact that it also comprises at least one CH1 domain.
8. Polypeptide according to claim 7, characterized by the fact that it further comprises a CH1 domain, a CH2 and a CH3.
9. Isolated heavy chain polypeptide according to any one of claims 1 to 8, characterized in that it is in combination with a variable region of the light chain comprising an HVR-L1, HVR-L2 and HVR-L3, where: (a) the HVR-L1 sequence is TGTX7X8DVGX9YNYVS (SEQ ID NO: 8); (b) the HVR-L2 sequence is X10VX11X12RPS (SEQ ID NO: 9); (c) the HVR-L3 sequence is SSX13TX14X15X16X17RV (SEQ ID NO: 10); yet where: X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is I, N or S; X12 is D, H or N; X13 is F or Y; X14 is N or S; X15 is R, T or S; X16 is G or S; X17 is I or T.
10. Polypeptide according to claim 9, characterized by the fact that X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is N or S; X12 is N; X13 is F or Y; X14 is S; X15 is S; X16 is G or S; X17 is T.
11. Polypeptide according to claim 9, characterized by the fact that X7 is S; X8 is S; X9 is G; X10 is D; X11 is S; X12 is N; X13 is Y; X14 is S; X15 is S; X16 is S; X17 is T.
12. Polypeptide according to any one of claims 9 to 11, characterized by the fact that it also comprises sequences of the variable region of the light chain LC-FR1, LC-FR2, LC-FR3 and LC-FR4 , juxtaposed between HVRs, thus forming the formula sequence: (LC-FR1) - (HVR-L1) - (LC-FR2) - (HVR-L2) - (LC-FR3) - (HVR-L3 ) - (LC-FR4).
13. Polypeptide according to claim 12, characterized by the fact that one or more of the framework sequences are as follows: LC-FR1 is QSALTQPASVSGSPGQSITISC (SEQ ID NO: 11); LC-FR2 is WYQQHPGKAPKLMIY (SEQ ID NO: 12); LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC (SEQ ID NO: 13); LC-FR4 is FGTGTKVTVL (SEQ ID NO: 14).
14. Polypeptide according to claim 13, characterized by the fact that it further comprises a CL domain.
15. Isolated anti-PD-L1 antibody or antigen-binding fragment thereof, characterized by the fact that it comprises a sequence of the variable region of the heavy chain and one of the light chain, in which: (a) the heavy chain comprises a HVR-H1, HVR-H2 and HVR-H3, where further: (i) the sequence of HVR-H1 is X1YX2MX3 (SEQ ID NO: 1); (ii) the HVR-H2 sequence is SIYPSGGX4TFYADX5VKG (SEQ ID NO: 2); (iii) the HVR-H3 sequence is IKLGTVTTVX6Y, and a (SEQ ID NO: 3); (b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, where further: (iv) the HVR-L1 sequence is TGTX7X8DVGX9YNYVS (SEQ ID NO: 8); (v) the HVR-L2 sequence is X10VX11X12RPS (SEQ ID NO: 9); (vi) the HVR-L3 sequence is SSX13TX14X15X16X17RV (SEQ ID NO: 10);
where X1 is K, R, T, Q, G, A, W, M, I or S; X2 is V, R, K, L, M or I; X3 is H, T, N, Q, A, V, Y, W, F or M; X4 is F or I; X5 is S or T; X6 is E or D; X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is I, N or S; X12 is D, H or N; X13 is F or Y; X14 is N or S; X15 is R, T or S; X16 is G or S; X17 is I or T.
16. Antibody or antibody fragment, according to claim 15, characterized by the fact that X1 is M, I or S; X2 is R, K, L, M or I; X3 is F or M; X4 is F or I; X5 is S or T; X6 is E or D; X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is N or S; X12 is N; X13 is F or Y; X14 is S; X15 is S; X16 is G or S; X17 is T.
17. Antibody or antibody fragment, according to claim 15, characterized by the fact that X1 is M, I or S; X2 is L, M or I; X3 is F or M; X4 is I; X5 is S or T; X6 is D; X7 is N or S; X8 is T, R or S; X9 is A or G; X10 is E or D; X11 is N or S; X12 is N; X13 is F or Y; X14 is S; X15 is S; X16 is G or S; X17 is T.
Antibody or antibody fragment according to claim 15, characterized in that X1 is S; X2 is I; X3 is M; X4 is I; X5 is T; X6 is D; X7 is S; X8 is S; X9 is G; X10 is D; X11 is S; X12 is N; X13 is Y; X14 is S; X15 is S; X16 is S, X17 is T.
23. Antibody or antibody fragment, according to any one of claims 17 to 22, characterized in that it further comprises: (a) framework sequences of the variable region of the heavy chain HC-FR1, HC-FR2, HC-FR3 and HC-FR4, juxtaposed between the HVRs, thus forming the sequence of the formula: (HC-FR1) - (HVR-H1) - (HC-FR2) - (HVR-H2) - (HC-FR3) - (HVR -H3) - (HC-FR4), and (b) framework sequences of the variable region of the light chain LC-FR1, LC-FR2, LC-FR3 and LC-FR4, juxtaposed between the HVRs, thus forming the sequence of formula: (LC-FR1) - (HVR-L1) - (LC-FR2) - (HVR-L2) - (LC-FR3) - (HVR-L3) - (LC-FR4).
20. Antibody or antibody fragment, according to claim 19, characterized by the fact that one or more of the framework sequences are as follows: HC-FR1 is EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 4); HC-FR2 is WVRQAPGKGLEWVS (SEQ ID NO: 5); HC-FR3 is RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 6); HC-FR4 is WGQGTLVTVSS (SEQ ID NO: 7).
21. Antibody or antibody fragment, according to claim 19, characterized by the fact that one or more of the framework sequences are as follows: LC-FR1 is QSALTQPASVSGSPGQSITISC (SEQ ID NO: 11); LC-FR2 is WYQQHPGKAPKLMIY (SEQ ID NO: 12); LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC; (SEQ ID NO: 13); LC-FR4 is FGTGTKVTVL (SEQ ID NO: 14).
22. The antibody or antibody fragment according to claim 19, characterized in that: (a) the variable heavy chain framework sequences are as follows: (i) HC-FR1 is EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 4) ; (ii) HC-FR2 is WVRQAPGKGLEWVS (SEQ ID NO: 5); (iii) HC-FR3 is RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 6); (iv) HC-FR4 is WGQGTLVTVSS (SEQ ID NO: 7); and (b) the variable light chain framework sequences are as follows: (i) LC-FR1 is QSALTQPASVSGSPGQSITISC (SEQ ID NO: 11);
(ii) LC-FR2 is WYQQHPGKAPKLMIY (SEQ ID NO: 12); (iii) LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC (SEQ ID NO: 13); (iv) LC-FR4 is FGTGTKVTVL (SEQ ID NO: 14).
23. The antibody or antibody fragment according to claim 22, characterized in that it further comprises at least one CH1 domain.
24. The antibody or antibody fragment according to claim 22 or 23, characterized in that it further comprises a CL domain.
25. The antibody or antibody fragment according to claim 22, characterized in that it further comprises a CH1 domain, a CH2 and a CH3.
26. The antibody or antibody fragment according to claim 22, characterized in that it further comprises a human or murine constant region.
27. Antibody or antibody fragment, according to claim 26, characterized by the fact that the constant region is selected from the group consisting of lgG1, lgG2, lgG3 and lgG4.
28. Antibody or antibody fragment, according to claim 27, characterized by the fact that the constant region is IgG1.
29. Antibody or antigen-binding fragment thereof, characterized by the fact that it comprises a sequence of the variable region of the heavy chain and one of the light chain, where: (a) the heavy chain comprises an HVR-H1, an HVR - H2 and an HVR-H3, having at least 80% total sequence identity to SYIMM (SEQ ID NO: 15), SIYPSGGITFYADTVKG (SEQ ID NO: 16) and IKLGTVTTVDY (SEQ ID NO: 17), respectively, and ( b) the light chain comprises an HVR-L1, an HVR-L2 and an HVR-L3, having at least 80% total sequence identity to TGTSSDVGGYNYVS (SEQ ID NO: 18), DVSNRPS (SEQ ID NO: 19) and SSYTSSSTRV (SEQ ID NO: 20), respectively.
30. Antibody or antibody fragment according to claim 29, characterized by the fact that the sequence identity is at least 90%.
31. Antibody or antibody fragment, according to claim 29, characterized by the fact that, comparing with the sequences of HVR-H1 (SEQ ID NO: 15), HVR-H2 (SEQ ID NO: 16) and HVR- H3 (SEQ ID NO: 17), at least those amino acids that remain unchanged are highlighted by underlining as follows: (a) in HVR-H1 SYIMM (SEQ ID NO: 15), (b) in HVR-H2 SIYPSGGITFYADTVKG ( SEQ ID NO: 16), (c) in HVR-H3 IKLGTVTTVDY (SEQ ID NO: 17); and furthermore, comparing with the sequences of HVR-L1 (SEQ ID NO: 18), HVR-L2 (SEQ ID NO: 19) and HVR-L3 (SEQ ID NO: 20 at least those amino acids that remain unchanged are highlighted underlining as follows: (a) HVR-L1 TGTSSDVGGYNYVS (SEQ ID NO: 18) (b) HVR-L2 DVSNRPS (SEQ ID NO: 19) (c) HVR-L3 SSYTSSSTRV (SEQ ID NO: 20).
32. Antibody or antibody fragment according to any one of claims 29 to 31, characterized by the fact that it further comprises: (a) HC-FR1, HC-FR2 heavy chain (VH) variable region framework sequences, HC-FR3 and HC-FR4, juxtaposed between the HVRs, thus forming the sequence of the formula: (HC-FR1) - (HVR-H1) - (HC-FR2) - (HVR-H2) - (HC-FR3) - (HVR-H3) - (HC-FR4), and (b) light chain variable region (VL) framework sequences LC-FR1, LC-FR2, LC-FR3 and LC-FR4, juxtaposed between
HVRs, thus forming the sequence of the formula: (LC-FR1) - (HVR-L1) - (LC-FR2) - (HVR-L2) - (LC-FR3) - (HVR-L3) - (LC-FR4 ).
33. Antibody or antibody fragment, according to claim 32, characterized by the fact that the VH and VL framework sequences are derived from human germline sequences.
34. Antibody or antibody fragment, according to claim 32, characterized by the fact that the VH framework sequences are as follows: HC-FR1 is EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 4); HC-FR2 is WVRQAPGKGLEWVS (SEQ ID NO: 5); HC-FR3 is RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 6); HC-FR4 is WGQGTLVTVSS (SEQ ID NO: 7).
35. Antibody or antibody fragment according to claim 32, characterized in that the VL framework sequences are as follows: LC-FR1 is QSALTQPASVSGSPGQSITISC (SEQ ID NO: 11); LC-FR2 is WYQQHPGKAPKLMIY (SEQ ID NO: 12); LC-FR3 is GVSNRFSGSKSGNTASLTISGLQAEDEADYYC (SEQ ID NO: 13); LC-FR4 is FGTGTKVTVL (SEQ ID NO: 14).
36. Isolated anti-PD-L1 antibody or antigen binding fragment, characterized by the fact that it comprises a sequence of the variable region of the heavy chain and a sequence of the variable region of the light chain, being that: (a ) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVR- QAPGKGLEWVSSIYPSGGITFYADTVKGRFTIS-
RDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQ GTLVTVSS (SEQ ID NO: 24), and (b) the light chain sequence of sequence identity is at least 85% to the sequence of the light chain: QSALTQPASVSGSPGQSITISCTGTSSDVGGYNY- VSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTIS- GLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL (SEQ ID NO: 25).
37. Antigen or antibody-binding fragment according to claim 36, characterized by the fact that the sequence identity is at least 90%.
38. Isolated anti-PD-L1 antibody or antigen-binding fragment thereof, characterized by the fact that it comprises a sequence of the variable region of the heavy chain and sequence of the variable region of the light chain, in which: (a) the chain heavy comprises the sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVR- QAPGKGLEWVSSIYPSGGITFYADTVKGRFTIS- RDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDWGQG- TLVTVSS (SEQ ID NO: 24), and (b) the light chain comprises the sequence: QSALTQPASVSGSPGQSITISCTGTSSDVGGYNY- VSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTIS- GLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL (SEQ ID NO: 25).
39. Antibody according to claim 38, characterized in that the antibody further comprises a CH1 domain, a CH2, a CH3 and a CL.
40. Antibody according to any one of claims 17 to 39, characterized in that the antibody binds to human, mouse or cynomolgus monkey PD-L1.
41. Antibody according to any of the claims
sections 17 to 40, characterized by the fact that the antibody is able to block the interaction between human PD, L1 or mouse cynomolgus monkeys and the respective human PD, 1, mouse or cynomolgus monkey receptors.
42. Antibody according to any one of claims 17 to 41, characterized in that the antibody binds to human PD-L1 with a KD of 5x10-9 M or less.
43. Isolated anti-PD-L1 antibody or antigen-binding fragment thereof, characterized by the fact that it binds to a functional epitope comprising residues Y56 and D61 of human PD-L1 (SEQ ID NO: 28).
44. Isolated anti-PD-L1 antibody or antigen-binding fragment according to claim 43, characterized by the fact that the functional epitope further comprises residues E58, E60, Q66, R113 and M115 of human PD-L1 ( SEQ ID NO: 28).
45. Isolated anti-PD-L1 antibody or antigen-binding fragment thereof, characterized by the fact that it binds to a conformational epitope comprising residues 54-66 and 112-122 of human PD-L1 (SEQ ID NO: 28) .
46. Isolated anti-PD-L1 antibody or antigen-binding fragment thereof, characterized by the fact that the antibody cross-competes for binding to PD-L1 with an antibody or antigen-binding fragment, as defined in any of the claims 19 to 51.
47. Composition, characterized by the fact that it comprises the anti-PD-L1 antibody or antigen binding fragment, as defined in any one of claims 17 to 46, and at least one pharmaceutically acceptable carrier.
48. Isolated nucleic acid, characterized by the fact that it encodes the polypeptide as defined in any of the claims
1 to 16.
49. Isolated nucleic acid, characterized by the fact that it encodes a light chain or heavy chain sequence of an anti-PD-L1 antibody or antigen-binding fragment, as defined in any of claims 17 to 46.
50. Nucleic acid according to claim 49, characterized by the fact that it is SEQ ID NO: 30 for the heavy chain and SEQ ID NO: 31 for the light chain.
51. Vector, characterized by the fact that it comprises nucleic acid, as defined in any one of claims 48 to 50.
52. Host cell, characterized by the fact that it comprises the vector, as defined in claim 51.
53. Process for producing an anti-PD-L1 antibody or antigen-binding fragment thereof, characterized by the fact that it comprises the culture of the host cell, as defined in claim 52, under conditions suitable for the expression of the vector that encodes the anti-PD-L1 antibody or antigen binding fragment, and recovery of the antibody or fragment.
54. Kit of parts, characterized by the fact that it comprises the composition, as defined in claim 47, and at least one additional therapeutic agent or vaccine.
55. Kit of parts according to claim 54, characterized by the fact that the additional therapeutic agent is a chemotherapeutic agent.
56. Pharmaceutical composition for the treatment of cancer, characterized by the fact that it comprises an anti-PD-L1 antibody that induces antibody dependent cell mediated cytotoxicity (ADCC).
57. Pharmaceutical composition according to claim
tion 56, characterized by the fact that the anti-PD-L1 antibody constant region is IgG1.
58. Pharmaceutical composition according to claim 57, characterized in that the anti-PD-L1 antibody is an antibody, as defined in any one of claims 17 to 46.
59. Pharmaceutical composition for the treatment of cancer, characterized by the fact that it comprises the administration to an individual in need of an effective amount of the composition, as defined in claim 47.
60. Pharmaceutical composition according to any of claims 56 to 59, characterized by the fact that cancer is selected from the group consisting of: breast, lung, colon, ovarian, melanoma, bladder, kidney, liver, salivary, stomach, gloma, thyroid, thymic, epithelial, head and neck cancers, gastric and pancreatic cancer.
61. Pharmaceutical composition for the treatment of a dysfunctional T-cell disorder, characterized by the fact that it comprises the composition, as defined in claim 47, for a patient suffering from a dysfunctional T-cell disorder.
62. Pharmaceutical composition according to claim 61, characterized by the fact that the dysfunctional T cell disorder is tumor immunity.
63. Pharmaceutical composition according to claim 62, characterized by the fact that tumor immunity results from a cancer selected from the group consisting of: breast, lung, colon, ovarian, melanoma, bladder, kidney, liver, salivary, stomach, gliomas, thyroid, thymic, epithelial, head and neck cancers, gastric and pancreatic cancer.
64. Pharmaceutical composition according to any one of claims 56 to 63, characterized by the fact that it
it also includes the administration of at least one additional therapeutic agent or vaccine.
65. Pharmaceutical composition according to any one of claims 56 to 64, characterized by the fact that the method further comprises the application of a treatment regimen selected from the group consisting of: surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, inhibition of angiogenesis and palliative care.

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2020-11-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2021-04-20| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-09-08| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021 |

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2021-09-21| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201161563903P| true| 2011-11-28|2011-11-28|

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US61/563,903|2011-11-28|

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PCT/EP2012/004822|WO2013079174A1|2011-11-28|2012-11-21|Anti-pd-l1 antibodies and uses thereof|

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