US2015322153A1PendingUtilityA1
Anti-pd-l1 antibodies and articles of manufacture
Est. expiryDec 9, 2028(~2.4 yrs left)· nominal 20-yr term from priority
Inventors:Bryan IrvingHenry ChiuHeather MaeckerSanjeev MariathasanSophie M. LeharYan WuJeanne Cheung
A61P 37/02A61P 31/12A61P 35/00A61P 31/04A61P 31/00A61P 43/00A61P 37/00A61P 33/02A61P 31/10A61P 37/04A61P 33/00C07K 16/1145C07K 16/30C07K 2317/565A61K 2039/507A61K 39/3955A61K 39/39558C07K 2317/73A61K 2039/505C07K 2317/14C07K 16/28C07K 16/2827C07K 2317/74C07K 2317/52A61K 45/06A61K 31/7068C07K 2317/567C07K 16/22C07K 2317/71C07K 2317/76C07K 2317/56C07K 2317/24C07K 2317/92C07K 16/3046A61K 39/00Y02A50/30A61K 2300/00
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Claims
Abstract
The present application relates to anti-PD-L1 antibodies, which have therapeutic use to enhance T-cell function to upregulate cell-mediated immune responses and for the treatment of T cell dysfunctional disorders, including infection (e.g., acute and chronic) and tumor immunity.
Claims
exact text as granted — not AI-modified1 . An isolated heavy chain variable region polypeptide comprising an HVR-H1, HVR-H2 and HVR-H3 sequence, wherein:
(a) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1); (b) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2); (c) the HVR-H3 sequence is RHWPGGFDY (SEQ ID NO:3); further wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S.
2 . The polypeptide of claim 1 wherein X 1 is D; X 2 is S and X 3 is T.
3 . The polypeptide of claim 1 further comprising variable region heavy chain framework sequences juxtaposed between the HVRs according to the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4).
4 . The polypeptide of claim 3 wherein the framework sequences are derived from human consensus framework sequences.
5 . The polypeptide of claim 4 wherein the framework sequences are VH subgroup III consensus framework.
6 . The polypeptide of claim 5 wherein one or more of the framework sequences is the following:
HC-FR1 is
(SEQ ID NO: 4)
EVQLVESGGGLVQPGGSLRLSCAAS
HC-FR2 is
(SEQ ID NO: 5)
WVRQAPGKGLEWV
HC-FR3 is
(SEQ ID NO: 6)
RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR
HC-FR4 is
(SEQ ID NO: 7)
WGQGTLVTVSA.
7 . The isolated heavy chain polypeptide of claim 1 in combination with a variable region light chain comprising an HVR-L1, HVR-L2 and HVR-L3, wherein:
(a) the HVR-L1 sequence is RASQX4X5X6TX7X8A (SEQ ID NOs:8);
(b) the HVR-L2 sequence is SASX9LX10S, and (SEQ ID NOs:9);
(c) the HVR-L3 sequence is QQX11X12X13X14PX15T (SEQ ID NOs:10);
further wherein: X 4 is D or V; X 5 is V or I; X 6 is S or N; X 7 is A or F; X 8 is V or L; X 9 is F or T; X 10 is Y or A; X 11 is Y, G, F, or S; X 12 is L, Y, F or W; X 13 is Y, N, A, T, G, F or I; X 14 is H, V, P, T or I; X 15 is A, W, R, P or T.
8 . The polypeptide of claim 7 wherein X 4 is D; X 5 is V; X 6 is 5; X 7 is A; X 8 is V; X 9 is F; X 10 is Y; X 11 is Y; X 12 is L; X 13 is Y; X 14 is H; X 15 is A.
9 . The polypeptide of claim 7 further comprising variable region light chain framework sequences juxtaposed between the HVRs according to the formula: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4).
10 . The polypeptide of claim 9 wherein the framework sequences are derived from human consensus framework sequences.
11 . The polypeptide of claim 10 wherein the framework sequences are VL kappa I consensus framework.
12 . The polypeptide of claim 11 wherein one or more of the framework sequences is the following:
LC-FR1 is
(SEQ ID NO: 11)
DIQMTQSPSSLSASVGDRVTITC;
LC-FR2 is
(SEQ ID NO: 12)
WYQQKPGKAPKLLIY;
LC-FR3 is
(SEQ ID NO: 13)
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC;
LC-FR4 is
(SEQ ID NO: 14)
FGQGTKVEIKR.
13 . An isolated anti-PD-L1 antibody or antigen binding fragment comprising a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX1SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX2PYGGSX3YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX4X5X6TX7X8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX9LX10S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX11X12X13X14PX15T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
14 . The antibody or antibody fragment of claim 13 wherein X 1 is D; X 2 is S and X 3 is T.
15 . The antibody or antibody fragment of claim 13 , wherein X 4 =D, X 5 =V, X 6 =S, X 7 =A and X 8 =V, X 9 =F, and X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
16 . The antibody or antibody fragment of claim 13 , wherein X 1 =D, X 2 =S and X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A and X 8 =V, X 9 =F, and X 10 —Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
17 . The antibody or antibody fragment of any of claims 13 - 16 further comprising:
(a) variable region heavy chain framework sequences juxtaposed between the HVRs according to the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and
(b) variable region light chain framework sequences juxtaposed between the HVRs according to the formula: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4).
18 . The antibody or antibody fragment of claim 17 wherein the framework sequences are derived from human consensus framework sequences.
19 . The antibody or antibody fragment of claim 18 wherein the variable region heavy chain framework sequences are VH subgroup III consensus framework.
20 . The antibody or antibody fragment of claim 19 wherein one or more of the framework sequences is the following:
HC-FR1 is
(SEQ ID NO: 4)
EVQLVESGGGLVQPGGSLRLSCAAS;
HC-FR2 is
(SEQ ID NO: 5)
WVRQAPGKGLEWV;
HC-FR3 is
(SEQ ID NO: 6)
RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;
HC-FR4 is
(SEQ ID NO: 7)
WGQGTLVTVSA.
21 . The antibody or antibody fragment of claim 18 wherein the variable region light chain framework sequences are VL kappa I consensus framework.
22 . The antibody or antibody fragment of claim 21 wherein one or more of the framework sequences is the following:
LC-FR1 is
(SEQ ID NO: 11)
DIQMTQSPSSLSASVGDRVTITC;
LC-FR2 is
(SEQ ID NO: 12)
WYQQKPGKAPKLLIY;
LC-FR3 is
(SEQ ID NO: 13)
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC,;
and
LC-FR4 is
(SEQ ID NO: 14)
FGQGTKVEIKR.
23 . The antibody of or antibody fragment of claim 18 wherein:
(a) the variable heavy chain framework sequences are the following:
(i) HC-FR1 is
(SEQ ID NO: 4)
EVQLVESGGGLVQPGGSLRLSCAAS;
(ii) HC-FR2 is
(SEQ ID NO: 5)
WVRQAPGKGLEWV;
(iii) HC-FR3 is
(SEQ ID NO: 6)
RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;
(iv) HC-FR4 is
(SEQ ID NO: 7)
WGQGTLVTVSA;;
and
(b) the variable light chain framework sequences are the following:
(i) LC-FR1 is
(SEQ ID NO: 11)
DIQMTQSPSSLSASVGDRVTITC;
(ii) LC-FR2 is
(SEQ ID NO: 12)
WYQQKPGKAPKLLIY;
(iii) LC-FR3 is
(SEQ ID NO: 13)
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC;
(iv) LC-FR4 is
(SEQ ID NO: 14)
FGQGTKVEIKR.
24 . The antibody or antibody fragment of claim 23 further comprising a human constant region.
25 . The antibody or antibody fragment of claim 24 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
26 . The antibody of antibody fragment of claim 25 wherein the constant region is IgG1.
27 . The antibody or antibody fragment of claim 23 , further comprising murine constant region.
28 . The antibody or antibody fragment of claim 27 wherein the constant region is selected from the group consisting of IgG1, IgG2A, IgG2B and IgG3.
29 . The antibody or antibody fragment of claim 28 , wherein the constant region is IgG2A.
30 . The antibody or antibody fragment of claim 25 or 28 having reduced or minimal effector function.
31 . The antibody or antibody fragment of claim 30 , wherein the minimal effector function results from an effector-less Fc mutation.
32 . The antibody or antibody fragment of claim 31 , wherein the effector-less Fc mutation is N297A.
33 . The antibody or antibody fragment of claim 31 , wherein the effector-less Fc mutation is D265A/N297A.
34 . The antibody or antibody fragment of claim 30 , wherein the minimal effector function results from aglycosylation.
35 . An antibody or antigen binding fragment comprising a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and an HVR-H3, having at least 85% overall sequence identity to GFTFSDSWIH (SEQ ID NO:15), AWISPYGGSTYYADSVKG (SEQ ID NO:16) and RHWPGGFDY (SEQ ID NO:3), respectively, and (b) the light chain comprises an HVR-L1, HVR-L2 and an HVR-L3, having at least 85% overall sequence identity to RASQDVSTAVA (SEQ ID NO:17), SASFLYS (SEQ ID NO:18) and QQYLYHPAT (SEQ ID NO:19), respectively.
36 . The antibody or antibody fragment of claim 35 , wherein the sequence identity is at least 90%.
37 . The antibody or antibody fragment of claim 36 further comprising:
(a) variable region heavy chain (VH) framework sequences juxtaposed between the HVRs according to the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and
(b) variable region light chain (VL) framework sequences juxtaposed between the HVRs according to the formula: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4).
38 . The antibody or antibody fragment of claim 37 , further comprising a VH and VL framework region derived from a human consensus sequence.
39 . The antibody or antibody fragment of claim 38 , wherein the VH framework sequence is derived from a Kabat subgroup I, II, or III sequence.
40 . The antibody or antibody fragment of claim 39 , wherein the VH framework sequence is a Kabat subgroup III consensus framework sequence.
41 . The antibody or antibody fragment of claim 40 wherein the VH framework sequences are the following:
HC-FR1 is
(SEQ ID NO: 4)
EVQLVESGGGLVQPGGSLRLSCAAS;
HC-FR2 is
(SEQ ID NO: 5)
WVRQAPGKGLEWV;
HC-FR3 is
(SEQ ID NO: 6)
RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;
HC-FR4 is
(SEQ ID NO: 7)
WGQGTLVTVSA.
42 . The antibody or antibody fragment of claim 38 , wherein the VL framework sequence is derived from a Kabat kappa I, II, III or IV subgroup sequence.
43 . The antibody or antibody fragment of claim 42 wherein the VL framework sequence is a Kabat kappa I consensus framework sequence.
44 . The antibody or antibody fragment of claim 43 wherein the VL framework sequences are the following:
LC-FR1 is
(SEQ ID NO: 11)
DIQMTQSPSSLSASVGDRVTITC;
LC-FR2 is
(SEQ ID NO: 12)
WYQQKPGKAPKLLIY;
LC-FR3 is
(SEQ ID NO: 13)
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC;
LC-FR4 is
(SEQ ID NO: 14)
FGQGTKVEIKR.
45 . An isolated anti-PD-L1 antibody or antigen binding fragment comprising a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPG KGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARR HWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain sequence has at least 85% sequence identity to the light chain sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGK APKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
46 . The antibody or antigen binding fragment of claim 45 , wherein the sequence identity is at least 90%.
47 . An isolated anti-PD-L1 antibody or antigen binding fragment comprising a heavy chain and light chain variable region sequence, wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
48 . A composition comprising the anti-PD-L1 antibody or antigen binding fragment of any of claims 13 - 47 and at least one pharmaceutically-acceptable carrier.
49 . An isolated nucleic acid encoding the polypeptide of any of claims 1 - 11 .
50 . An isolated nucleic acid encoding a light chain or a heavy chain variable sequence of an anti-PD-L1 antibody or antigen binding fragment, wherein:
(a) the heavy chain further comprises and HVR-H1, HVR-H2 and an HVR-H3 sequence having at least 85% sequence identity to GFTFSDSWIH (SEQ ID NO:15), AWISPYGGSTYYADSVKG (SEQ ID NO:16) and RHWPGGFDY (SEQ ID NO:3), respectively, or (b) the light chain further comprises an HVR-L1, HVR-L2 and an HVR-L3 sequence having at least 85% sequence identity to RASQDVSTAVA (SEQ ID NO:17), SASFLYS (SEQ ID NO:18) and QQYLYHPAT (SEQ ID NO:19), respectively.
51 . The nucleic acid of claim 50 , wherein sequence identity is 90%.
52 . The nucleic acid of claim 50 , wherein the anti-PD-L1 antibody further comprises a VL and a VH framework region derived from a human consensus sequence.
53 . The nucleic acid of claim 52 , wherein the VH sequence is derived from a Kabat subgroup I, II, or III sequence.
54 . The nucleic acid of claim 52 , wherein the VL sequence is derived from a Kabat kappa I, II, III or IV subgroup sequence.
55 . The nucleic acid of claim 50 , wherein the anti-PD-L1 antibody comprises a constant region derived from a murine antibody.
56 . The nucleic acid of claim 50 , wherein the anti-PD-L1 antibody comprises a constant region derived from a human antibody.
57 . The nucleic acid of claim 56 , wherein the constant region is IgG1.
58 . The nucleic acid of claim 57 , having reduced or minimal effector function.
59 . The nucleic acid of claim 58 , wherein the minimal effector function results from an effector-less Fc mutation.
60 . The nucleic acid of claim 59 , wherein the effector-less Fc mutation is N297A.
61 . A vector comprising the nucleic acid of any of claims 49 - 60 .
62 . A host cell comprising the vector of claim 61 .
63 . The host cell of claim 62 which is eukaryotic.
64 . The host cell of claim 63 which is mammalian.
65 . The host cell of claim 64 which is a Chinese Hamster Ovary (CHO) cell.
66 . The host cell of claim 62 which is prokaryotic.
67 . The host cell of claim 66 which is E. coli.
68 . A process for making an anti-PD-L1 antibody comprising culturing the host cell of any of claims 62 - 67 under conditions suitable for the expression of the vector encoding the anti-PD-L1 antibody or antigen binding fragment, and recovering the antibody or fragment.
69 . An article of manufacture comprising the composition of claim 48 and at least one BNCA molecule.
70 . An article of manufacture comprising the composition of claim 48 and at least one chemotherapeutic agent.
71 . The article of manufacture according to claim 70 , wherein the chemotherapeutic agent is gemcitabine.
72 . An article of manufacture comprising the composition of claim 48 and at least one agonist to a positive costimulatory molecule.
73 . The article of manufacture according to claim 72 , further comprising a BNCA antagonist.
74 . An article of manufacture comprising the composition of claim 48 and at least one antibiotic.
75 . The article of manufacture according to claim 74 , wherein the antibiotic is an anti-viral agent.
76 . The article of manufacture according to claim 75 , wherein anti-viral agent is a reverse transcriptase inhibitor.
77 . The article of manufacture according to claim 76 , wherein the reverse transcriptase inhibitor is a polymerase inhibitor.
78 . The article of manufacture according to claim 75 , wherein the anti-viral agent is a protease inhibitor.
79 . An article of manufacture comprising the composition of claim 48 and at least one vaccine.
80 - 95 . (canceled)
96 . A method of treating cancer comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof, wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSDSWIH (SEQ ID NO:15);
(ii) the HVR-H2 sequence is AWISPYGGSTYYADSVKG (SEQ ID NO:16);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQDVSTAV (SEQ ID NOs:17);
(v) the HVR-L2 sequence is SASFLYS (SEQ ID NOs:18);
(vi) the HVR-L3 sequence is QQYLYHPAT (SEQ ID NOs:19).
97 . The method of claim 96 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
98 . The method of claim 96 , wherein the method further comprises administering an effective amount of a second anti-cancer agent.
99 . A method of treating infection comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof, wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSDSWIH (SEQ ID NO:15);
(ii) the HVR-H2 sequence is AWISPYGGSTYYADSVKG (SEQ ID NO:16);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQDVSTAV (SEQ ID NOs:17);
(v) the HVR-L2 sequence is SASFLYS (SEQ ID NOs:18);
(vi) the HVR-L3 sequence is QQYLYHPAT (SEQ ID NOs:19).
100 . The method of claim 99 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
101 . The method of claim 99 , wherein the infection results from a pathogen selected from the group consisting of bacteria, virus, fungi and protozoan.
102 . The method of claim 101 , wherein the pathogen is a bacteria and the method further comprises the administration of an anti-bacterial agent.
103 . The method of claim 101 , wherein the pathogen is virus and the method further comprises the administration of an anti-viral agent.
104 . The method of claim 101 , wherein the pathogen is a fungi and the method further comprises the administration of an anti-fungal agent.
105 . The method of claim 101 , wherein the pathogen is a protozoan and the method further comprising the administration of an anti-protozoan agent.
106 . A method of enhancing an immune response comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof.
107 . The method of claim 106 , wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
108 . The method of claim 107 , wherein X 1 =D, X 2 =S, X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A, X 8 =V, X 9 =F, X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
109 . The method of claim 108 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
110 . The method of claim 106 , wherein the immune response is a cell-mediated immune response.
111 . The method of claim 110 , wherein the cell-mediated immune response is a T-cell mediated response.
112 . The method of claim 80 , wherein the enhanced T-cell function is stimulating a T-cell to have sustained or amplified biological function, renewing or reactivating exhausted or inactive T-cells, increasing antigen responsiveness or increasing T-cell proliferation.
113 . A method of increasing T-cell proliferation comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof.
114 . The method of claim 113 , wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
115 . The method of claim 114 , wherein X 1 =D, X 2 =S, X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A, X 8 =V, X 9 =F, X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
116 . The method of claim 115 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
117 . A method of rendering dysfunctional T-cells non-dysfunctional comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof.
118 . The method of claim 117 , wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
119 . The method of claim 118 , wherein X 1 =D, X 2 =S, X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A, X 8 =V, X 9 =F, X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
120 . The method of claim 119 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
121 . A method of treating a T-cell dysfunctional disorder comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof, wherein the disorder is associated with increased signaling through PD-1.
122 . The method of claim 121 , wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
123 . The method of claim 122 , wherein X 1 =D, X 2 =S, X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A, X 8 =V, X 9 =F, X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
124 . The method of claim 123 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
125 . A method of treating a T-cell dysfunctional disorder comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof, wherein the disorder is one in which the T-cells are anergic.
126 . The method of claim 125 , wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
127 . The method of claim 126 , wherein X 1 =D, X 2 =S, X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A, X 8 =V, X 9 =F, X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
128 . The method of claim 127 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
129 . A method of treating a T-cell dysfunctional disorder comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof, wherein the disorder is one in which the T-cells have decreased ability to secrete cytokines.
130 . The method of claim 129 , wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
131 . The method of claim 130 , wherein X 1 =D, X 2 =S, X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A, X 8 =V, X 9 =F, X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
132 . The method of claim 131 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
133 . A method of treating a T-cell dysfunctional disorder comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof, wherein the disorder is one in which the T-cells have decreased ability to proliferate.
134 . The method of claim 133 , wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
135 . The method of claim 134 , wherein X 1 =D, X 2 =S, X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A, X 8 =V, X 9 =F, X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
136 . The method of claim 135 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
137 . A method of treating a T-cell dysfunctional disorder comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof, wherein the disorder is one in which the T-cells have decreased ability to execute cytolytic activity.
138 . The method of claim 137 , wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
139 . The method of claim 138 , wherein X 1 =D, X 2 =S, X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A, X 8 =V, X 9 =F, X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
140 . The method of claim 139 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
141 . A method of treating one or more symptoms associated with a T-cell dysfunctional disorder comprising administering an effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof.
142 . The method of claim 141 , wherein the antibody or antibody fragment comprises a heavy chain and a light chain variable region sequence, wherein:
(a) the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
(i) the HVR-H1 sequence is GFTFSX 1 SWIH (SEQ ID NO:1);
(ii) the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG (SEQ ID NO:2);
(iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:3);
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(iv) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 (SEQ ID NOs:8);
(v) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(vi) the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T (SEQ ID NOs:10);
wherein: X 1 is D or G; X 2 is S or L; X 3 is T or S; X 4 may be D or V; X 5 may be V or I; X 6 may be S or N; X 7 may be A or F; X 8 may be V or L; X 9 may be F or T; X 10 may be Y or A; X 11 may be Y, G, F, or S; X 12 may be L, Y, F or W; X 13 may be Y, N, A, T, G, F or I; X 14 may be H, V, P, T or I; X 15 may be A, W, R, P or T.
143 . The method of claim 142 , wherein X 1 =D, X 2 =S, X 3 =T, X 4 =D, X 5 =V, X 6 =S, X 7 =A, X 8 =V, X 9 =F, X 10 =Y, X 11 =Y, X 12 =L, X 13 =Y, X 14 =H and X 15 =A.
144 . The method of claim 143 , wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).Join the waitlist — get patent alerts
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