US2013045200A1PendingUtilityA1
Methods of using anti-pd-l1 antibodies and their use to treat infection resulting from t-cell dysfunction
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 43/00A61P 33/02A61P 37/04A61P 37/02A61P 37/00A61P 35/00A61P 31/04A61P 31/00A61P 31/10A61P 33/00A61P 31/12C07K 16/1145C07K 2317/71A61K 39/39558C07K 2317/74C07K 16/22A61K 31/7068C07K 16/2827C07K 2317/24C07K 16/30C07K 2317/56C07K 2317/52C07K 2317/73C07K 2317/14A61K 45/06C07K 2317/565A61K 2039/507A61K 39/3955C07K 16/3046A61K 2039/505C07K 2317/92C07K 16/28C07K 2317/567C07K 2317/76A61K 39/00Y02A50/30A61K 2300/00
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Claims
Abstract
The present application relates to methods of using anti-PD-L1 antibodies 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 . A method of enhancing T-cell function 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:
(SEQ ID NO: 1)
(i)
the HVR-H1 sequence is GFTFSX 1 SWIH;
(SEQ ID NO: 2)
(ii)
the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG;
(SEQ ID NO: 3)
(iii)
the HVR-H3 sequence is RHWPGGFDY,;
and
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(SEQ ID NOs: 8)
(iv)
the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 A;
(SEQ ID NOs: 9)
(v)
the HVR-L2 sequence is SASX 9 LX 10 S;
(SEQ ID NOs: 10)
(vi)
the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T;
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.
2 . The method of claim 1 wherein X 1 is D; X 2 is S and X 3 is T.
3 . The method of claim 1 , 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.
4 . The method of claim 1 , 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.
5 . The method of claim 4 , wherein the encoded variable region heavy chain framework sequences are juxtaposed between the HVRs according to the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4) and/or the encoded 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).
6 . The method of claim 5 , wherein the framework sequences are human.
7 . The method of claim 6 wherein the variable heavy chain framework sequences are VH subgroup III consensus framework.
8 . The method of claim 6 wherein the variable region light chain framework sequences are VL kappa I consensus framework.
9 . The method of claim 7 wherein one or more of the heavy chain framework sequences is the following:
(SEQ ID NO: 4)
HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS;
(SEQ ID NO: 5)
HC-FR2 is WVRQAPGKGLEWV;
(SEQ ID NO: 6)
HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;
(SEQ ID NO: 7)
HC-FR4 is WGQGTLVTVSA.
10 . The method of claim 8 wherein one or more of the light chain framework sequences is the following:
(SEQ ID NO: 11)
LC-FR1 is DIQMTQSPSSLSASVGDRVTITC;
(SEQ ID NO: 12)
LC-FR2 is WYQQKPGKAPKLLIY;
(SEQ ID NO: 13)
LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC,;
and
(SEQ ID NO: 14)
LC-FR4 is FGQGTKVEIKR.
11 . The method of claim 6 wherein:
(a) one or more of the heavy chain framework sequences is the following:
(SEQ ID NO: 4)
HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS;
(SEQ ID NO: 5)
HC-FR2 is WVRQAPGKGLEWV;
(SEQ ID NO: 6)
HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;
(SEQ ID NO: 7)
HC-FR4 is WGQGTLVTVSA;
and
(b) one or more of the light chain framework sequences is the following:
(SEQ ID NO: 11)
LC-FR1 is DIQMTQSPSSLSASVGDRVTITC;
(SEQ ID NO: 12)
LC-FR2 is WYQQKPGKAPKLLIY;
(SEQ ID NO: 13)
LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC,;
and
(SEQ ID NO: 14)
LC-FR4 is FGQGTKVEIKR.
12 . The method of claim 11 further comprising a human constant region.
13 . The method of claim 12 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
14 . The method of claim 13 wherein the constant region is IgG1.
15 . The method of claim 14 having reduced or minimal effector function.
16 . The method of claim 15 , wherein the minimal effector function results from an effector-less Fc mutation.
17 . The method of claim 16 , wherein the effector-less Fc mutation is N297A.
18 . The method of claim 16 , wherein the effector-less Fc mutation is D265A/N297A.
19 . The method of claim 15 , wherein the minimal effector function results from aglycosylation.
20 . A method of treating a T-cell dysfunctional disorder resulting from an 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:
(SEQ ID NO: 1)
(i)
the HVR-H1 sequence is GFTFSX 1 SWIH;
(SEQ ID NO: 2)
(ii)
the HVR-H2 sequence is AWIX 2 PYGGSX 3 YYADSVKG;
(SEQ ID NO: 3)
(iii)
the HVR-H3 sequence is RHWPGGFDY,;
and
(b) the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
(SEQ ID NOs: 8)
(iv)
the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 A;
(SEQ ID NOs: 9)
(v)
the HVR-L2 sequence is SASX 9 LX 10 S;
(SEQ ID NOs: 10)
(vi)
the HVR-L3 sequence is QQX 11 X 12 X 13 X 14 PX 15 T;
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.
21 . The method of claim 20 wherein X 1 is D; X 2 is S and X 3 is T.
22 . The method of claim 20 , 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.
23 . The method of claim 20 , 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.
24 . The method of claim 23 , wherein the encoded variable region heavy chain framework sequences are juxtaposed between the HVRs according to the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4) and/or the encoded 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).
25 . The method of claim 24 , wherein the framework sequences are human.
26 . The method of claim 25 wherein the variable heavy chain framework sequences are VH subgroup III consensus framework.
27 . The method of claim 25 wherein the variable region light chain framework sequences are VL kappa I consensus framework.
28 . The method of claim 26 wherein one or more of the heavy chain framework sequences is the following:
(SEQ ID NO: 4)
HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS;
(SEQ ID NO: 5)
HC-FR2 is WVRQAPGKGLEWV;
(SEQ ID NO: 6)
HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;
(SEQ ID NO: 7)
HC-FR4 is WGQGTLVTVSA.
29 . The method of claim 27 wherein one or more of the light chain framework sequences is the following:
(SEQ ID NO: 11)
LC-FR1 is DIQMTQSPSSLSASVGDRVTITC;
(SEQ ID NO: 12)
LC-FR2 is WYQQKPGKAPKLLIY;
(SEQ ID NO: 13)
LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC,;
and
(SEQ ID NO: 14)
LC-FR4 is FGQGTKVEIKR.
30 . The method of claim 27 wherein:
(a) one or more of the heavy chain framework sequences is the following:
(SEQ ID NO: 4)
HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS;
(SEQ ID NO: 5)
HC-FR2 is WVRQAPGKGLEWV;
(SEQ ID NO: 6)
HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;
(SEQ ID NO: 7)
HC-FR4 is WGQGTLVTVSA;
and
(b) one or more of the light chain framework sequences is the following:
(SEQ ID NO: 11)
LC-FR1 is DIQMTQSPSSLSASVGDRVTITC;
(SEQ ID NO: 12)
LC-FR2 is WYQQKPGKAPKLLIY;
(SEQ ID NO: 13)
LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC,;
and
(SEQ ID NO: 14)
LC-FR4 is FGQGTKVEIKR.
31 . The method of claim 30 further comprising a human constant region.
32 . The method of claim 31 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
33 . The method of claim 32 , wherein the constant region is IgG1.
34 . The method of claim 33 having reduced or minimal effector function.
35 . The method of claim 34 , wherein the minimal effector function results from an effector-less Fc mutation.
36 . The method of claim 35 , wherein the effector-less Fc mutation is N297A.
37 . The method of claim 35 , wherein the effector-less Fc mutation is D265A/N297A.
38 . The method of claim 34 , wherein the minimal effector function results from aglycosylation.
39 . A method of treating a T-cell dysfunctional disorder resulting from an infection comprising administering to a patient a composition comprising a pharmaceutically-acceptable carrier and therapeutically effective amount of an anti-PD-L1 antibody or antigen binding fragment thereof, wherein the antibody or antibody fragment comprises a heavy chain and light chain variable region sequence, wherein:
(a) the heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVS A (SEQ ID NO:20), and (b) the light chain comprises the sequence: DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTL TISSLQPEDFATYYCQQYLYH PATFGQGTKVEIKR (SEQ ID NO:21).
40 . The method of claim 39 wherein the antibody further comprises a human constant region.
41 . The method of claim 40 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
42 . The method of claim 41 , wherein the constant region is IgG1.
43 . The method of claim 42 having reduced or minimal effector function.
44 . The nucleic acid of claim 43 , wherein the minimal effector function results from an effector-less Fc mutation.
45 . The method of claim 44 , wherein the effector-less Fc mutation is N297A.
46 . The method of claim 44 , wherein the effector-less Fc mutation is D265A/N297A.
47 . The method of claim 43 , wherein the minimal effector function results from aglycosylation.
48 . The method of any of claims 39 - 47 , further comprising the administration of an antibiotic.
49 . The method of claim 48 , wherein the antibiotic is an anti-viral agent.
50 . The method of claim 49 , wherein the anti-viral agent is a reverse transcriptase inhibitor.
51 . The method of claim 50 , wherein the reverse transcriptase inhibitor is a polymerase inhibitor.
52 . The method of claim 49 , wherein the anti-viral agent is a protease inhibitor.
53 . The method of any of claims 39 - 47 , further comprising the administration of at least one vaccine.
54 . The method of claim 39 , wherein the infection is chronic.
55 . The method of claim 54 , wherein the chronic infection is persistent.
56 . The method of claim 54 , wherein the chronic infection is latent.
57 . The method of claim 54 , where in the chronic infection is slow.
58 . The method of claim 39 , wherein the infection results from a pathogen selected from the group consisting of bacteria, virus, fungi and protozoan.
59 . The method of claim 58 , wherein the pathogen is a bacteria, and the method further comprises the administration of an anti-bacterial agent.
60 . The method of claim 58 , wherein the pathogen is a virus, and the method further comprises the administration of an anti-viral agent.
61 . The method of claim 58 , wherein the pathogen is a fungi, and the method further comprises the administration of an anti-fungal agent.
62 . The method of claim 58 , wherein the pathogen is a protozoan, and the method further comprises the administration of an anti-protozoan agent.Join the waitlist — get patent alerts
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