US2013045202A1PendingUtilityA1
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 43/00A61P 37/00A61P 33/02A61P 35/00A61P 31/12A61P 33/00A61P 31/04A61P 37/04A61P 37/02A61P 31/00A61P 31/10C07K 16/1145C07K 2317/52C07K 2317/73C07K 2317/71C07K 2317/56C07K 2317/74A61K 31/7068A61K 39/39558A61K 45/06C07K 2317/567C07K 16/30C07K 16/2827A61K 39/3955C07K 2317/92A61K 2039/507A61K 2039/505C07K 2317/565C07K 2317/76C07K 16/28C07K 16/22C07K 16/3046C07K 2317/14C07K 2317/24A61K 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 anti-PD-L1 antibody or antigen binding fragment comprising a light chain or a heavy chain variable region sequence, wherein:
(a) the heavy chain or antigen binding fragment thereof 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 or antigen binding fragment thereof 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.
2 . The antibody of claim 1 , wherein sequence identity is 90%.
3 . The antibody of claim 2 , wherein the sequence identity is 95%.
4 . The antibody of claim 1 , wherein the anti-PD-L1 antibody further comprises a VL and a VH framework region derived from a human consensus sequence.
5 . The antibody of claim 4 , wherein the VH sequence is derived from a Kabat subgroup I, II, or III sequence.
6 . The antibody of claim 5 , wherein the VH sequence is derived from Kabat subgroup III.
7 . The antibody of claim 6 , further wherein the 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).
8 . The antibody 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.
9 . The antibody of claim 4 , wherein the VL sequence is derived from a Kabat kappa I, II, III or IV subgroup sequence.
10 . The antibody of claim 9 , wherein the VL sequence is derived from Kabat kappa I.
11 . The antibody of claim 9 , further wherein the variable light chain framework sequences are juxtaposed between the HVRs according to the formula: (LC-FR1)—(HVR-L1)-(LC-FR2)—(HVR-L2)-(LC-FR3)—(HVR-L3)-(LC-FR4).
12 . The antibody of claim 11 , 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.
13 . The antibody of claim 1 , wherein the anti-PD-L1 antibody comprises a constant region derived from a human antibody.
14 . The antibody of claim 13 , wherein the constant region is IgG1.
15 . The antibody of claim 14 , wherein the encoded antibody has reduced or minimal effector function.
16 . The antibody of claim 15 , wherein the minimal effector function results from an effector-less Fc mutation.
17 . The antibody of claim 16 , wherein the effector-less Fc mutation is N297A.
18 . The antibody of claim 16 , wherein the effector-less Fc mutation is D265A/N297A.
19 . An isolated 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 sequence has at least 85% sequence identity to the heavy chain sequence:
(SEQ ID NO: 20)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWV
AWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC
ARRHWPGGFDYWGQGTLVTVSA,
further wherein, the heavy chain comprises an HVR-H1, HVR-H2 and HVR-H3, in which:
(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, and (SEQ ID NO:3); and
(b) the light chain sequence has at least 85% sequence identity to the light chain sequence:
(SEQ ID NO: 21)
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKP
GKYSASSFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFAT
YYCQQYLYH PATFGQGTKVEIKR;
further wherein, the light chain comprises an HVR-L1, HVR-L2 and HVR-L3, in which:
(A) the HVR-L1 sequence is RASQX 4 X 5 X 6 TX 7 X 8 A (SEQ ID NOs:8);
(B) the HVR-L2 sequence is SASX 9 LX 10 S (SEQ ID NOs:9);
(C) 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.
20 . The antibody of claim 19 wherein X 1 is D; X 2 is S and X 3 is T.
21 . The antibody of claim 19 , 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.
22 . The antibody of claim 19 , 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.
23 . The antibody of claim 22 , wherein the sequence identity is 90%.
24 . The antibody of claim 23 , wherein the sequence identity is 95%.
25 . The antibody of claim 24 , wherein the sequence identity is 96%.
26 . The antibody of claim 25 , wherein the sequence identity is 97%.
27 . The antibody of claim 26 , wherein the sequence identity is 98%.
28 . The antibody of claim 27 , wherein the sequence identity is 99%.
29 . The antibody of claim 19 wherein the antibody or antibody fragment comprises:
(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/or
(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).
wherein the variable heavy chain framework sequences are the following:
(SEQ ID NO: 4)
(i)
HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS;
(SEQ ID NO: 5)
(ii)
HC-FR2 is WVRQAPGKGLEWV;
(SEQ ID NO: 6)
(iii)
HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR;
(SEQ ID NO: 7)
(iv)
HC-FR4 is WGQGTLVTVSA;
and;
and/or
further wherein the variable light chain framework sequences are the following:
(SEQ ID NO: 11)
(v)
LC-FR1 is DIQMTQSPSSLSASVGDRVTITC;
(SEQ ID NO: 12)
(vi)
LC-FR2 is WYQQKPGKAPKLLIY;
(SEQ ID NO: 13)
(vii)
LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC;
(SEQ ID NO: 14)
(iv)
LC-FR4 is FGQGTKVEIKR.
30 . The antibody of claim 29 further comprising a human constant region.
31 . The antibody of claim 30 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
32 . The antibody of claim 31 , wherein the constant region is IgG1.
33 . The antibody of claim 32 having reduced or minimal effector function.
34 . The antibody of claim 33 , wherein the minimal effector function results from an effector-less Fc mutation.
35 . The antibody of claim 34 , wherein the effector-less Fc mutation is N297A.
36 . The antibody of claim 34 , wherein the effector-less Fc mutation is D265A/N297A.
37 . The antibody of claim 33 , wherein the minimal effector function results from aglycosylation.
38 . A composition comprising the antibody of claims 1 - 18 and a pharmaceutically acceptable carrier.
39 . A composition comprising the antibody of claims 19 - 37 and a pharmaceutically acceptable carrier.
40 . An article of manufacture comprising the composition of claim 39 and at least one vaccine.
41 . An article of manufacture comprising the composition of claim 39 and at least one anti-viral agent.
42 . An article of manufacture comprising the composition of claim 39 and at least one chemotherapeutic agent.
43 . The article of claim 42 , wherein the chemotherapeutic agent is an anti-VEGF antibody.
44 . The article of claim 43 , wherein the chemotherapeutic agent is oxaliplatin.
45 . The article of claim 43 , wherein the chemotherapeutic agent is a RAF inhibitor.Join the waitlist — get patent alerts
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