US2016222117A1PendingUtilityA1
Nucleic acid encoding anti-pd-l1 antibodies
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 31/10A61P 43/00A61P 33/00A61P 35/00A61P 37/02A61P 31/12A61P 33/02A61P 31/00A61P 37/00A61P 31/04A61P 37/04C07K 16/1145C07K 16/2827C07K 16/30A61K 39/3955C07K 16/22C07K 16/3046C07K 2317/565C07K 2317/74C07K 2317/71A61K 2039/505C07K 2317/56C07K 2317/73A61K 39/39558C07K 2317/52C07K 2317/24C07K 2317/92A61K 2039/507C07K 2317/76C07K 2317/14A61K 31/7068C07K 16/28A61K 45/06C07K 2317/567A61K 39/00Y02A50/30A61K 2300/00
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Claims
Abstract
The present application relates to nucleic acid encoding 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 nucleic acid encoding a heavy chain variable region polypeptide that specifically binds to PD-L1 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 nucleic acid of claim 1 wherein X 1 is D; X 2 is S and X 3 is T.
3 . The nucleic acid 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 nucleic acid of claim 3 wherein the framework sequences are human.
5 . The nucleic acid of claim 4 wherein the framework sequences are VH subgroup III consensus framework.
6 . The nucleic acid 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 nucleic acid of claim 1 , further comprising a second nucleic acid encoding a variable region light chain polypeptide comprising an HVR-L1, HVR-L2 and HVR-L3, wherein:
(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, and (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); 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 nucleic acid of claim 7 wherein X 4 is D; X 5 is V; X 6 is S; 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 nucleic acid of claim 7 further comprising variable region light chain framework sequences juxtaposed between the HVRs according to the formula: (LC-FR1)-(HVR-L 1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4).
10 . The nucleic acid of claim 9 wherein the framework sequences are human.
11 . The nucleic acid of claim 10 wherein the framework sequences are VL kappa I consensus framework.
12 . The nucleic acid 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 - 24 . (canceled)
25 . An isolated nucleic acid encoding a light chain or a heavy chain variable region sequence of an anti-PD-L1 antibody or antigen binding fragment, 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.
26 . The nucleic acid of claim 25 , wherein sequence identity is 90%.
27 . The nucleic acid of claim 26 , wherein the sequence identity is 95%.
28 . The nucleic acid of claim 25 , wherein the anti-PD-L1 antibody further comprises a VL and a VH framework region derived from a human consensus sequence.
29 . The nucleic acid of claim 28 , wherein the VH sequence is derived from a Kabat subgroup I, II, or III sequence.
30 . The nucleic acid of claim 29 , wherein the VH sequence is derived from Kabat subgroup III.
31 . The nucleic acid of claim 30 , 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).
32 . The nucleic acid of claim 31 , wherein one or more of the heavy chain 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.
33 . The nucleic acid of claim 28 , wherein the VL sequence is derived from a Kabat kappa I, II, III or IV subgroup sequence.
34 . The nucleic acid of claim 33 , wherein the VL sequence is derived from Kabat kappa I.
35 . The nucleic acid of claim 33 , further wherein the encoded 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).
36 . The nucleic acid of claim 35 , wherein one or more of the light chain 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.
37 . The nucleic acid of claim 25 , wherein the anti-PD-L1 antibody comprises a constant region derived from a murine antibody.
38 . The nucleic acid of claim 25 , wherein the anti-PD-L1 antibody comprises a constant region derived from a human antibody.
39 . The nucleic acid of claim 37 , wherein the constant region is IgG2A.
40 . The nucleic acid of claim 38 , wherein the constant region is IgG1.
41 . The nucleic acid of claim 40 , wherein the encoded antibody has reduced or minimal effector function.
42 . The nucleic acid of claim 41 , wherein the minimal effector function results from an effector-less Fc mutation.
43 . The nucleic acid of claim 42 , wherein the effector-less Fc mutation is N297A.
44 . The nucleic acid of claim 42 , wherein the effector-less Fc mutation is D265A/N297A.
45 . An isolated nucleic acid encoding 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 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 A (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.
46 . The nucleic acid of claim 45 wherein X 1 is D; X 2 is S and X 3 is T.
47 . The nucleic acid of claim 45 , wherein X 4 =D, X 5 =V, X 6 =5, 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.
48 . The nucleic acid of claim 45 , 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.
49 . The nucleic acid of claim 46 , 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).
50 . The nucleic acid of claim 49 , wherein the framework sequences are human.
51 . The nucleic acid of claim 50 wherein the framework sequences are VH subgroup III consensus framework.
52 . The nucleic acid of claim 51 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.
53 . The nucleic acid of 47 , wherein 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).
54 . The nucleic acid of claim 53 wherein the variable region light chain framework sequences are VL kappa I consensus framework.
55 . The nucleic acid of claim 54 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.
56 . The nucleic acid of claim 48 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
(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:
(i) HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4);
(ii) HC-FR2 is WVRQAPGKGLEWV (SEQ ID NO:5);
(iii) HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO:6);
(iv) HC-FR4 is WGQGTLVTVSA; and (SEQ ID NO:7); and
further wherein the variable light chain framework sequences are the following:
(i) LC-FR1 is DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11);
(ii) LC-FR2 is WYQQKPGKAPKLLIY (SEQ ID NO:12);
(iii) LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO:13);
(iv) LC-FR4 is FGQGTKVEIKR (SEQ ID NO:14).
57 . The nucleic acid of claim 56 further comprising a human constant region.
58 . The nucleic acid of claim 57 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
59 . The nucleic acid of claim 58 wherein the constant region is IgG1.
60 . The nucleic acid of claim 59 having reduced or minimal effector function.
61 . The nucleic acid of claim 60 , wherein the minimal effector function results from an effector-less Fc mutation.
62 . The nucleic acid of claim 61 , wherein the effector-less Fc mutation is N297A.
63 . The nucleic acid of claim 61 , wherein the effector-less Fc mutation is D265A/N297A.
64 . The nucleic acid of claim 60 , wherein the minimal effector function results from aglycosylation.
65 . The nucleic acid of claim 56 , further comprising a murine constant region.
66 . The nucleic acid of claim 65 , wherein the constant region is selected from the group consisting of IgG1, IgG2A, IgG2B and IgG3.
67 . The nucleic acid of claim 66 , wherein the constant region is IgG2A.
68 . The nucleic acid of claim 67 , which has reduced or minimal effector function.
69 . The nucleic acid of claim 68 , wherein the minimal effector function results from an effector-less Fc mutation.
70 . The nucleic acid of claim 69 , wherein the effector-less Fc mutation is N297A.
71 . The nucleic acid of claim 69 , wherein the effector-less Fc mutation is D265A/N297A.
72 . The nucleic acid of claim 68 , wherein the minimal effector function results from aglycosylation.
73 . An isolated nucleic acid encoding 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 TISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:21).
74 . The nucleic acid of claim 73 further comprising a human constant region.
75 . The nucleic acid of claim 74 , wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
76 . The nucleic acid of claim 75 , wherein the constant region is IgG1.
77 . The nucleic acid of claim 76 having reduced or minimal effector function.
78 . The nucleic acid of claim 77 , wherein the minimal effector function results from an effector-less Fc mutation.
79 . The nucleic acid of claim 78 , wherein the effector-less Fc mutation is N297A.
80 . The nucleic acid of claim 78 , wherein the effector-less Fc mutation is D265A/N297A.
81 . The nucleic acid of claim 77 , wherein the minimal effector function results from aglycosylation.
82 . A vector comprising the nucleic acid of any of claims 1 - 12 .
83 . (canceled)
84 . A vector comprising the nucleic acid of any of claims 25 - 44 .
85 . A vector comprising the nucleic acid of any of claims 45 - 72 .
86 . A vector comprising the nucleic acid of any of claims 73 - 81 .
87 . A host cell comprising the vector of claim 82 .
88 . A host cell comprising the vector of claim 84 .
89 . A host cell comprising the vector of claim 85 .
90 . A host cell comprising the vector of claim 86 .
91 . The host cell of any of claims 87 - 90 , which is eukaryotic.
92 . The host cell of claim 91 , which is mammalian.
93 . The host cell of claim 92 , which is a Chinese Hamster Ovary (CHO) cells.
94 . The host cell of any of claims 87 - 90 , which is prokaryotic.
95 . The host cell of claim 94 , which is E. coli.
96 . A process for making an anti-PD-L1 antibody comprising culturing the host cell of claim 93 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.Join the waitlist — get patent alerts
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