Antibodies to cd40 with enhanced agonist activity

Patent metadata

Field	Value
Publication number	US-2016376371-A1
Application number	US-201615195098-A
Country	US
Kind code	A1
Filing date	Jun 28, 2016
Priority date	Jun 29, 2015
Publication date	Dec 29, 2016
Grant date	—

Abstract

Provided herein are agonistic antibodies, or antigen binding portions thereof, that bind to human CD40. Such antibodies optionally comprise Fc regions with enhanced specificity for FcγRIIb. The invention also provides methods of treatment of cancer or chronic infection by administering the antibodies of the invention to a subject in need thereof.

First claim

We claim:

1 . An isolated antibody, or antigen binding portion thereof, that specifically binds to human CD40 and competes for binding to human CD40 in a cross-blocking assay with one or more of antibodies selected from the group consisting of 12D6 (SEQ ID NOs: 3 and 4), 5F11 (SEQ ID NOs: 23 and 24), 8E8 (SEQ ID NOs: 40 and 41), 5G7 (SEQ ID NOs: 52 and 53), and 19G3 (SEQ ID NOs: 58 and 59).

2 . The isolated antibody or antigen binding portion thereof of claim 1 , wherein the competition in a cross-blocking assay comprises the ability to reduce binding of the selected antibody to human CD40 in a competition ELISA by at least 20% when used at an equal molar concentration with the selected antibody.

3 . An isolated antibody, or antigen binding portion thereof, that specifically binds to human CD40 at:
a. an epitope comprising or consisting of the sequence EPPTACREKQYLINS (residues 21-35 of SEQ ID NO: 1) (antibodies 12D6, 5G7 and 19G3); or b. an epitope comprising or consisting of the sequence ECLPCGESE (residues 58-66 of SEQ ID NO: 1) (antibody 5F11).

4 . An isolated antibody, or antigen binding portion thereof, that specifically binds to human CD40 comprising:
a) heavy chain CDR sequences derived at least in part from murine V region germline VH1-39_01 and J region germline IGHJ4 and
light chain CDR sequences derived at least in part from murine V region germline VK1-110_01 and J region germline IGKJ1 (12D6);
b) heavy chain CDR sequences derived at least in part from murine V region germline VH1-4_02 and J region germline IGHJ3 and
light chain CDR sequences derived at least in part from murine V region germline VK3-5_01 and J region germline IGKJ5 (5F11);
c) heavy chain CDR sequences derived at least in part from murine V region germline VH1-80_01 and J region germline IGHJ2 and
light chain CDR sequences derived at least in part from murine V region germline VK1-110_01 and J region germline IGKJ2 (8E8);
d) heavy chain CDR sequences derived at least in part from murine V region germline VH1-18_01 and J region germline IGHJ4 and
light chain CDR sequences derived at least in part from murine V region germline VK10-96_01 and J region germline IGKJ2 (5G7); or
e) heavy chain CDR sequences derived at least in part from murine V region germline VH5-9-4_01 and J region germline IGHJ3 and
light chain CDR sequences derived at least in part from murine V region germline VK1-117_01 and J region germline IGKJ2 (19G3).

5 . The isolated antibody or antigen binding portion thereof of claim 1 comprising a heavy chain and a light chain, wherein the heavy chain comprises CDRH1, CDRH2 and CDRH3 sequences and the light chain comprises CDRL1, CDRL2 and CDRL3 sequences selected from the group consisting of:
a) the CDRs of antibody 12D6-03 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-108, respectively, of SEQ ID NO:5 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:6;
b) the CDRs of antibody 12D6-22 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-108, respectively, of SEQ ID NO:7 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:9;
c) the CDRs of antibody 12D6-23 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-108, respectively, of SEQ ID NO:10 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO: 11;
d) the CDRs of antibody 12D6-24 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-108, respectively, of SEQ ID NO:12 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:9;
e) the CDRs of antibody 5F11-17 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-106, respectively, of SEQ ID NO:25 and CDRL1, CDRL2 and CDRL3 comprise residues 24-38, 54-60 and 93-101, respectively, of SEQ ID NO:26;
f) the CDRs of antibody 5F11-23 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-106, respectively, of SEQ ID NO:27 and CDRL1, CDRL2 and CDRL3 comprise residues 24-38, 54-60 and 93-101, respectively, of SEQ ID NO:28;
g) the CDRs of antibody 5F11-45 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-106, respectively, of SEQ ID NO:29 and CDRL1, CDRL2 and CDRL3 comprise residues 24-38, 54-60 and 93-101, respectively, of SEQ ID NO:30;
h) the CDRs of antibody 8E8-56 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-111, respectively, of SEQ ID NO:42 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:43;
i) the CDRs of antibody 8E8-62 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-111, respectively, of SEQ ID NO:44 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:45;
j) the CDRs of antibody 8E8-67 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-111, respectively, of SEQ ID NO:46 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:47;
k) the CDRs of antibody 8E8-70 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-111, respectively, of SEQ ID NO:48 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:49;
l) the CDRs of antibody 8E8-71 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-111, respectively, of SEQ ID NO:50 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:51;
m) the CDRs of antibody 5G7-22 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-102, respectively, of SEQ ID NO:54 and CDRL1, CDRL2 and CDRL3 comprise residues 24-34, 50-56 and 89-97, respectively, of SEQ ID NO:55;
n) the CDRs of antibody 5G7-25 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-102, respectively, of SEQ ID NO:56 and CDRL1, CDRL2 and CDRL3 comprise residues 24-34, 50-56 and 89-97, respectively, of SEQ ID NO:57;
o) the CDRs of antibody 19G3-11 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-101, respectively, of SEQ ID NO:60 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:62; and
p) the CDRs of antibody 19G3-22 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-101, respectively, of SEQ ID NO:63 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:64.

6 . The antibody of claim 5 comprising heavy and light chain variable domain sequences selected from the groups consisting of:
a) the heavy and light chain variable regions of antibody 12D6-03 comprising residues 1-119 and 1-112 of SEQ ID NO:5 and SEQ ID NO:6, respectively;
b) the heavy and light chain variable regions of antibody 12D6-22 comprising residues 1-119 and 1-112 of SEQ ID NO:7 and SEQ ID NO:9, respectively;
c) the heavy and light chain variable regions of antibody 12D6-23 comprising residues 1-119 and 1-112 of SEQ ID NO:10 and SEQ ID NO: 11, respectively;
d) the heavy and light chain variable regions of antibody 12D6-24 comprising residues 1-119 and 1-112 of SEQ ID NO: 12 and SEQ ID NO:9, respectively;
e) the heavy and light chain variable regions of antibody 5F11-17 comprising residues 1-117 and 1-111 of SEQ ID NO:25 and SEQ ID NO:26, respectively;
f) the heavy and light chain variable regions of antibody 5F11-23 comprising residues 1-117 and 1-111 of SEQ ID NO:27 and SEQ ID NO:28, respectively;
g) the heavy and light chain variable regions of antibody 5F11-45 comprising residues 1-117 and 1-111 of SEQ ID NO:29 and SEQ ID NO:30, respectively;
h) the heavy and light chain variable regions of antibody 8E8-56 comprising residues 1-122 and 1-112 o

Assignees

• Univ Rockefeller
• Bristol Myers Squibb Co

Inventors

• Ravetch Jeffrey V
• Dahan Rony
• Barnhart Bryan C
• Devaux Brigitte
• Yamniuk Aaron P
• Okada Shannon L
• Stevens Brenda L

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/72

  Increased effector function due to an Fc-modification · CPC title