Monospecific and bispecific anti-IGF-1R and anti-ERBB3 antibodies

Patent metadata

Field	Value
Publication number	US-9556274-B2
Application number	US-201313778984-A
Country	US
Kind code	B2
Filing date	Feb 27, 2013
Priority date	Apr 19, 2011
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

Provided are monospecific and bispecific antibodies that are useful as anti-neoplastic agents and that bind specifically to human IGF-1R and human ErbB3. Exemplary antibodies inhibit signal transduction through either or both of IGF-1R and ErbB3. Exemplary polyvalent proteins comprise at least one anti-IGF-1R binding site and at least one anti-ErbB3 binding site. In certain embodiments the binding sites may be linked through an immunoglobulin constant region. AntiErbB3 and anti-IGF-1R antibodies (e.g., monoclonal antibodies) are also provided.

First claim

The invention claimed is:

1. A polyvalent bispecific antibody (PBA) comprising two pairs of polypeptide chains, wherein each pair comprises at least one anti-IGF-1R binding site and at least one anti-ErbB3 binding site; and
(i) the anti-IGF-1R binding site comprises (a) a heavy chain variable (VH) domain comprising a set of three VH Complementarity Determining Regions (CDRs) comprising VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66), and VHCDR3 (amino acid numbers 99-111) of a heavy chain comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12-31, 226, and 384-385; and (b) a light chain variable (VL) domain comprising a set of three VLCDRs comprising VLCDR1 (amino acid numbers 24-34), VLCDR2 (amino acid numbers 50-56), and VLCDR3 (amino acid numbers 89-97) of a light chain comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:3, 32, 33, 36-133, 204, and 386-387, and
(ii) the anti-ErbB3 binding site comprises (a) a heavy chain variable (VH) domain comprising a set of three VH CDRs comprising VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66), and VHCDR3 (amino acid numbers 99-111) of a heavy chain comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:5, 134-141, 143-165, and 388, or VHCDR1 (amino acid numbers 492-501), VHCDR2 (amino acid numbers 517-532), and VHCDR3 (amino acid numbers 565-577) of a molecule comprising the amino acid sequence of SEQ ID NO:226; and (b) a light chain variable (VL) domain comprising a set of three VLCDRs comprising VLCDR1 (amino acid numbers 23-33), VLCDR2 (amino acid numbers 49-55), and VLCDR3 (amino acid numbers 88-98) of a light chain comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:7, 166-173, and 176-200, or VLCDR1 (amino acid numbers 634-644), VLCDR2 (amino acid numbers 660-666), and VLCDR3 (amino acid numbers 699-709) of a molecule comprising the amino acid sequence of SEQ ID NO:226.

2. A polyvalent bispecific antibody that is:
a. an SF-G1-P1 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:212; and
two light chains, each comprising a light chain sequence of SEQ ID NO:202, or;

b. an SF-G1-M1.3 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:214; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:202, or;

c. an SF-G1-M27 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:216; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:202, or;

d. an SF-G1-P6 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:218; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:202, or;

e. an SF-G1-B69 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:220; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:202, or;

f. a P4-G1-P1 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:224; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:204, or;

g. a P4-G1-M27 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:228; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:204, or;

h. a P4-G1-P6 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:230; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:204, or;

i. a P4-G1-B69 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:232; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:204, or;

j. an M78-G1-C8 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:234; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:206, or;

k. an M78-G1-P1 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:236; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:206, or;

l. an M78-G1-M1.3 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:238; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:206, or;

m. an M78-G1-M27 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:240; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:206, or;

n. an M78-G1-P6 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:242; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:206, or;

o. an M78-G1-B69 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:244; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:206, or;

p. an M57-G1-C8 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:246; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:208, or;

q. an M57-G1-P1 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:248; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:208, or;

r. an M57-G1-M1.3 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:250; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:208, or;

s. an M57-G1-M27 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:252; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:208, or;

t. an M57-G1-P6 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:254; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:208, or;

u. an M57-G1-B69 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:256; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:208, or;

v. a P1-G1-P4 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:268; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:258, or;

w. a P1-G1-M57 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:270; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:258, or;

x. A P1-G1-M78 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:272; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:258, or;

y. a

Assignees

• Merrimack Pharmaceuticals Inc

Inventors

• Baum Jason
• Johnson Bryan
• Lugovskoy Alexey Alexandrovich
• Xu Lihui
• Kohli Neeraj
• Fitzgerald Jonathan Basil
• Adams Sharlene

Classifications

• C07K2317/52

  Constant or Fc region; Isotype · CPC title

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K16/40

  against enzymes · CPC title