Monospecific and bispecific anti-IGF-1R and anti-ERBB3 antibodies
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.
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. an M27-G1-P4 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:274; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:260, or;
z. an M27-G1-M57 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:276; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:260, or;
aa. an M27-G1-M78 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:278; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:260, or;
bb. an M7-G1-P4 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:280; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:262, or;
cc. an M7-G1-M57 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:282; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:262, or;
dd. a B72-G1-P4 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:286; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:264, or;
ee. a B72-G1-M57 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:288; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:264, or;
ff. a B72-G1-M78 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:290; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:264, or;
gg. a B60-G1-P4 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:292; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:266, or;
hh. a B60-G1-M57 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:294; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:266, or;
ii. a B60-G1-M78 polyvalent bispecific antibody comprising:
two heavy chains, each comprising a heavy chain amino acid sequence of SEQ ID NO:296; and
two light chains, each comprising a light chain amino acid sequence of SEQ ID NO:266.
3. An anti-IGF-1R monoclonal antibody comprising:
a. a light chain comprising in amino to carboxy order VLCDR1 (amino acid numbers 24-34), VLCDR2 (amino acid numbers 50-56) and VLCDR3 (amino acid numbers 89-96) of SEQ ID NO:204, said antibody further comprising a heavy chain comprising in amino to carboxy order a VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66) and VHCDR3 (amino acid numbers 99-111) of SEQ ID NO:222, or;
b. a light chain comprising in amino to carboxy order VLCDR1 (amino acid numbers 24-34), VLCDR2 (amino acid numbers 50-56) and VLCDR3 (amino acid numbers 89-96) of SEQ ID NO:206, said antibody further comprising a heavy chain comprising in amino to carboxy order VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66) and VHCDR3 (amino acid numbers 99-111) of SEQ ID NO:234, or;
c. a light chain comprising in amino to carboxy order VLCDR1 (amino acid numbers 24-34), VLCDR2 (amino acid numbers 50-56) and VLCDR3 (amino acid numbers 89-96) of SEQ ID NO:208, said antibody further comprising a heavy chain comprising in amino to carboxy order VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66) and VHCDR3 (amino acid numbers 99-111) of SEQ ID NO:246.
4. An anti-ErbB3 monoclonal antibody comprising:
a. a light chain comprising in amino to carboxy order VLCDR1 (amino acid numbers 23-33), VLCDR2 (amino acid numbers 49-55) and VLCDR3 (amino acid numbers 88-98) of SEQ ID NO:258, said antibody further comprising a heavy chain comprising in amino to carboxy order VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66) and VHCDR3 (amino acid numbers 99-111) of SEQ ID NO:268, or
b. a light chain comprising in amino to carboxy order VLCDR1 (amino acid numbers 23-33) sequence, VLCDR2 (amino acid numbers 49-55) and VLCDR3 (amino acid numbers 88-98) of SEQ ID NO:260, said antibody further comprising a heavy chain comprising in amino to carboxy order VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66) and VHCDR3 (amino acid numbers 99-111) of SEQ ID NO:274, or;
c. a light chain comprising in amino to carboxy order VLCDR1 (amino acid numbers 23-33), VLCDR2 (amino acid numbers 49-55) and VLCDR3 (amino acid numbers 88-98) of SEQ ID NO:262, said antibody further comprising a heavy chain comprising in amino to carboxy order VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66) and VHCDR3 (amino acid numbers 99-111) of SEQ ID NO:280, or;
d. a light chain comprising in amino to carboxy order VLCDR1 (amino acid numbers 23-33), VLCDR2 (amino acid numbers 49-55) and VLCDR3 (amino acid numbers 88-98) of SEQ ID NO:264, said antibody further comprising a heavy chain comprising in amino to carboxy order VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66) and VHCDR3 (amino acid numbers 99-111) of SEQ ID NO:286, or;
e. a light chain comprising in amino to carboxy order VLCDR1 (amino acid numbers 23-33), VLCDR2 (amino acid numbers 49-55) and VLCDR3 (amino acid numbers 88-98) of SEQ ID NO:266, said antibody further comprising a heavy chain comprising in amino to carboxy order VHCDR1 (amino acid numbers 26-35), VHCDR2 (amino acid numbers 51-66) and VHCDR3 (amino acid numbers 99-111) of SEQ ID NO:292, wherein
the antibody does not comprise the C8 module.
5. The polyvalent bispecific antibody of claim 1 in a pharmaceutically acceptable carrier.
6. The polyvalent bispecific antibody of claim 2 in a pharmaceutically acceptable carrier.
7. The monoclonal antibody of claim 3 in a pharmaceutically acceptable carrier.
8. The monoclonal antibody of claim 4 in a pharmaceutically acceptable carrier.
9. 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 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 of SEQ ID NO:226, and 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 of SEQ ID NO:204, and
(ii) the anti-ErbB3 binding site comprises a heavy chain variable (VH) domain comprising a set of three VH CDRs comprising 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 a light chain variable (VL) domain comprising a set of three VLCDRs comprising 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.
10. A composition comprising the polyvalent bispecific antibody of claim 9 and a pharmaceutically acceptable carrier.