IGF1R ANTIBODIES
Described herein are antibodies that bind and inhibit signaling through the insulin-like growth factor receptor 1.
1 . An antibody or antigen binding fragment thereof that binds insulin like growth factor 1 receptor (IGF1R), wherein the antibody or antigen binding fragment thereof comprises:
a. an immunoglobulin heavy chain CDR1 (HCDR1) comprising the amino acid sequence SX 1 GMH, wherein X 1 is H, Y, A, or T;
b. an immunoglobulin heavy chain CDR2 (HCDR2) comprising the amino acid sequence X 1 IX 2 X 3 DX 4 SX 5 TYYADSVRG, wherein X 1 is I, T, or Y, X 2 is W, N, or A, X 3 is F, H, A, or G, X 4 is G or A, X 5 is S or T;
c. an immunoglobulin heavy chain CDR3 (HCDR3) comprising the amino acid sequence ELX 1 RRYFDL, wherein X 1 is G or N;
d. an immunoglobulin light chain CDR1 (LCDR1) comprising the amino acid sequence RASQSVSSX 1 LA, wherein X 1 is Y, A, or T;
e. an immunoglobulin light chain CDR2 (LCDR2) comprising the amino acid sequence DASKRAT; and
f. an immunoglobulin light chain CDR3 (LCDR3) comprising the amino acid sequence QQRX 1 KX 2 PPWT, wherein X 1 is S or G, X 2 is Y or W;
wherein the antibody or antigen binding fragment thereof does not comprise an immunoglobulin heavy chain variable region identical to SEQ ID NO: 1 and/or an immunoglobulin light chain variable region identical to SEQ ID NO: 2.
2 . The antibody or antigen binding fragment thereof of claim 1 , wherein the amino acid residue corresponding to X 2 of the LCDR3 is a tyrosine.
3 . The antibody or antigen binding fragment thereof of claim 1 , wherein:
a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 30 (SHGMH);
b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 35 (YIWFDGSSTYYADSVRG);
c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 41 (ELGRRYFDL);
d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 43 (RASQSVSSALA);
e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46 (DASKRAT); and
f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48 (QQRSKYPPWT).
4 . The antibody or antigen binding fragment thereof of claim 1 , wherein:
a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 33 (SYGMH);
b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 38 (IIWFDGSSTYYADSVRG);
c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 41 (ELGRRYFDL);
d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45 (RASQSVSSYLA);
e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46 (DASKRAT); and
f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48 (QQRSKYPPWT).
5 . The antibody or antigen binding fragment thereof of claim 1 , wherein:
a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 30 (SHGMH);
b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 34 (IIAGDASTTYYADSVRG);
c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 41 (ELGRRYFDL);
d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45 (RASQSVSSYLA);
e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46 (DASKRAT); and
f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48 (QQRSKYPPWT).
6 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 3; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 4.
7 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 5; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 6.
8 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 7; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 8.
9 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 9; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 10.
10 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 11; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 12.
11 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 13; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 14.
12 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 15; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 16.
13 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 18.
14 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 19; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 20.
15 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 21; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 22.
16 . The antibody or antigen binding fragment thereof of claim 1 , comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 51; and wherein the immunoglobulin light chain comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 52.
17 . The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof is an IgG antibody.
18 . The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a Fab, F(ab) 2 , or a single chain variable fragment (scFv).
19 . The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof is chimeric or humanized.
20 . The antibody or antigen binding fragment thereof of claim 1 , comprising a M252Y/S254T/T256E substitution according to EU numbering in one or both heavy chain constant regions.
21 . The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof is characterized by a half-life of 25 days or longer in a human.
22 . (canceled)
23 . The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody inhibits signaling through IGF1R.
24 . The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody inhibits phosphorylation of IGF1R with an EC50 of 10 ng/mL or less.
25 . (canceled)
26 . (canceled)
27 . The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody possesses a K D of less than 5×10 −9 M.
28 . (canceled)
29 . (canceled)
30 . A nucleic acid encoding the antibody or antigen binding fragment thereof of claim 1 .
31 . A cell line comprising the nucleic acid of claim 30 .
32 . The cell line of claim 31 , wherein the cell line is a Chinese Hamster Ovary cell line.
33 . A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.
34 . The pharmaceutical composition of claim 33 , formulated for intravenous administration.
35 . The pharmaceutical composition of claim 33 , formulated for subcutaneous administration.
36 . The antibody or antigen binding fragment thereof of claim 1 or the pharmaceutical composition of claim 33 for use in method of inhibiting IGF1R signaling in an individual.
37 . A method of inhibiting IGF1R signaling in an individual comprising administering to the individual a therapeutically effective amount of the antibody or antigen binding fragment thereof of claim 1 or the pharmaceutical composition of claim 33 .