Anti-GPRC5D antibodies, bispecific antigen binding molecules that bind GPRC5D and CD3, and uses thereof
Provided herein are antibodies that specifically bind to GPRC5D. Also described are related polynucleotides capable of encoding the provided GPRC5D-specific antibodies or antigen-binding fragments, cells expressing the provided antibodies or antigen-binding fragments, as well as associated vectors and detectably labeled antibodies or antigen-binding fragments. In addition, methods of using the provided antibodies are described. For example, the provided antibodies may be used to diagnose, treat, or monitor GPRC5D-expressing cancer progression, regression, or stability; to determine whether or not a patient should be treated for cancer; or to determine whether or not a subject is afflicted with GPRC5D-expressing cancer and thus may be amenable to treatment with a GPRC5D-specific anti-cancer therapeutic, such as the multispecific antibodies against GPRC5D and CD3 described herein.
1. An isolated antibody, or an antigen-binding fragment thereof, that binds
specifically to GORC5D wherein
a. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 5, and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 9, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 13, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 16, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 19;
b. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 13, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 16, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 19;
c. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 7, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 11, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 14, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 20;
d. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 4, said heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 8, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 12, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 15, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 18, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 21;
e. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 61, said heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 67, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 72, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 13, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 78, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 80;
f. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 2, said heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 28, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 30, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 13, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 6, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 19;
g. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 27, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 29, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 73, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 14, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 20;
h. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 27, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 29, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 11, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 14, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 20;
i. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 62, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 68, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 74, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 14, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 20;
j. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 63, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 69, and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 75, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 13, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 78, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 80;
k. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 61, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 67, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 72, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 13, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 78, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 80;
l. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 65, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 68, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 76 a light chain CDR1 having the amino acid sequence of SEQ ID NO: 95, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 79, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 81; or
m. said antibody comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 66, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 71, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 77, a light chain CDR1 having the amino acid sequence of SEQ ID NO: 15, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 18, and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 21.
2. The antibody of claim 1 , wherein the VH chain region comprises SEQ ID NOs: 52, 53, or 83 paired with a VL chain region comprising SEQ ID NO: 56.
3. The antibody of claim 1 , wherein the VH chain region comprises SEQ ID NOs: 54, 84, 85, 86, or 91 paired with a VL chain region comprising SEQ ID NO: 57.
4. The antibody of claim 1 , wherein the VH chain region comprises SEQ ID NOs: 55 or 88 paired with a VL chain region comprising SEQ ID NO: 58.
5. The antibody of claim 1 , wherein the VH chain region comprises SEQ ID NOs: 82 or 87 paired with a VL chain region comprising SEQ ID NO: 92.
6. The antibody of claim 1 , wherein the VH chain region comprises SEQ ID NO: 89 paired with a VL chain region comprising SEQ ID NO: 93.
7. The antibody of claim 1 , wherein the VH chain region comprises SEQ ID NO: 91 paired with a VL chain region comprising SEQ ID NO: 94.
8. The antibody or antigen-binding fragment of claim 1 wherein the antibody or antigen-binding fragment thereof binds to a polypeptide having the amino acid sequence of SEQ ID NO: 22.
9. The antibody or antigen-binding fragment of claim 1 wherein the antibody or antigen-binding fragment is a human antibody or antigen-binding fragment.
10. The antibody or antigen-binding fragment of claim 1 wherein the antibody or antigen-binding fragment is recombinant.
11. The antigen binding fragment of claim 1 wherein the antigen binding fragment is a Fab fragment, a Fab2 fragment, or a single chain antibody.
12. The antibody or antigen-binding fragment of claim 1 wherein the antibody or antigen-binding fragment thereof are of IgG1, IgG2, IgG3, or IgG4 isotype.
13. The antibody or antigen-binding fragment of claim 1 is an IgG1 or an IgG4 isotype.
14. The antibody of claim 13 wherein the IgG1 has a K409R substitution in its Fc region.
15. The antibody of claim 13 wherein the IgG1 has an F405L substitution in Its Fc region.
16. The antibody of claim 13 wherein the IgG4 has an F405L substitution and an R409K substitution in its Fc region.
17. The antibody of claim 12 further comprising an S228P substitution, an L234A substitution, and an L235A substitution in its Fc region.
18. The antibody or antigen-binding fragment of claim 1 wherein the antibody or antigen-binding fragment thereof specifically binds human GPRC5D and cross reacts to cynomolgus monkey GPRC5D.
19. The antibody or antigen-binding fragment of claim 1 wherein the antibody or antigen-binding fragment induces ADCC in vitro with an EC 50 of less than about 28 nM.