METHODS OF TREATING CANCERS AND ENHANCING EFFICACY OF GPRC5DXCD3 BISPECIFIC ANTIBODIES

Abstract

Disclosed are methods of treating cancers and enhancing efficacy of T cell redirecting therapeutics. In particular, methods are disclosed of using a GPRC5DxCD3 bispecific antibody, an anti-CD38 antibody and/or pomalidomide to treat cancers.

Description

Claims

1. A method of treating a cancer in a subject in need thereof, comprising: (1) administering to the subject a GPRC5DxCD3 bispecific antibody at a dose of 60 µg/kg to 1200 µg/kg every 1-2 weeks; and(2) administering to the subject an anti-CD38 antibody at a dose of 1200 mg to 2400 mg every 1-4 weeks.

2. The method of claim 1, wherein the method comprises: (1) subcutaneously administering to the subject the GPRC5DxCD3 bispecific antibody at a dose of 300 µg/kg to 1200 µg/kg every 1-2 weeks; and(2) subcutaneously administering to the subject the anti-CD38 antibody at a dose of 1600 mg to 2000 mg every 1-4 weeks.

3. The method of claim 2, further comprising subcutaneously administering to the subject the GPRC5DxCD3 bispecific antibody at a dose lower than that used in step (1) prior to step (1).

4. The method of claim 2, wherein the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject at a dose of about 300 µg/kg, 400 µg/kg, 450 µg/kg, 500 µg/kg, 550 µg/kg, 600 µg/kg, 700 µg/kg, 750 µg/kg, 800 µg/kg, 850 µg/kg, 900 µg/kg, 950 µg/kg, or 1000 µg/kg, or any dose from about 300 µg/kg to about 1000 µg/kg, once every week or once every two weeks.

5. The method of claim 4, wherein the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject at a dose of 400 µg/kg weekly or biweekly, or 800 µg/kg biweekly.

6. The method of claim 5, wherein the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject at a dose of 400 µg/kg weekly or 800 µg/kg biweekly.

7. The method of claim 1, wherein the anti-CD38 antibody is subcutaneously administered to the subject at the dose of 1800 mg once every week during week 1 to week 8 of the treatment, once every two weeks during week 9 to week 24 of the treatment, and once every four weeks after week 24 of the treatment.

8. The method of claim 1, wherein the anti-CD38 antibody is administered or provided for administration together with rHuPH20 .

9. The method of claim 1, wherein the GPRC5DxCD3 bispecific antibody comprises: (1) a GPRC5D binding domain comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2 and HCDR3 of the amino acid sequences of SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 29, respectively, and a light chain variable region (VL) comprising light chain complementarity determining regions (LCDRs) LCDR1, LCDR2 and LCDR3 of the amino acid sequences of SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32, respectively, and(2) a CD3 binding domain comprising a VH comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively, and a VL comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO:22, respectively.

10. The method of claim 9, wherein the GPRC5D binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 33 and the VL comprising the amino acid sequence of SEQ ID NO: 34; the CD3 binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 23 and the VL comprising the amino acid sequence of SEQ ID NO: 24.

11. The method of claim 10, wherein the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) comprising the amino acid sequence of SEQ ID NO: 35, a first light chain (LC1) comprising the amino acid sequence of SEQ ID NO: 36, a second heavy chain (HC2) comprising the amino acid sequence of SEQ ID NO: 25, and a second light chain (LC2) comprising the amino acid sequence of SEQ ID NO: 26.

12. The method of claim 1, wherein the anti-CD38 antibody comprises a VH comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, respectively, and a VL comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively.

13. The method of claim 12, wherein the anti-CD38 antibody comprises the VH comprising the amino acid sequence of SEQ ID NO: 5, and the VL comprising the amino acid sequence of SEQ ID NO: 6.

14. The method of claim 1, wherein the cancer is multiple myeloma.

15. A method of treating multiple myeloma in a subject in need thereof, comprising: (1) subcutaneously administering to the subject 400 µg/kg of a GPRC5DxCD3 bispecific antibody weekly; or 800 µg/kg of a GPRC5DxCD3 bispecific antibody biweekly, and(2) subcutaneously administering to the subject 1800 mg of an anti-CD38 antibody once every week during week 1 to week 8 of the treatment, once every two weeks during week 9 to week 24 of the treatment, and once every four weeks after week 24 of the treatment, wherein the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) of SEQ ID NO: 35, a first light chain (LC1) of SEQ ID NO: 36, a second heavy chain (HC2) of SEQ ID NO: 25, and a second light chain (LC2) of SEQ ID NO: 26, and the anti-CD38 antibody comprises the HC of SEQ ID NO: 13 and the LC of SEQ ID NO: 14.

16. The method of claim 15, further comprising subcutaneously administering to the subject one or more first step-up doses of the GPRC5DxCD3 bispecific antibody, wherein said first step up doses comprise 10 µg/kg on day 2 of the treatment and 60 µg/kg on day 4 of the treatment, prior to the initial dose of 400 µg/kg of the GPRC5DxCD3 bispecific antibody, or subcutaneously administering to the subject one or more second step-up doses of the GPRC5DxCD3 bispecific antibody, wherein said second step up doses comprise 10 µg/kg on day 2 of the treatment, 60 µg/kg on day 4 of the treatment, and 300 µg/kg on day 8 of the treatment, prior to the initial dose of 800 µg/kg of the GPRC5DxCD3 bispecific antibody.

17. The method of claim 1, wherein the subject has received at least one prior treatment for multiple myeloma, or the subject is relapsed or refractory to the at least one prior treatment, wherein the prior treatment comprises at least one of a proteasome inhibitor (PI) or an immunomodulatory agent (IMiD).

18. The method of claim 17, wherein the subject is refractory or relapsed to a treatment selected from the group consisting of an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, isatuximab, melphalan and thalidomide, or any combination thereof.

19. The method of claim 1, further comprising administering to the subject an additional therapeutic, wherein the additional therapeutic is pomalidomide and/or dexamethasone.

20. The method of claim 1, wherein said treating results in T-cell activation, wherein said T-cell activation comprises an increase in at least one of CD25, PD-1, CD38 on CD4 and CD8 T cells, or said treating results in an increase in frequency of at least of CD38+ CD8+ T cells, CD38+ CD4+ T cells and Tregs T cells.