Combination therapies with anti-CD38 antibodies

Patent metadata

Field	Value
Publication number	US-10604580-B2
Application number	US-201615386391-A
Country	US
Kind code	B2
Filing date	Dec 21, 2016
Priority date	Sep 9, 2014
Publication date	Mar 31, 2020
Grant date	Mar 31, 2020

Abstract

The present invention relates to combination therapies with anti-CD38 antibodies and all-trans retinoic acid.

First claim

The invention claimed is:

1. A method of treating a subject having a refractory or resistant CD38-positive multiple myeloma (MM), comprising administering to the subject in need thereof an anti-CD38 antibody in combination with all-trans retinoic acid (ATRA), wherein the anti-CD38 antibody comprises the heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively, and the light chain complementarity determining regions (LCDR) 1(LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively, and wherein the subject is resistant to or has acquired resistance to treatment with the anti-CD38 antibody or a combination of at least one chemotherapeutic agent and the anti-CD38 antibody.

2. The method of claim 1 , wherein the anti-CD38 antibody induces killing of CD38-expressing cells in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC).

3. The method of claim 2 , wherein the anti-CD38 antibody induces killing of the CD38-expressing cells by CDC in vitro.

4. The method of claim 2 , wherein the anti-CD38 antibody induces killing of the CD38-expressing cells by ADCC in vitro.

5. The method of claim 1 , wherein the at least one chemotherapeutic agent is lenalidomide, bortezomib, melphalan, dexamethasone or thalidomide.

6. The method of claim 5 , wherein the at least one chemotherapeutic agent is lenalidomide or bortezomib.

7. The method of claim 1 , wherein the anti-CD38 antibody is of IgG1, IgG2, IgG3 or IgG4 isotype.

8. The method of claim 7 , wherein the anti-CD38 antibody is of IgG1 isotype.

9. The method of claim 1 , wherein the anti-CD38 antibody binds to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

10. The method of claim 1 , wherein the anti-CD38 antibody comprises the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5.

11. The method of claim 1 , wherein the anti-CD38 antibody comprises a heavy chain comprising an amino acid sequence that is 95%, 96%, 97%, 98% or 99% identical to that of SEQ ID NO: 12 and a light chain comprising an amino acid sequence that is 95%, 96%, 97%, 98% or 99% identical to that of SEQ ID NO: 13.

12. The method of claim 1 , wherein the anti-CD38 antibody comprises the heavy chain of SEQ ID NO: 12 and the light chain of SEQ ID NO: 13.

13. The method of claim 1 , wherein administering to the subject the anti-CD38 antibody in combination with the ATRA results in inducing the complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity of the anti-CD38 antibody.

14. The method of claim 1 , wherein administering to the subject the anti-CD38 antibody in combination with the ATRA results in augmented anti-CD38 antibody-induced complement-dependent cytotoxicity of the anti-CD38 antibody.

15. The method of claim 1 , wherein administering to the subject the anti-CD38 antibody in combination with the ATRA results in slowing of tumor growth in the subject.

16. A method of augmenting anti-CD38 antibody-induced complement-dependent cytotoxicity in a subject having a refractory or resistant CD38-positive multiple myeloma, comprising:
administering to the subject in need thereof the anti-CD38 antibody in combination with all-trans retinoic acid,
wherein the anti-CD38 antibody comprises the heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively, and the light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively, and
wherein the subject is resistant to or has acquired resistance to treatment with at least one chemotherapeutic agent, the anti-CD38 antibody, or a combination of at least one chemotherapeutic agent and the anti-CD38 antibody.

17. A method of inducing anti-CD38 antibody-mediated cytotoxicity in a subject having a refractory or resistant CD38-positive multiple myeloma, comprising:
administering to the subject in need thereof the anti-CD38 antibody in combination with all-trans retinoic acid,
wherein the anti-CD38 antibody comprises the heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively, and the light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively,
and wherein the subject is resistant to or has acquired resistance to treatment with at least one chemotherapeutic agent, the anti-CD38 antibody, or a combination of at least one chemotherapeutic agent and the anti-CD38 antibody,
and further wherein the cytotoxicity is complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity.

18. The method of claim 17 , wherein the cytotoxicity is complement-dependent cytotoxicity.

Assignees

• Janssen Biotech Inc

Inventors

• Lokhorst Henk M
• Mutis Tuna
• Nijhof Inger S
• Van De Donk Niels

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title

• C07K2317/92

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

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• A61K31/203 Primary

  Retinoic acids {; Salts thereof} · CPC title