Combination therapies for treatment of bcma-related cancers and autoimmune disorders

Patent metadata

Field	Value
Publication number	US-2019359727-A1
Application number	US-201816486764-A
Country	US
Kind code	A1
Filing date	Feb 16, 2018
Priority date	Feb 17, 2017
Publication date	Nov 28, 2019
Grant date	—

Abstract

The present disclosure relates to methods for using BCMA-specific binding molecules (such as a BCMA-specific chimeric antigen receptor or antibody) in combination with γ-secretase inhibitors, which can be done concurrently or sequentially, to treat or prevent a B-cell related proliferative disease, such as a cancer or autoimmune disease, or the like. A BCMA-specific binding molecule in combination with γ-secretase inhibitor can be used in, for example, adoptive immunotherapy.

First claim

What is claimed is:

1 . A method of treating
(i) a proliferative disease or disorder, such as a cancer, and/or (ii) an autoimmune disease or disorder, in a subject having or suspected having the disease or disorder associated with BCMA expression, comprising administering to the subject a therapeutically effective amount of a BCMA-specific binding protein and a therapeutically effective amount of a γ-secretase inhibitor.

2 . The method of claim 1 , wherein the BCMA-specific binding protein is a BCMA-specific antibody or antigen-binding portion thereof, a chimeric antigen receptor (CAR), or a tagged chimeric antigen receptor molecule (T-ChARM).

3 . The method of claim 2 , wherein the BCMA-specific binding protein is human or humanized.

4 . The method of any one of claims 1 to 3 , wherein the BCMA-specific binding protein comprises a BCMA-specific scFv, a BCMA-specific scTCR, or a BCMA ligand or binding portion thereof.

5 . The method of claim 4 , wherein the binding BCMA-specific binding protein is a scFv comprising heavy chain and light chain variable regions based on BCMA antibody J22.0-xi, J22.9-xi, J6M0, J6M1, J6M2, J9M0, J9M1, J9M2, 11D5-3, CAB, A7D12.2, C11 D5.3, C12A3.2, C13F12.1, 13C2, 17A5, 83A10, 13A4, 13D2, 14B11, 14E1, 29B11, 29F3, 13A7, CA7, S307118G03, SG1, S332121F02, S332126E04, S322110D07, S336105A07, S335115G01, S335122F05, ET140-3, ET140-24, ET140-37, ET140-40, ET140-54, TBL-CLN1, C4.E2.1, Vicky-1, pSCHLI333, pSCHLI372, or pSCHLI373.

6 . The method of any one of claims 1 to 5 , wherein the BCMA-specific binding protein is a chimeric antigen receptor comprising a hydrophobic portion disposed between an extracellular component and an intracellular component, wherein the extracellular component comprises the BCMA-specific binding protein, the BCMA-specific binding protein comprising (a) a BCMA-specific antigen-binding portion from BCMA antibody J22.0-xi, J22.9-xi, J6M0, 110D5-3, CA8, A7D12.2, C11 D5.3, C12A3.2, C13F12.1, 13C2, 17A5, 83A10, 13A4, 13D2, 14B11, 14E1, 29B11, 29F3, 13A7, CA7, SG1, S307118G03, S332121F02, S332126E04, S322110D07, S336105A07, S335115G01, S335122F05, ET140-3, ET140-24, ET140-37, ET140-40, ET140-54, TBL-CLN1, C4.E2.1, Vicky-1, pSCHLI333, pSCHLI372, or pSCHLI373; or (b) a BCMA ligand or binding portion thereof based on or derived from BAFF or APRIL.

7 . The method of claim 6 , wherein the hydrophobic portion is a transmembrane domain.

8 . The method of claim 7 , wherein the transmembrane domain is a CD4, CD8, CD28, or CD27 transmembrane domain.

9 . The method of any one of claims 6 to 8 , wherein the intracellular component comprises an effector domain or functional portion thereof, a costimulatory domain or functional portion thereof, or any combination thereof.

10 . The method of claim 9 , wherein the intracellular component comprises 4-1BB (CD137), CD3ε, CD3δ, CD3ζ, CD25, CD27, CD28, CD79A, CD79B, CARD11, DAP10, FcRα, FcRβ, FcRγ, Fyn, HVEM, ICOS, Lck, LAG3, LAT, LRP, NKG2D, NOTCH1, NOTCH2, NOTCH3, NOTCH4, OX40 (CD134), ROR2, Ryk, SLAMF1, Slp76, pTα, TCRα, TCRβ, TRIM, Zap70, PTCH2, or a functional portion thereof, or in any combination thereof.

11 . The method of claim 9 or 10 , wherein the effector domain comprises CD3ζ or functional portion thereof.

12 . The method of any one of claims 6 to 11 , wherein the intracellular component comprises a costimulatory domain or a functional portion thereof selected from CD27, CD28, 4-1BB (CD137), OX40 (CD134), or any combination thereof.

13 . The method of any one of claims 6 to 12 , wherein the effector domain or effector portion thereof comprises CD3ζ or functional portion thereof, and one or more costimulatory domain or a functional portion thereof of 4-1BB (CD137), CD27, CD28, and OX40 (CD134).

14 . The method of any one of claims 6 to 13 , wherein the intracellular component comprises (a) 4-1BB or a functional portion thereof and CD3ζ, (b) CD27 or a functional portion thereof and CD3ζ, (c) CD28 or a functional portion thereof and CD3ζ, (d) OX40 or a functional portion thereof and CD3ζ, (e) CD28 or a functional portion thereof, 4-1BB or a functional portion thereof and CD3ζ, (f) OX40 or a functional portion thereof, 4-1BB or a functional portion thereof and CD3ζ, or (g) CD28 or a functional portion thereof, OX40 or a functional portion thereof and CD34.

15 . The method of any one of claims 6 to 14 , wherein the extracellular component comprises an immunoglobulin hinge region, a CH2 domain and a CH3 domain, a CH3 domain, or any combination thereof disposed between the BCMA-specific binding protein and the hydrophobic portion.

16 . The method of claim 15 , wherein the immunoglobulin hinge region is an IgG1 hinge region.

17 . The method of claim 15 or 16 , wherein the CH2 domain is an IgG1 CH2 domain and the CH3 domain is an IgG1 CH3 domain.

18 . The method of any one of claims 1 to 17 , wherein the BCMA-specific binding protein is encoded by an exogenous polynucleotide and is expressed in a host cell.

19 . The method of claim 18 , wherein the host cell is a human immune system cell.

20 . The method of claim 19 , wherein the human immune system cell is a CD4+ T cell, a CD8+ T cell, a CD4− CD8− double negative T cell, a γδ T cell, a natural killer cell, a dendritic cell, or any combination thereof.

21 . The expression vector according to claim 20 , wherein the human immune system cell is a T cell, the T cell is a naïve T cell, a central memory T cell, an effector memory T cell, bulk T cells, or any combination thereof.

22 . The method of any one of claims 1 to 21 , wherein the γ-secretase inhibitor is avagacestat, DAPT, BMS-906024, BMS-986115, MK-0752, PF-03084014, RO4929097, or YO-01027.

23 . The method of claim 22 , wherein the γ-secretase inhibitor is a nicastrin-specific binding protein.

24 . The method of claim 23 , wherein the nicastrin-specific binding protein is scFvG9, antibody A5226A, antibody 2H6, or antibody 10C11.

25 . The method of any one of claims 1 to 24 , wherein the BCMA-specific binding protein comprises a variable domain comprising CDR1, CDR2, and CDR3 of the amino acid sequence of any one of SEQ ID NOS.:14-16 and a variable domain comprising CDR1, CDR2, and CDR3 of the amino acid sequence of any one of SEQ ID NOS.:17-21.

26 . The method of any one of claims 1 to 25 , wherein the method further comprises pre-conditioning the subject with an immunosuppressive regimen prior to or concurrent with the BCMA-specific binding protein and the γ-secretase inhibitor.

27 . The method of claim 26 , wherein the immunosuppressive regimen is a non-myeloablative treatment or myeloablative treatment.

28 . The method of claim 27 , wherein the non-myeloablative treatment comprises cyclophosphamide or cyclophosphamide in combination with fludarabine.

29 . The method of any one of claims 1 to 28 , wherein the BCMA-specific binding protein and the γ-secretase inhibitor are administered sequentially.

30 . The method of any one of claims 1 to 28 , wherein the BCMA-specific binding protein and the γ-secretase inhibitor are administered concurrently.

31 . The method of claim 30 , wherein the BCMA-specific binding protein and the γ-secretase inhibitor are formulated together.

32 . The method of any one of claims 1 to 31 ,

Assignees

• Hutchinson Fred Cancer Res

Inventors

• Riddell Stanley R
• Green Damian
• Hill Tyler

Classifications

• C07K14/52

  Cytokines; Lymphokines; Interferons · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61K31/5513

  1,4-Benzodiazepines, e.g. diazepam {or clozapine} · CPC title

• C07K14/475

  Growth factors; Growth regulators · CPC title