Anti-cspg4 fusions with interferon for the treatment of malignancy

Patent metadata

Field	Value
Publication number	US-2016115242-A1
Application number	US-201414893912-A
Country	US
Kind code	A1
Filing date	May 29, 2014
Priority date	May 29, 2013
Publication date	Apr 28, 2016
Grant date	—

Abstract

In various embodiments chimeric moieties (constructs) are provided that show significant efficacy against cancers. In certain embodiments the constructs comprise a targeting moiety that specifically binds CSPG4 attached to an interferon or to a mutant interferon. In certain embodiments, the constructs comprise anti-CSPG4 antibody attached to an interferon alpha (IFN-α) or to a mutant interferon alpha or to an interferon beta (IFN-β) or to a mutant interferon beta, or to an interferon gamma (IFN-γ) or to a mutant interferon gamma.

First claim

What is claimed is:

1 . A chimeric construct comprising an interferon attached to an antibody that binds chondroitin sulfate proteoglycan 4 (CSPG4).

2 . The construct of claim 1 , wherein said construct when contacted to a cell that expresses or overexpresses CSPG4 cell results in the killing or inhibition of growth or proliferation of said cell.

3 . The construct of claim 2 , wherein said cell that expresses or overexpresses CSPG4 is a cancer cell.

4 . The construct of claim 2 , wherein said cell that expresses or overexpresses CSPG4 is a cancer selected from the group consisting of tumors of neuroectodermal origin including melanoma and glioma, breast cancer including triple negative breast cancer, squamonous cell carcinoma of head and neck, myeloid leukemia, pancreatic carcinoma, chondrosarcoma, chordoma, mesothelioma, renal cell carcinoma, lung carcinoma, ovarian carcinoma and cancer stem cells representing various histologies.

5 . The construct of claim 2 , wherein said cell that expresses or overexpresses CSPG4 is a cancer stem cell.

6 . The construct according to any one of claims 1 - 5 , wherein said interferon is a type I interferon.

7 . The construct of claim 6 , wherein said interferon is an interferon-alpha (IFNα).

8 . The construct of claim 6 , wherein said interferon is an IFN-α2.

9 . The construct of claim 6 , wherein said interferon is an IFN-α10.

10 . The construct of claim 6 , wherein said interferon is an IFN-α14.

11 . The construct of claim 6 , wherein said interferon is an interferon-beta (IFNβ).

12 . The construct according to any one of claims 1 - 5 , wherein said interferon is a type II interferon (IFNγ).

13 . The construct of claim 12 , wherein said interferon gamma is a full-length interferon gamma.

14 . The construct of claim 12 , wherein said interferon gamma is a truncated interferon gamma.

15 . The construct of claim 12 , wherein said interferon gamma is an interferon gamma having 1-15 amino acids truncated from the carboxyl terminus and/or 1-3 amino acids truncated from the amino terminus.

16 . The construct of claim 12 , wherein said interferon gamma is a truncated interferon gamma where the amino acid sequence of said truncated interferon gamma consists of the sequence DPYVKEAE NLKKYFNAGH SDVADNGTLF LGILKNWKEE SDRKIMQSQI VSFYFKLFKN FKDDQSIQKS VETIKEDMNV KFFNSNKKKR DDFEKLTNYS VTDLNVQRKA IHELIQVMAE LSPAAKTGKR KRSQM (SEQ ID NO:29).

17 . The construct according to any one of claims 1 - 16 , wherein said interferon is a human interferon.

18 . The construct according to any one of claims 1 - 16 , wherein said interferon is a non-human interferon.

19 . The construct of claim 18 , wherein said interferon is a murine interferon.

20 . The construct according to any one of claims 1 - 5 , wherein said interferon is a mutant interferon gamma.

21 . The construct according to any one of claims 1 - 5 , wherein said interferon is a mutant type I interferon.

22 . The construct of claim 21 , wherein said interferon is a mutant interferon-alpha.

23 . The construct of claim 21 , wherein said interferon is a mutant interferon-alpha having lower activity than native interferon alpha.

24 . The construct of claim 21 , wherein said interferon is a mutant interferon-alpha having higher activity than native interferon alpha.

25 . The construct of claim 21 , wherein said interferon is a mutant human interferonα-2 having mutations at one or more sites selected from the group consisting of His57, Glu58, and Gln61.

26 . The construct of claim 25 , wherein said interferon is an interferonα-2 having a mutation at His57.

27 . The construct of claim 26 , wherein said mutation at His57 is a mutation to an amino acid selected from the group consisting of A, Y, and M.

28 . The construct according to any one of claims 25 - 27 , wherein said interferon is an interferon α-2 having a mutation at Glu58.

29 . The construct of claim 28 , wherein said mutation at Glu58 is a mutation to an amino acid selected from the group consisting of A, N, D, and L.

30 . The construct according to any one of claims 25 - 29 , wherein said interferon is an interferonα-2 having a mutation at Gln61.

31 . The construct of claim 30 , wherein said mutation at Gln61 is a mutation to an amino acid selected from the group consisting of A, S, and D.

32 . The construct of claim 25 , wherein said interferon comprises the mutations H57Y, E58N, and Q61S.

33 . The construct of claim 25 , wherein said interferon comprises the mutations H57M, E58L, and Q61D.

34 . The construct of claim 25 , wherein said interferon comprises the mutations H57Y, E58L, and Q61D.

35 . The construct of claim 25 , wherein said interferon comprises the mutations H57Y, E58A, and Q61S.

36 . The construct of claim 25 , wherein said interferon comprises the mutations H57A, E58A, and Q61A.

37 . The construct according to any one of claims 1 - 36 , wherein said antibody binds to a CSPG4 at an epitope bound by one or more antibodies selected from the group consisting of 9.2.27, VF1-TP34, VF1-TP34, VF1-TP41.2, TP61.5, 149.53, 149.53, 225.28, 225.28s, 763.74, and scFv-FcC21.

38 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of an antibody selected from the group consisting of 9.2.27, VF1-TP34, VF1-TP34, VF1-TP41.2, TP61.5, 149.53, 149.53, 225.28, 225.28s, 763.74, and scFv-FcC21.

39 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the 92.2.27 antibody.

40 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the 225.28 antibody.

41 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the scFv-FcC21 antibody.

42 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the VF1-TP34 antibody.

43 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the VF1-TP34 antibody.

44 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the VF1-TP41.2 antibody.

45 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the TP61.5 antibody.

46 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the 149.53 antibody.

47 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the 149.53 antibody.

48 . The construct of claim 37 , wherein said antibody comprises 3 complementarity determining regions from the VH domain of the 225.28s antibody.

49 . The construct of claim 37 ,

Assignees

• Univ California

Inventors

• Morrison Sherie L
• Timmerman John M
• Trinh Kham M

Classifications

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K14/57

  IFN-gamma · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title