Cd138-targeted interferon demonstrates potent apoptotic and anti-tumor activities

Patent metadata

Field	Value
Publication number	US-2016115239-A1
Application number	US-201314649888-A
Country	US
Kind code	A1
Filing date	Dec 5, 2013
Priority date	Dec 7, 2012
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 CD138 attached to an interferon or to a mutant interferon. In certain embodiments, the constructs comprise anti-CD138 antibody attached to an interferon alpha (IFN-α) or to a mutant interferon alpha.

First claim

What is claimed is:

1 . A chimeric construct comprising an interferon attached to an antibody that binds CD138.

2 . The construct of claim 1 , wherein said construct when contacted to a cell that expresses or overexpresses CD138 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 CD138 is a cancer cell.

4 . The construct of claim 2 , wherein said cell that expresses or overexpresses CD138 is a cancer from a cancer selected from the group consisting of multiple myeloma, ovarian carcinoma, cervical cancer, endometrial cancer, kidney carcinoma, gall bladder carcinoma, transitional cell bladder carcinoma, gastric cancer, prostate adenocarcinoma, breast cancer, prostate cancer, lung cancer, colon carcinoma, Hodgkin's and non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), a solid tissue sarcoma, colon carcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma, colorectal carcinoma, hepato-carcinoma, pancreatic cancer, and head and neck carcinoma.

5 . The construct according to any one of claims 1 - 4 , wherein said interferon is a type I interferon.

6 . The construct according to any one of claims 1 - 4 , wherein said interferon is a type II interferon (IFNγ).

7 . The construct of claim 5 , wherein said interferon is an interferon-alpha (IFNα).

8 . The construct of claim 5 , wherein said interferon is an interferon-beta (IFNβ).

9 . The construct according to any one of claims 7 - 8 , wherein said interferon is a human interferon.

10 . The construct according to any one of claims 7 - 8 , wherein said interferon is a non-human interferon.

11 . The construct of claim 10 , wherein said interferon is a murine interferon.

12 . The construct according to any one of claims 1 - 4 , wherein said interferon is a mutant type I interferon.

13 . The construct of claim 12 , wherein said interferon is a mutant interferon-alpha.

14 . The construct of claim 12 , 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.

15 . The construct of claim 14 , wherein said interferon is an interferonα-2 having a mutation at His57.

16 . The construct of claim 15 , wherein said mutation at His57 is a mutation to an amino acid selected from the group consisting of A, Y, and M.

17 . The construct according to any one of claims 14 - 16 , wherein said interferon is an interferonα-2 having a mutation at Glu58.

18 . The construct of claim 17 , wherein said mutation at Glu58 is a mutation to an amino acid selected from the group consisting of A, N, D, and L.

19 . The construct according to any one of claims 14 - 18 , wherein said interferon is an interferonα-2 having a mutation at Gln61.

20 . The construct of claim 17 , wherein said mutation at Gln61 is a mutation to an amino acid selected from the group consisting of A, S, and D.

21 . The construct of claim 14 , wherein said interferon comprises the mutations H57Y, E58N, and Q61S.

22 . The construct of claim 14 , wherein said interferon comprises the mutations H57M, E58L, and Q61D.

23 . The construct of claim 14 , wherein said interferon comprises the mutations H57Y, E58L, and Q61D.

24 . The construct of claim 14 , wherein said interferon comprises the mutations H57Y, E58A, and Q61S.

25 . The construct of claim 14 , wherein said interferon comprises the mutations H57A, E58A, and Q61A.

26 . The construct according to any one of claims 1 - 25 , wherein said antibody comprises the complementarity determining regions of the B-B4 monoclonal antibody.

27 . The construct of claim 26 , wherein said antibody comprises the VH and/or VL domain of the B-B4 monoclonal antibody.

28 . The construct according to any one of claims 1 - 27 , wherein said antibody is an antibody selected from the group consisting of is a single chain Fv (scFv), a FAB, a (Fab′)2, an (ScFv) 2 , and a full IgG.

29 . The construct according to any one of claims 1 - 27 , wherein said antibody is an scFv.

30 . The construct according to any one of claims 1 - 27 , wherein said antibody is a full IgG.

31 . The construct of claim 27 , wherein said antibody is the B-B4 monoclonal antibody.

32 . The construct according to any of claims 1 - 31 , wherein said antibody is chemically coupled to said interferon.

33 . The construct according to any of claims 1 - 31 , wherein said antibody is directly joined to said interferon.

34 . The construct according to any of claims 1 - 31 , wherein said antibody is directly joined to said interferon with a peptide linker.

35 . The construct of claim 34 , wherein said peptide linker is proteolysis resistant.

36 . The construct of according to any one of claims 34 - 35 , wherein said peptide linker is fewer than 15 amino acids in length.

37 . The construct of according to any one of claims 34 - 36 , wherein said peptide linker is not (Gly 4 Ser) 3 .

38 . The construct of claim 33 , wherein the amino acid sequence of said peptide linker is selected from the group consisting of

GGG, GGS, GGGGS, SGGGGS, GGGGSGGGGS, A EAAAK A,

A EAAAK EAAAK A, A EAAAK EAAAK EAAAK A EAAAK

EAAAK EAAAK EAAAK A, A EAAAK EAAAK EAAAK EAAAK

EAA A, AEAAAKEAAAKAG, AEAAAKEAAAKAGS, GGGGG,

GGAGG, GGGGGGGG, GAGAGAGAGA, RPLSYRPPFPFGFPSVRP,

YPRSIYIRRRHPSPSLTT, TPSHLSHILPSFGLPTFN, RPVSPFT

FPRLSNSWLPA, SPAAHFPRSIPRPGPIRT, APGPSAPSHRSLPSR

AFG, PRNSIHFLHPLLVAPLGA, MPSLSGVLQVRYLSPPDL, SPQ

YPSPLTLTLPPHPSL, NPSLNPPSYLHRAPSRIS, LPWRTSLLPSL

PLRRRP, PPLFAKGPVGLLSRSFPP, VPPAPVVSLRSAHARPPY,

LRPTPPRVRSYTCCPTP, PNVAHVLPLLTVPWDNLR, CNPLLPL

CARSPAVRTFP, LGTPTPTPTPTGEF, EDFTRGKL, L EAAAR

EAAAR EAAAR EAAAR, L EAAAR EAAAR EAAAR, L EAAAR

EAAAR, L EAAAR, EAAAR EAAAR EAAAR EAAAR, EAAAR

EAAAR EAAAR, EAAAR EAAAR,

and

Assignees

• Univ California

Inventors

• Morrison Sherie L

Classifications

• C07K16/2896 Primary

  against molecules with a "CD"-designation, not provided for elsewhere · 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

• A61K38/212

  IFN-alpha · CPC title

• C07K14/57

  IFN-gamma · CPC title