CD138-targeted interferon demonstrates potent apoptotic and anti-tumor activities

Patent metadata

Field	Value
Publication number	US-10975158-B2
Application number	US-201715789828-A
Country	US
Kind code	B2
Filing date	Oct 20, 2017
Priority date	Dec 7, 2012
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

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 alpha, or a mutant interferon alpha comprising mutations H57Y, E58A, and Q61, attached by a proteolysis-resistant peptide linker that has a length shorter than 15 amino acids to a full-length antibody that binds CD138, where the amino acid sequence of said linker consists of the sequence SGGGGS (SEQ ID NO:8), and where said chimeric construct is effective to synergistically enhance the activity of lenalidomide in inducing apoptosis of cancer cells.

2. The construct of claim 1 , wherein said construct, when contacted to a cell that expresses or overexpresses CD138, 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 of claim 1 , wherein said interferon is an interferon-alpha (IFN-α).

6. The construct of claim 5 , wherein said interferon is an interferon alpha 2 (IFNα2).

7. The construct of claim 5 , wherein said interferon is an interferon alpha 14 (IFNα14).

8. The construct of claim 1 , wherein said interferon is a mutant interferon alpha comprising mutations H57Y, E58A, and Q61S.

9. The construct of claim 1 , wherein said antibody comprises the complementarity determining regions of the B-B4 monoclonal antibody.

10. The construct of claim 9 , wherein said antibody comprises the VH and/or VL domain of the B-B4 monoclonal antibody.

11. The construct of claim 10 , wherein said antibody is the B-B4 monoclonal antibody.

12. A pharmaceutical formulation comprising a construct of claim 1 in a pharmaceutically acceptable excipient.

13. The formulation of claim 12 , wherein said formulation further comprises bortezomib and/or lenalidomide.

Assignees

• Univ California

Inventors

• Morrison Sherie L

Classifications

• A61K38/215

  IFN-beta · CPC title

• A61K38/212

  IFN-alpha · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title