Constructs targeting afp peptide/mhc complexes and uses thereof

Patent metadata

Field	Value
Publication number	US-2018079815-A1
Application number	US-201715829783-A
Country	US
Kind code	A1
Filing date	Dec 1, 2017
Priority date	Apr 3, 2015
Publication date	Mar 22, 2018
Grant date	—

Abstract

The present application provides constructs comprising an antibody moiety that specifically binds to a complex comprising an AFP peptide and an MHC class I protein. Also provided are methods of making and using these constructs.

First claim

What is claimed is:

1 . An isolated anti-AMC construct comprising an antibody moiety that specifically binds to a complex comprising an alpha-fetoprotein (AFP) peptide and a major histocompatibility (MHC) class I protein (AFP/MHC class I complex, or AMC), wherein the antibody moiety comprises:
a heavy chain variable domain comprising a heavy chain complementarity determining region (HC-CDR)1 comprising the amino acid sequence of SEQ ID NO: 63, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 73, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 83; and a light chain variable domain comprising a light chain complementarity determining region (LC-CDR)1 comprising the amino acid sequence of SEQ ID NO: 96, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 116.

2 . The isolated anti-AMC construct of claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 23 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 33.

3 . The isolated anti-AMC construct of claim 1 , wherein the isolated anti-AMC construct is a chimeric antigen receptor (CAR) comprising an extracellular domain comprising the antibody moiety, a transmembrane domain, and an intracellular signaling domain.

4 . The isolated anti-AMC construct of claim 3 , wherein the intracellular signaling domain comprises a CD3ζ intracellular signaling sequence and a co-stimulatory signaling sequence.

5 . The isolated anti-AMC construct of claim 4 , wherein the co-stimulatory signaling sequence comprises a CD28 or 4-1BB intracellular signaling sequence.

6 . The isolated anti-AMC construct of claim 5 , wherein the co-stimulatory signaling sequence comprises a CD28 intracellular signaling sequence.

7 . The isolated anti-AMC construct of claim 6 , wherein the transmembrane domain comprises a CD28 transmembrane region.

8 . The isolated anti-AMC construct of claim 3 , wherein the antibody moiety is an scFv.

9 . The isolated anti-AMC construct of claim 1 , wherein the isolated anti-AMC construct is a tandem scFv comprising a first scFv linked by a peptide linker to a second scFv, wherein the first scFv is the antibody moiety that specifically binds to the AFP/MHC class I complex.

10 . The isolated anti-AMC construct of claim 9 , wherein the second scFv is specific for CD3ε.

11 . The isolated anti-AMC construct of claim 10 , wherein the first scFv is N-terminal to the second scFv.

12 . The isolated anti-AMC construct of claim 1 , wherein the isolated anti-AMC construct is an immunoconjugate comprising the antibody moiety and an effector molecule, wherein the effector molecule is a therapeutic agent selected from the group consisting of a drug, a toxin, a radioisotope, a protein, a peptide, and a nucleic acid.

13 . The isolated anti-AMC construct of claim 1 , wherein the isolated anti-AMC construct is an immunoconjugate comprising the antibody moiety and a label.

14 . A nucleic acid encoding the polypeptide components of the isolated anti-AMC construct of claim 1 .

15 . A host cell expressing the isolated anti-AMC construct of claim 1 .

16 . An effector cell expressing the isolated anti-AMC construct of claim 1 .

17 . A CAR T cell expressing the isolated anti-AMC construct of claim 3 .

18 . A pharmaceutical composition comprising the CAR T cell of claim 17 .

19 . A method of treating an individual having an AFP-positive disease, comprising
administering to the individual an effective amount of the pharmaceutical composition of claim 18 .

20 . The method of claim 19 , wherein the administration is via intravenous or intratumoral route.

21 . The method of claim 19 , wherein the administration is to an injection site distal to a first disease site.

22 . The method of claim 19 , wherein the AFP-positive disease is cancer.

23 . The method of claim 22 , wherein the cancer is hepatocellular carcinoma, germ cell tumor, or breast cancer.

24 . The method of claim 23 , wherein the cancer is hepatocellular carcinoma.

25 . The method of claim 24 , wherein the cancer is metastatic hepatocellular carcinoma.

Assignees

• Eureka Therapeutics Inc

Inventors

• Liu Cheng
• Liu Hong
• Xu Yiyang
• Xiang Jingyi
• Long Li

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• C07K2319/03

  containing a transmembrane segment · CPC title