Compositions and methods for targeting stromal cells for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-11718685-B2
Application number	US-201916417125-A
Country	US
Kind code	B2
Filing date	May 20, 2019
Priority date	Oct 1, 2012
Publication date	Aug 8, 2023
Grant date	Aug 8, 2023

Abstract

The present invention provides compositions and methods for treating cancer in a human. The invention relates to targeting the stromal cell population in a tumor microenvironment. For example, in one embodiment, the invention provides a composition that is targeted to fibroblast activation protein (FAP). The invention includes a chimeric antigen receptor (CAR) which comprises an anti-FAP domain, a transmembrane domain, and a CD3zeta signaling domain.

First claim

What is claimed is:

1. A chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain derived from an F19 binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the antigen binding domain binds to a stromal cell antigen, and wherein the antigen binding domain comprises:
(a) a light chain variable region comprising a light chain complementary region 1 comprising the amino acids 24-39 of SEQ ID NO:9 (RSSQSIVHSNGNTYLE), a light chain complementary region 2 comprising the amino acids 55-61 of SEQ ID NO: 9 (KVSNRFS), a light chain complementary region 3 comprising amino acids 94-102 of SEQ ID NO: 9 (FGGSHVPYT); or
(b) a heavy chain variable region comprising a heavy chain complementary region 1 comprising the amino acids 30-34 of SEQ ID NO: 8 (SYGMS), a heavy chain complementary region 2 comprising the amino acids 49-65 of SEQ ID NO: 8 (TTNNNGGVTYYPDSVKG), a heavy chain complementary region 3 comprising the amino acids 98-105 (YGYYAMDY).

2. The CAR of claim 1 , wherein the antigen binding domain is selected from the group consisting of an antibody or an antigen-binding fragment thereof, a Fab, or a single-chain variable fragment (scFv).

3. The CAR of claim 1 , wherein the stromal cell antigen is expressed on a stromal cell present in a tumor microenvironment.

4. The CAR of claim 3 , wherein the tumor is a carcinoma.

5. The CAR of claim 1 , wherein the stromal cell antigen is fibroblast activation protein (FAP).

6. The CAR of claim 1 , wherein the costimulatory signaling region comprises the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof.

7. The CAR of claim 1 , wherein the transmembrane domain comprises a transmembrane domain selected from the group consisting of an artificial hydrophobic sequence, and a transmembrane domain of a type I transmembrane protein, an alpha, beta, or zeta chain of a T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, OX40 (CD134), 4-1BB (CD137), and CD154, or a transmembrane domain derived from a killer immunoglobulin-like receptor (KIR).

8. The CAR of claim 1 , wherein the antigen binding domain comprises:
(a) a light chain variable region comprising a light chain complementary region 1 comprising the amino acids 24-39 of SEQ ID NO:9 (RSSQSIVHSNGNTYLE), a light chain complementary region 2 comprising the amino acids 55-61 of SEQ ID NO: 9 (KVSNRFS), a light chain complementary region 3 comprising amino acids 94-102 of SEQ ID NO: 9 (FGGSHVPYT); and
(b) a heavy chain variable region comprising a heavy chain complementary region 1 comprising the amino acids 30-34 of SEQ ID NO: 8 (SYGMS), a heavy chain complementary region 2 comprising the amino acids 49-65 of SEQ ID NO: 8 (TTNNNGGVTYYPDSVKG), a heavy chain complementary region 3 comprising the amino acids 98-105 (YGYYAMDY).

Assignees

• Univ Pennsylvania
• Wistar Inst

Inventors

• June Carl H
• Pure Ellen
• Wang Liang-Chuan
• Albelda Steven
• Scholler John

Classifications

• A61K40/4249

  Serine proteases, e.g. kallikrein · CPC title

• A61K40/31

  Chimeric antigen receptors [CAR] · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K2239/55

  Lung · CPC title

• A61K2239/31

  characterized by the route of administration · CPC title