Chimeric receptors targeting ADGRE2 and/or CLEC12A and uses thereof

Patent metadata

Field	Value
Publication number	US-12331129-B2
Application number	US-202217728183-A
Country	US
Kind code	B2
Filing date	Apr 25, 2022
Priority date	Apr 26, 2021
Publication date	Jun 17, 2025
Grant date	Jun 17, 2025

Abstract

The presently disclosed subject matter provides for chimeric receptors that target ADGRE2 and chimeric receptors that target CLEC12A. The presently disclosed subject matter also provides for cells comprising the ADGRE2-targeted chimeric receptors, cells comprising the CLEC12A-targeted chimeric receptors, and cells comprising the ADGRE2-targeted chimeric receptors and the CLEC12A-targeted chimeric receptors. The presently disclosed subject matter further provides uses of such cells for treating tumors, e.g., AML.

First claim

What is claimed is:

1. A cell comprising a chimeric antigen receptor (CAR) and a chimeric co-stimulatory receptor (CCR), wherein
a) the CAR comprises an extracellular antigen-binding domain that binds to ADGRE2, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 36, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 37, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 38; and
b) the CCR comprises an extracellular antigen-binding domain that binds to CLEC12A, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain comprises:
i) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 69, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 70, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 71; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74;
ii) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 81, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 82, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 85;
iii) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 93, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 94;
iv) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 93, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 94;
v) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 81, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 103, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 105;
vi) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 109, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 103, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 110, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 85;
vii) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 114; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 115, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 93, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116; or
viii) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 120, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 121, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 122; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 123, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 124, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125.

2. The cell of claim 1 , wherein the CAR comprises a heavy chain variable region comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 39, SEQ ID NO:43, SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO: 52, SEQ ID NO: 55, or SEQ ID NO: 146; and a light chain variable region comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 50, SEQ ID NO: 53, SEQ ID NO: 56, or SEQ ID NO: 147.

3. The cell of claim 2 , wherein the CAR comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 39, SEQ ID NO:43, SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO: 52, SEQ ID NO: 55, or SEQ ID NO: 146; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 50, SEQ ID NO: 53, SEQ ID NO: 56, or SEQ ID NO: 147.

4. The cell of claim 3 , wherein the CAR comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 39; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 40.

5. The cell of claim 1 , wherein the CCR comprises a heavy chain variable region comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 75, SEQ ID NO: 86, SEQ ID NO: 95, SEQ ID NO: 100, SEQ ID NO: 106, SEQ ID NO: 111, SEQ ID NO: 117, or SEQ ID NO: 126; and a light chain variable region comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 76, SEQ ID NO: 87, SEQ ID NO: 96, SEQ ID NO: 101, SEQ ID NO: 107, SEQ ID NO: 112, SEQ ID NO: 118, or SEQ ID NO: 127.

6. The cell of claim 1 , wherein the cell is transduced with the CAR and the CCR.

7. The cell of claim 1 , wherein the CAR and/or the CCR is constitutively expressed on the surface of the cell.

8. The cell of claim 1 , wherein the cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, a stem cell from which a lymphoid cell may be differentiated, and a stem cell from which a myeloid cell may be differentiated.

9. The cell of claim 8 , wherein the stem cell is a pluripotent stem cell.

10. The cell of claim 1 , wherein the cell is a T cell.

11. The cell of claim 10 , wherein the T cell is selected from the group consisting of helper T cells, cytotoxic T cells, memory T cells, regulatory T cells, tumor-infiltrating lymphocyte (T

Assignees

• Memorial Sloan Kettering Cancer Center
• Millennium Pharm Inc
• Sloan Kettering Inst Cancer Res
• Memorial Hospital For Cancer And Allied Diseases

Inventors

• Sadelain Michel
• Haubner Sascha P
• Mansilla-Soto Jorge
• He Xingyue
• Shapiro Gary

Classifications

• A61K40/4224

  Molecules with a "CD" designation not provided for elsewhere · CPC title

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/4202

  Receptors, cell surface antigens or cell surface determinants · 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