Engineered immune effector cells for cancer immunotherapy that are resistant to fratricide by virtue of having genetically modified surface antigens

Patent metadata

Field	Value
Publication number	US-12576148-B2
Application number	US-202418429213-A
Country	US
Kind code	B2
Filing date	Jan 31, 2024
Priority date	Nov 26, 2014
Publication date	Mar 17, 2026
Grant date	Mar 17, 2026

Abstract

This disclosure provides a system for preventing or reducing side effects in a patent undergoing immunotherapy to remove diseased cells that express a target antigen: for example, by CAR T cell therapy. Side effects can ensue from concurrent depletion of hematopoietic cells bearing the same target antigen. A population of engineered hematopoietic cells is prepared by obtaining healthy hematopoietic cells from the patient or a third party donor, and using them to produce engineered hematopoietic cells. The engineered cells either do not express the target antigen, express it at a lower density, or express it in a modified form. The engineered hematopoietic cells are formulated for administration to the patient, whereupon they reconstitute hematopoietic cell function, thereby preventing or reducing the side effects.

First claim

The invention claimed is:

1 . A method of treating a patient having a cancer characterized by malignant cells that express a cluster of differentiation (CD) target antigen that is also expressed on at least some hematopoietic cells in the patient, the method comprising:
(a) producing a population of engineered immune effector cells that are resistant to fratricide by: (i) obtaining immune effector cells from a donor; (ii) genetically modifying the immune effector cells to express a receptor that recognizes the target antigen; and (iii) genetically modifying the immune effector cells to express the target antigen in a modified form that is not recognized by the receptor, whereby the immune effector cells are resistant to fratricide; then (b) administering the population of engineered immune effector cells to the patient.

2 . The method of claim 1 , wherein the receptor that recognizes the target antigen is a T cell receptor (TCR) or a chimeric antigen receptor (CAR).

3 . The method of claim 1 , wherein the immune effector cells are CAR-NK cells.

4 . The method of claim 1 , wherein the immune effector cells are CAR-T cells.

5 . The method of claim 1 , wherein the patient has a hematopoietic cell malignancy.

6 . The method of claim 1 , wherein the engineered immune effector cells express a truncated form of the target antigen.

7 . The method of claim 1 , wherein the engineered immune effector cells express a modified form of the target antigen that comprises one or a plurality of amino acid substitutions or deletions, whereby said receptor not recognize the modified form of the target antigen.

8 . The method of claim 7 , wherein the modified form of the target antigen expressed by the engineered immune effector cells has an amino acid sequence that is over 90% identical to the target antigen expressed on the malignant cells.

9 . The method of claim 1 , wherein said receptor has a binding affinity for the engineered immune effector cells that is one tenth or less of the binding affinity for the malignant cells.

10 . The method of claim 1 , wherein the target antigen is modified in way that does not alter or affect its natural function.

11 . The method of claim 1 , wherein the donor of the immune effector cells is the patient.

12 . The method of claim 1 , wherein the donor of the immune effector cells is a person other than the donor.

13 . A method of producing a population of immune effector cells that are resistant to fratricide for treating a patient who has cancer,
wherein the cancer is characterized by malignant cells that express a cluster of differentiation (CD) target antigen that is also expressed on at least some hematopoietic cells in the patient, the method comprising: (i) obtaining immune effector cells from a donor; (ii) genetically modifying the immune effector cells to express a receptor that recognizes the target antigen; (iii) genetically modifying the immune effector cells to express the target antigen in a modified form that is not recognized by the receptor, whereby the immune effector cells are resistant to fratricide; then (iv) formulating the genetically modified immune effector cells that are resistant to freatricide as a medicament for administration to the patient.

14 . The method of claim 13 , wherein the receptor that recognizes the target antigen is a T cell receptor (TCR) or a chimeric antigen receptor (CAR).

15 . The method of claim 13 , wherein the genetically modified immune effector cells are CAR-NK cells.

16 . The method of claim 13 , wherein the genetically modified immune effector cells are CAR-T cells.

17 . The method of claim 13 , wherein the malignant cells are hematopoietic cells.

18 . The method of claim 13 , wherein the genetically modified immune effector cells express a truncated form of the target antigen.

19 . The method of claim 13 , wherein the genetically modified immune effector cells express a modified form of the target antigen that comprises one or a plurality of amino acid substitutions or deletions, whereby said receptor does not recognize the modified form of the target antigen.

20 . The method of claim 19 , wherein the modified form of the target antigen expressed by the genetically modified immune effector cells has an amino acid sequence that is over 90% identical to the target antigen expressed on the malignant cells.

21 . The method of claim 13 , wherein said receptor has a binding affinity for the genetically modified immune effector cells that is one tenth or less of the binding affinity for the malignant cells.

22 . The method of claim 13 , wherein the target antigen is modified in way that does not alter or affect its natural function.

Assignees

• Miltenyi Biotec Bv & Co Kg
• Mitenyi Biotec B V & Co Kg

Inventors

• Lutteropp Michael
• Richter Anne
• Kaiser Andrew
• Assenmacher Mario
• Miltenyi Stefan

Classifications

• A61K40/4221

  CD20 · 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

• A61K2039/5156

  expressing foreign proteins · CPC title

• A61K2035/124

  the cells being hematopoietic, bone marrow derived or blood cells · CPC title