Engineered T cells

Patent metadata

Field	Value
Publication number	US-12590136-B2
Application number	US-202017608860-A
Country	US
Kind code	B2
Filing date	May 7, 2020
Priority date	May 8, 2019
Publication date	Mar 31, 2026
Grant date	Mar 31, 2026

Abstract

The present disclosure provides improved compositions for adoptive T cell therapies for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.

First claim

The invention claimed is:

1 . A method of treating a subject having a solid cancer, comprising administering to the subject an effective amount of a T cell comprising a first polynucleotide encoding a MAGEA4 TCR; and a second polynucleotide encoding a fusion polypeptide, wherein the MAGEA4 TCR comprises an alpha chain comprising an amino acid sequence set forth in SEQ ID NO: 2 or 5 and a beta chain comprising an amino acid sequence set forth in SEQ ID NO: 3 or 6, and wherein the fusion polypeptide comprises:
(a) a first polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR2;
(ii) an IL-12Rβ2 transmembrane domain or an IL-12Rβ1 transmembrane domain; and
(iii) an IL-12Rβ2 intracellular signaling domain or an IL-12Rβ1 intracellular signaling domain;
(b) a polypeptide cleavage signal; and (c) a second polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR1;
(ii) an IL-12Rβ2 transmembrane domain or an IL-12Rβ1 transmembrane domain; and
(iii) an IL-12Rβ2 intracellular signaling domain or an IL-12Rβ1 intracellular signaling domain.

2 . The method of claim 1 , wherein the solid cancer comprises liver cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, brain cancer, sarcoma, head and neck cancer, bone cancer, thyroid cancer, kidney cancer, esophageal cancer, or skin cancer.

3 . The method of claim 1 , wherein the solid cancer is an esophageal cancer.

4 . The method of claim 1 , wherein the solid cancer is synovioma.

5 . The method of claim 1 , wherein the solid cancer is ovarian cancer.

6 . The method of claim 1 , wherein the solid cancer is non-small cell lung cancer.

7 . The method of claim 1 , wherein the solid cancer expresses MAGEA4.

8 . The method of claim 1 , wherein the first polypeptide comprises the IL-12Rβ2 intracellular signaling domain and the second polypeptide comprises the IL-12Rβ1 intracellular signaling domain.

9 . The method of claim 8 , wherein the first polypeptide comprises the IL-12Rβ2 transmembrane domain and/or the second polypeptide comprises the IL-12Rβ1 transmembrane domain.

10 . The method of claim 1 , wherein the first polypeptide comprises the IL-12Rβ1 intracellular signaling domain and the second polypeptide comprises the IL-12Rβ2 intracellular signaling domain.

11 . The method of claim 10 , wherein the first polypeptide comprises the IL-12Rβ1 transmembrane domain and/or the second polypeptide comprises the IL-12Rβ2 transmembrane domain.

12 . The method of claim 1 , wherein the polypeptide cleavage signal is a viral self-cleaving polypeptide.

13 . The cell of claim 12 , wherein the polypeptide cleavage signal is a viral self-cleaving 2A polypeptide.

14 . The method of claim 1 , wherein the MAGEA4 TCR comprises an alpha chain comprising an amino acid sequence set forth in SEQ ID NO: 2 and a beta chain comprising an amino acid sequence set forth in SEQ ID NO: 3.

15 . The method of claim 1 , wherein the MAGEA4 TCR comprises an alpha chain comprising an amino acid sequence set forth in SEQ ID NO: 5 and a beta chain comprising an amino acid sequence set forth in SEQ ID NO: 6.

16 . The method of claim 1 , wherein the fusion polypeptide comprises an amino acid sequence set forth in SEQ ID NO: 8.

17 . The method of claim 1 , wherein the source of the T cell is peripheral blood mononuclear cells, bone marrow, lymph nodes tissue, cord blood, thymus issue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, or tumors.

18 . A method of treating a subject having a solid cancer, comprising administering to the subject an effective amount of a T cell comprising a first polynucleotide encoding a MAGEA4 TCR; and a second polynucleotide encoding a fusion polypeptide, wherein the MAGEA4 TCR comprises an alpha chain comprising an amino acid sequence set forth in SEQ ID NO: 2 or 5 and a beta chain comprising an amino acid sequence set forth in SEQ ID NO: 3 or 6, and wherein the fusion polypeptide comprises:
(a) a TGFβR2 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR2;
(ii) an IL-12Rβ2 transmembrane domain; and
(iii) an IL-12Rβ2 intracellular signaling domain;
(b) a viral self-cleaving 2A peptide; and (c) a TGFβR1 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR1;
(ii) an IL-12Rβ1 transmembrane domain; and
(iii) an IL-12Rβ1 intracellular signaling domain.

19 . The method of claim 18 , wherein the solid cancer comprises liver cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, brain cancer, sarcoma, head and neck cancer, bone cancer, thyroid cancer, kidney cancer, esophageal cancer, or skin cancer.

20 . The method of claim 18 , wherein the solid cancer is an esophageal cancer.

21 . The method of claim 18 , wherein the solid cancer is synovioma.

22 . The method of claim 18 , wherein the solid cancer is ovarian cancer.

23 . The method of claim 18 , wherein the solid cancer is non-small cell lung cancer.

24 . The method of claim 18 , wherein the solid expresses MAGEA4.

25 . The method of claim 18 , wherein the MAGEA4 TCR comprises an alpha chain comprising an amino acid sequence set forth in SEQ ID NO: 2 and a beta chain comprising an amino acid sequence set forth in SEQ ID NO: 3.

26 . The method of claim 18 , wherein the MAGEA4 TCR comprises an alpha chain comprising an amino acid sequence set forth in SEQ ID NO: 5 and a beta chain comprising an amino acid sequence set forth in SEQ ID NO: 6.

27 . The method of claim 18 , wherein the source of the T cell is peripheral blood mononuclear cells, bone marrow, lymph nodes tissue, cord blood, thymus issue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, or tumors.

28 . A method of treating a subject having a solid cancer, comprising administering to the subject an effective amount of a T cell comprising a first polynucleotide encoding a MAGEA4 TCR; and a second polynucleotide encoding a fusion polypeptide, wherein the MAGEA4 TCR comprises an alpha chain comprising an amino acid sequence set forth in SEQ ID NO: 2 or 5 and a beta chain comprising an amino acid sequence set forth in SEQ ID NO: 3 or 6, and wherein the fusion polypeptide comprises:
(a) a TGFβR2 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR2;
(ii) an IL-12Rβ1 transmembrane domain; and
(iii) an IL-12Rβ1 intracellular signaling domain;
(b) a viral self-cleaving 2A peptide; and (c) a TGFβR1 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR1;
(ii) an IL-12Rβ2 transmembrane domain; and
(iii) an IL-12Rβ2 intracellular signaling domain.

29 . The method of claim 28 , wherein the solid cancer comprises liver cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, brain cancer, sarcoma, head and neck cancer, bone cancer, thyroid cancer, kidney cancer, esophageal cancer, or skin cancer.

30 . The method of claim 28 , wherein the solid cancer is an esophageal cancer.

31 . The method of claim 28 , wherein the solid cancer is synovioma.

32 . The method of claim 28 , wherein the solid ca

Assignees

• Regeneron Pharma
• Medigene Immunotherapies Gmbh

Inventors

• Mann Jasdeep
• Ellinger Christian
• Sommermeyer Daniel
• Boyerinas Benjamin

Classifications

• A61K40/4268

  MAGE · CPC title

• A61K40/4234

  Interleukins [IL] · CPC title

• A61K40/4229

  Transforming growth factor [TGF] · CPC title

• A61K40/32

  T-cell receptors [TCR] · CPC title

• A61K40/11 Primary

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