IP Library › Granted Patent US 12,653,886
Granted Patent B2
US 12,653,886 · App. 17/636,314 · Granted Jun 16, 2026

T-cell immunotherapy specific for WT-1

Inventors: Thomas M. Schmitt (Seattle, WA); Aude G. Chapuis (Seattle, WA); Philip D. Greenberg (Mercer Island, WA)
Assignee: Fred Hutchinson Cancer Center
A61K40/11A61K40/32A61K40/4243A61P35/00C12N5/0636C12N5/0646A61K2239/54
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Quick Facts
Patent No.
US 12,653,886
App. No.
17/636,314
Granted
Jun 16, 2026
Kind
B2
Abstract

The present disclosure provides binding proteins specific for human Wilms tumor protein 1 (WT-1) epitopes, as well as host cells that express the binding proteins. Also provided are polynucleotides that encode a binding protein and vectors that comprise a polynucleotide. Related methods and uses of the presently disclosed compositions are provided for treating diseases or disorders associated with WT-1 expression, such as various cancers.

Claims (61)

1 . A host cell, comprising a heterologous polynucleotide that encodes a binding protein comprising a T cell receptor (TCR) α chain variable (Vα) domain and a TCR β-chain variable (Vβ) domain,

wherein the encoded TCR Vα and Vβ domains comprise CDR1α, CDR2α, CDR3α, CDR1β, CDR2β, and CDR3β amino acid sequences of:

(i) SEQ ID NOs.: 26-28 and 38-40, respectively; or

(ii) SEQ ID NOs.: 23, 27, 28, and 38-40, respectively,

and wherein the encoded binding protein is capable of binding to a RMFPNAPYL (SEQ ID NO.: 94): human leukocyte antigen (HLA) complex.

2 . The host cell of claim 1 , wherein the HLA comprises HLA-A*201.

3 . The host cell of claim 1 , wherein:

(i) the encoded Vβ domain comprises an amino acid sequence having at least 90% identity to the amino acid sequence of any one of SEQ ID NOs.: 16 and 8; and/or

(ii) the encoded Vα domain comprises an amino acid sequence having at least 90% identity to the amino acid sequence of any one of SEQ ID NOs.: 12 and 4.

4 . The host cell of claim 1 , wherein the encoded TCR Vα and Vβ domains comprise CDR1α, CDR2α, CDR3α, CDR1β, CDR2β, and CDR3β amino acid sequences of SEQ ID NOs.: 26-28 and 38-40, respectively.

5 . The host cell of claim 1 , wherein:

the encoded Vβ domain comprises the amino acid sequence of SEQ ID NO.: 16, and the encoded Vα domain comprises of the amino acid sequence of SEQ ID NO.: 12.

6 . The host cell of claim 1 , wherein the encoded VB domain comprises the amino acid sequence of SEQ ID NO.: 8, and the encoded Va domain comprises the amino acid sequence of SEQ ID NO.: 4.

7 . The host cell of claim 1 , wherein:

(i) the encoded TCR Vβ domain comprises an amino acid sequence according to a TRBJ02-03 gene segment; and/or

(ii) the encoded TCR Vα domain comprises an amino acid sequence according to a TRAJ43 gene segment.

8 . The host cell of claim 1 , wherein the encoded Vβ domain comprises the amino acid sequence of SEQ ID NO.: 16 or 8, and the encoded Vα domain comprises the amino acid sequence of SEQ ID NO.: 12 or 4.

9 . The host cell of claim 1 , wherein the encoded binding protein further comprises:

(i) a TCR α chain constant domain (Cα), or a fragment thereof; and/or

(ii) a TCR β chain constant domain (Cβ), or a fragment thereof.

10 . The host cell of claim 9 , wherein: (i) the encoded Cα comprises an amino acid sequence having at least 90% identity to SEQ ID NO.: 44; and/or (ii) the encoded Cβ comprises an amino acid sequence having at least 90% identity to SEQ ID NO.: 45.

11 . The host cell of claim 1 , wherein the encoded binding protein comprises a TCR β chain having at least 90% identity to the amino acid sequence of SEQ ID NO.: 61 or 57, and a TCR α chain having at least 90% identity to the amino acid sequence of SEQ ID NO.: 53 or 49.

12 . The host cell of claim 1 , wherein the encoded binding protein is a TCR, a chimeric antigen receptor (CAR), or a single-chain TCR (scTCR).

13 . The host cell of claim 1 , wherein the host cell is an immune system cell.

14 . The host cell of claim 1 , wherein the host cell is a human T cell.

15 . The host cell of claim 14 , wherein the T cell is a naïve T cell, a central memory T cell, an effector memory T cell, a stem cell memory T cell, or any combination thereof.

16 . The host cell of claim 1 , wherein the polynucleotide encoding the binding protein comprises a polynucleotide having at least 75% identity to the polynucleotide sequence set forth in any one of SEQ ID NOs.: 65, 69, 73, and 77.

17 . The host cell of claim 1 , further comprising:

(i) a heterologous polynucleotide encoding a polypeptide that comprises an extracellular portion of a CD8 co-receptor α chain, wherein, optionally, the encoded polypeptide comprises a CD8 co-receptor α chain;

(ii) a heterologous polynucleotide encoding a polypeptide that comprises an extracellular portion of a CD8 co-receptor β chain, wherein, optionally, the encoded polypeptide comprises a CD8 co-receptor β chain; or

(iii) the polynucleotide of (i) and the polynucleotide of (ii),

wherein, optionally, the host cell comprises a CD4+ T cell.

18 . An isolated polynucleotide encoding a binding protein, wherein the encoded binding protein comprises a TCR Vα domain and a TCR Vβ domain and is capable of binding to a RMFPNAPYL (SEQ ID NO.: 94): HLA complex, wherein the HLA optionally comprises HLA-A*0201, and

wherein the encoded TCR Vα and Vβ domains comprise CDR1α, CDR2α, CDR3α, CDR1β, CDR2β, and CDR3β amino acid sequences of:

(i) SEQ ID NOs.: 26-28 and 38-40, respectively; or

(ii) SEQ ID NOs.: 23, 27, 28, and 38-40, respectively.

19 . The isolated polynucleotide of claim 18 , wherein the polynucleotide comprises a polynucleotide having at least 75% identity to the polynucleotide sequence set forth in any one of SEQ ID Nos.: 65, 69, 73, 77 and 81.

20 . A vector, comprising the polynucleotide of claim 18 .

21 . A composition, comprising:

the host cell of claim 1 ; and

a pharmaceutically acceptable carrier, excipient, or diluent.

22 . A method for treating a HLA-A*201-positive subject having a hyperproliferative disorder associated with WT-1 expression, comprising administering to the subject an effective amount of the host cell of claim 1 , wherein the host cell comprises a CD4+ T cell, a CD8+ T cell, or both.

23 . The method of claim 22 , wherein the hyperproliferative disorder is a hematological malignancy or a solid cancer.

24 . The method of claim 23 , wherein the hematological malignancy is selected from acute lymphoblastic leukemia (ALL), acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloid leukemia (AML, including refractory and relapsed AML, and including acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelocytic leukemia, acute myelomonocytic leukemia (e.g., with or without eosinophilia), acute monocytic leukemia, acute erythroid leukemia, and acute megakaryoblastic leukemia), chronic myelogenous leukemia (CML), chronic myelocytic leukemia, chronic eosinophilic leukemia (CEL), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or multiple myeloma (MM, including refractory and relapsed MM).

25 . The method of claim 23 , wherein the solid cancer is selected from biliary cancer, bladder cancer, bone and soft tissue carcinoma, brain tumor, breast cancer, breast carcinoma, cervical cancer, colon cancer, colorectal adenocarcinoma, colorectal cancer, desmoid tumor, embryonal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastric adenocarcinoma, glioblastoma multiforme, glioblastoma, melanoma, diffuse peritoneal mesothelioma, malignant pleural mesothelioma, glioma, astrocytoma, gynecological tumor, head and neck squamous cell carcinoma, hepatic cancer, hepatocellular carcinoma, lung cancer, non small-cell lung cancer, malignant melanoma, osteosarcoma, ovarian cancer (e.g., epithelial ovarian cancer, ovarian carcinoma), fallopian tube cancer, endometrial carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, primary astrocytic tumor, primary thyroid cancer, prostate cancer, renal cancer, renal cell carcinoma, rhabdomyosarcoma, skin cancer, soft tissue sarcoma, osteogenic sarcoma, testicular germ-cell tumor, urothelial cancer, uterine sarcoma, uterine carcinosarcoma, or uterine cancer.

26 . A binding protein comprising a T cell receptor (TCR) α chain variable (Vα) domain and a TCR β chain variable (Vβ) domain, wherein the encoded TCR Vα and Vβ domains comprise CDR1α, CDR2α, CDR3α, CDR1β, CDR2β, and CDR3β amino acid sequences of:

(i) SEQ ID NOs.: 26-28 and 38-40, respectively; or

(ii) SEQ ID NOs.: 23, 27, 28, and 38-40, respectively.

27 . The binding protein of claim 26 , which is a TCR comprising a TCR Cα and a TCR Cβ, wherein the TCR Cα and the TCR Cβ each comprise a cysteine amino acid in place of a native amino acid.

28 . A method comprising introducing the polynucleotide of claim 18 into a host cell.

29 . The method of claim 22 , wherein the encoded binding protein is a TCR and wherein:

(i) the encoded Vβ domain comprises the amino acid sequence of SEQ ID NO.: 16, and the encoded Vα domain comprises the amino acid sequence of SEQ ID NO.: 12; or

(ii) the encoded Vβ domain comprises or consists of the amino acid sequence of SEQ ID NO.: 8, and the encoded Vα domain comprises or consists of the amino acid sequence of SEQ ID NO.: 4.

30 . The isolated polynucleotide of claim 18 , wherein:

the encoded binding protein is a TCR comprising a TCR α chain constant domain (Ca) and a TCR β chain constant domain (Cβ), and wherein the TCR Cα and the TCR Cβ each comprise a cysteine amino acid in place of a native amino acid; and/or

the encoded binding protein is a TCR comprising a TCR α chain and a TCR β chain, and wherein the polynucleotide comprises: a sequence encoding a self-cleaving peptide, wherein the sequence encoding a self-cleaving peptide is disposed between (i) a sequence encoding the TCR β chain and (ii) a sequence encoding the TCR α chain.

31 . The vector of claim 20 , which is a lentiviral, retroviral, or adenoviral expression vector.

32 . The host cell of claim 14 , wherein:

the host cell is a human CD8+ T cell; and/or

(i) the encoded Vβ domain consists of the amino acid sequence of SEQ ID NO.: 8, and the encoded Vα domain consists of the amino acid sequence of SEQ ID NO.: 4; or

(ii) the encoded Vβ domain consists of the amino acid sequence of SEQ ID NO.: 16, and the encoded Vα domain consists of the amino acid sequence of SEQ ID NO.: 12.

Assignments (3)
MERGER AND CHANGE OF NAME Recorded Mar 19, 2026
From: FRED HUTCHINSON CANCER RESEARCH CENTER; SEATTLE CANCER CARE ALLIANCE
To: FRED HUTCHINSON CANCER CENTER
Reel/Frame 075147/0160 →
CONFIRMATORY LICENSE Recorded Mar 15, 2022
From: FRED HUTCHINSON CANCER RESEARCH CENTER
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 059365/0405 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 18, 2022
From: SCHMITT, THOMAS M.; CHAPUIS, AUDE G.; GREENBERG, PHILIP D.
To: FRED HUTCHINSON CANCER RESEARCH CENTER
Reel/Frame 059047/0083 →
Continuity (2)
Provisional Application 62889519 · Aug 20, 2019
Related Publication 20220409661A1 · Dec 29, 2022
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Wang et al., “Optimizing Adoptive Polyclonal T Cell Immunotherapy of Lymphomas, Using a Chimeric T Cell Receptor Possessing CD28 and CD137 Costimulatory Domains,” [cited by applicant]
Warren et al., “Exhaustive T-cell repertoire sequencing of human peripheral blood samples reveals signatures of antigen selection and a directly measured repertoire size of at least 1 million clonotypes,” [cited by applicant]
Wilson, “Analyzing Biomolecular Interactions,” [cited by applicant]
Wolfe et al., “Analysis of Zinc Fingers Optimized via Phage Display: Evaluating the Utility of a Recognition Code,” [cited by applicant]
Wolff et al., “Monoclonal Antibody Homodimers: Enhanced Antitumor Activity in Nude Mice,” [cited by applicant]
Xie et al., “sgRNAcas9: A Software Package for Designing CRISPR sgRNA and Evaluating Potential Off-Target Cleavage Sites,” [cited by applicant]
Zhao et al., “High-Affinity TCRs Generated by Phage Display Provide CD4+ T Cells with the Ability to Recognize and Kill Tumor Cell Lines,” [cited by applicant]
Zhao et al., “Primary Human Lymphocytes Transduced with NY-ESO-1 Antigen-SpecificTCR Genes Recognize and Kill Diverse Human Tumor Cell Lines,” [cited by applicant]
Zhou et al., “Improving the Safety of T Cell Therapies using an Inducible Caspase-9 Gene,” [cited by applicant]