Murine anti-NY-ESO-1 T cell receptors
Inventors
Parkhurst, Maria R. • Morgan, Richard A. • Rosenberg, Steven A. • Rosati, Shannon Faith
Assignees
US Department of Health and Human Services
Publication Number
US-10407485-B2
Publication Date
2019-09-10
Expiration Date
2033-05-22
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Abstract
The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for NY-ESO-1. Also provided are related polypeptides, proteins, nucleic acids, recombinant expression vectors, isolated host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions. The invention further provides a method of detecting the presence of cancer in a mammal and a method of treating or preventing cancer in a mammal using the inventive TCRs or related materials.
Core Innovation
The invention provides isolated or purified T cell receptors (TCRs) that have antigenic specificity for NY-ESO-1, a cancer testis antigen expressed exclusively in tumor cells and select germ cells. These TCRs comprise murine variable regions and can specifically bind to various forms of NY-ESO-1, including the NY-ESO-1157-165 peptide. The TCRs may be used in methods of detecting the presence of cancer in animals, as well as for treating or preventing cancer. Accompanying these TCRs are related polypeptides, proteins, nucleic acids, recombinant vectors, host cells, populations of cells, antibodies, and pharmaceutical compositions.
A primary problem addressed by the invention is the difficulty in generating tumor-reactive T cells for use in adoptive cell therapy, especially for non-melanoma cancers. Challenges include that only about half of melanoma tumor samples yield tumor-reactive T cells, and many patients have tumors that are not amenable to surgical resection. There is a need for effective T cell receptors capable of targeting cancer cells for treatment, overcoming limitations in current adoptive therapies.
The invention further provides TCRs with murine variable regions, optionally including murine constant regions, which are expressed on human host cells. It is posited that these murine TCRs offer advantages such as enhanced expression and functionality on human cells compared to human TCRs. The inventive murine TCRs recognize NY-ESO-1 presented by MHC class I molecules, e.g., HLA-A2, enabling specific immune responses against NY-ESO-1 expressing cancer cells, while minimizing off-target toxicity to normal tissues.
Claims Coverage
The patent claims comprise one independent claim primarily directed to a method of detecting NY-ESO-1 positive cancer using host cells expressing a murine variable region TCR specific for NY-ESO-1. The inventive features include TCR specificity, amino acid compositions, cancer types, and methods of detection.
Method of detecting NY-ESO-1 positive cancer using isolated host cells expressing murine variable region TCR
The claimed method involves contacting a sample containing cells from a mammal with isolated host cells or populations thereof expressing a TCR with antigenic specificity for NY-ESO-1. The TCR comprises murine variable regions and the amino acid sequences of SEQ ID NOs: 3-8. Detection of the TCR-cell complex indicates the presence of NY-ESO-1 positive cancer.
Specificity for multiple cancer types
The method includes detection of cancers such as melanoma, breast cancer, lung cancer, prostate cancer, thyroid cancer, ovarian cancer, or synovial cell sarcoma.
TCR antigenic specificity for NY-ESO-1157-165 peptide
The TCR exhibits antigenic specificity particularly for the NY-ESO-1157-165 peptide (SEQ ID NO: 2).
TCR comprising defined amino acid sequences
The TCR contains amino acid sequences comprising CDRs and variable regions as set forth by SEQ ID NOs: 9 and 10 or full-length alpha and beta chains as SEQ ID NOs: 11 and 12.
Use of human isolated host cells
The isolated host cells expressing the murine variable region TCR are human cells, enabling application in human mammals.
The claims cover a method for detecting NY-ESO-1 positive cancer in mammals using human host cells expressing murine variable region TCRs with defined amino acid sequences, offering specificity for multiple cancer types and the NY-ESO-1157-165 peptide.
Stated Advantages
The inventive TCRs can destroy multiple types of cancer cells due to NY-ESO-1 expression in various cancers.
Due to NY-ESO-1 expression only in tumor cells and select germ cells, the TCRs minimize destruction of normal cells, reducing toxicity.
Murine TCRs offer increased expression levels and enhanced functionality, including cytokine release and cytotoxicity, compared to human TCRs on human host cells.
Reduced mixing of endogenous and exogenous TCR chains ensures efficient replacement of human TCRs on host cells by murine TCRs.
Murine TCRs provide improved TCR chain pairing and interactions with human CD3 complexes, enhancing immune responses.
Documented Applications
Method of detecting the presence of cancer in mammals by contacting a sample of cancer cells with murine TCRs or related materials and detecting the complex formed.
Method of treating or preventing cancer in mammals by administering TCRs, polypeptides, nucleotide sequences, recombinant vectors, or host cells expressing murine anti-NY-ESO-1 TCRs.
Adoptive cell transfer therapies employing human T cells transduced with murine anti-NY-ESO-1 TCRs to target melanoma, breast, lung, prostate, thyroid, ovarian cancers, and synovial cell sarcoma.
Use of recombinant expression vectors and pharmaceutical compositions comprising murine anti-NY-ESO-1 TCRs for cancer therapy.
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