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-9487573-B2
Publication Date
2016-11-08
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 an isolated or purified T cell receptor (TCR) having antigenic specificity for NY-ESO-1 and comprising a murine variable region. The invention further encompasses related polypeptides, proteins, nucleic acids, recombinant expression vectors, isolated host cells and populations of cells, antibodies or antigen binding portions thereof, and pharmaceutical compositions. Methods are provided for detecting the presence of cancer in a mammal and treating or preventing cancer in a mammal using the inventive TCRs or related materials.
Current adoptive cell therapies face limitations such as difficulty generating tumor-reactive T cells from many cancers and the inability to surgically resect tumors in many patients, prompting the need for effective TCRs suitable for treating cancer patients. NY-ESO-1, a cancer testis antigen expressed in various tumor types but limitedly in normal tissue, serves as a specific target for the inventive murine TCRs. The invention includes TCRs comprising murine variable and preferably murine constant regions, recognizing NY-ESO-1 in the context of MHC class I molecules, especially HLA-A2.
The inventive murine TCRs unexpectedly provide improved functionality and expression on human host cells compared to human TCRs, believed to be due to reduced mixing of endogenous and exogenous TCR chains, better pairing of TCR chains, and enhanced interactions with the CD3 complex. These features enable effective targeting and destruction of multiple NY-ESO-1 expressing cancer types while minimizing off-target toxicity to normal cells. The invention also covers functional portions and variants of the TCRs, nucleic acids encoding them, recombinant expression vectors with different arrangements of alpha and beta chains, host cells expressing the TCRs, populations thereof, and antibodies specifically binding to the TCRs.
Claims Coverage
The patent includes 26 inventive features focused on the isolated murine anti-NY-ESO-1 TCRs, their polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, pharmaceutical compositions, and methods of cancer detection and treatment.
TCRs possessing murine variable regions with defined amino acid sequences
An isolated or purified TCR having antigenic specificity for NY-ESO-1 and comprising a murine variable region with amino acid sequences of SEQ ID NOs: 3-8.
Antigen specificity for NY-ESO-1 157-165 peptide
The TCRs specifically recognizing NY-ESO-1157-165 peptide sequence (SEQ ID NO: 2).
TCRs comprising defined variable region amino acid sequences
The TCRs include those comprising amino acid sequences of SEQ ID NOs: 9 and 10 or SEQ ID NOs: 11 and 12.
Polypeptides and proteins derived from TCR sequences
Isolated or purified polypeptides comprising amino acid sequences SEQ ID NOs: 3-8 and proteins comprising such polypeptides, including fusion proteins and recombinant antibodies.
Nucleic acids encoding inventive TCRs
Isolated or purified nucleic acids encoding the murine anti-NY-ESO-1 TCRs, including codon-optimized sequences and combinations of SEQ ID NOs: 15 and 16 or 19 and 20.
Recombinant expression vectors encoding TCR sequences
Vectors containing nucleotide sequences encoding complementarity determining regions with arrangements positioning alpha chain sequences 5' or 3' of beta chain sequences, including those comprising SEQ ID NO: 17 or 18.
Host cells and populations expressing the recombinant TCR vectors
Isolated host cells and populations thereof comprising the recombinant expression vectors encoding the inventive TCRs, preferably human cells.
Pharmaceutical compositions comprising the inventive TCRs
Pharmaceutical compositions including the inventive murine anti-NY-ESO-1 TCRs and pharmaceutically acceptable carriers.
Methods for detecting cancer using the inventive TCRs
Methods involving contacting a sample from a mammal with the TCRs and detecting complexes indicative of the presence of melanoma, breast cancer, lung cancer, prostate cancer, thyroid cancer, ovarian cancer, or synovial cell sarcoma.
Methods for treating melanoma using the inventive TCRs
Administering the inventive murine anti-NY-ESO-1 TCRs to a mammal in an amount effective to treat melanoma.
The claims comprehensively cover the isolated murine anti-NY-ESO-1 TCRs with specific amino acid and nucleotide sequences, their polypeptides, proteins, recombinant vectors and host cells, pharmaceutical compositions, and methods of detecting and treating multiple cancer types, particularly melanoma, using these inventive TCRs.
Stated Advantages
Ability to destroy cells of multiple cancer types due to NY-ESO-1 expression, enabling treatment or prevention of diverse cancers.
Selective targeting of tumor cells expressing NY-ESO-1, minimizing destruction of normal non-cancerous cells and reducing toxicity.
Murine TCRs provide increased surface expression on human host cells and enhanced functionality compared to human TCRs.
Improved pairing of TCR chains and interaction with the human CD3 complex leads to more effective replacement of endogenous TCRs, enhancing immune response.
Documented Applications
Treating or preventing melanoma, breast cancer, lung cancer, prostate cancer, thyroid cancer, ovarian cancer, and synovial cell sarcoma by administering the murine anti-NY-ESO-1 TCRs or related materials.
Detecting the presence of cancer in a mammal by contacting a sample comprising cells with the murine anti-NY-ESO-1 TCRs or derivatives and detecting complexes indicative of cancer.
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