Human alpha fetoprotein-specific murine T cell receptors and uses thereof
Inventors
He, Yukai • Zhu, Wei • Celis, Esteban • Peng, Yibing • Wang, Lan
Assignees
US Government Nih Division Of Extramural Inventionsl And Technology Resources Deitr • National Institutes of Health NIH • Augusta University Research Institute Inc • US Department of Health and Human Services
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Publication Number
US-11041011-B2
Publication Date
2021-06-22
Expiration Date
2038-05-02
Abstract
T cell receptors that specifically recognize hAFP158 and methods of their use are provided.
Core Innovation
The invention provides engineered murine T cell receptors (mTCRs) that specifically recognize the human alpha fetoprotein epitope hAFP158 (SEQ ID NO:1). These mTCRs include various Vα and Vβ chain polypeptides, full length chains, and regions such as CDR3 with defined sequence identities to specified SEQ ID NOs, all designed to bind specifically to the HLA-A2/hAFP158 complex. Methods include genetically engineering human T cells, including autologous T cells, to express these mTCRs for adoptive cell transfer immunotherapy.
The background identifies hepatocellular carcinoma (HCC) as a common and lethal cancer lacking effective treatments. Tumor-associated antigens such as human glypican 3 (hGPC3) and human alpha fetoprotein (hAFP) are expressed on HCC cells, making them targets for immunotherapy. However, prior human TCRs specific to hAFP158 showed low affinity and weak antitumor effects. Attempts to enhance affinity by mutating CDR regions have not yet demonstrated clinical efficacy and may cause off-target toxicity. There is an urgent need for additional TCRs with high affinity and low toxicity for engineering patient T cells for immunotherapy.
The invention addresses this need by isolating multiple pairs of murine TCR α and β chain genes specific for hAFP158 through immunizing transgenic mice, generating T cell hybridomas, identifying paired α and β chains, and synthesizing codon-optimized gene constructs. Expression of these mTCRs in human T cells results in functional TCRs with high affinity for the HLA-A2/hAFP158 complex, capable of recognizing, responding to, and killing hAFP-positive human tumor cells in vitro and in vivo. The invention also includes soluble forms of these TCRs and fusion proteins enabling diagnostic and therapeutic applications.
Claims Coverage
The patent includes three independent claims covering recombinant T cell receptors with specific Vα and Vβ domains.
Recombinant TCR with defined Vα and Vβ domains
A recombinant T cell receptor (TCR) comprising a Vα domain with amino acid sequence SEQ ID NO:16 and a Vβ domain with amino acid sequence SEQ ID NO:24.
Humanized recombinant TCR
A recombinant TCR as above wherein the TCR is humanized.
Recombinant TCR polypeptide binding HLA-A2/hAFP158 complex
A recombinant TCR polypeptide comprising at least one Vα chain polypeptide with sequence SEQ ID NO:3 and at least one Vβ chain polypeptide with sequence SEQ ID NO:11, specifically binding to the HLA-A2/hAFP158 complex.
The independent claims primarily cover recombinant murine TCRs with defined Vα and Vβ domains specific for the HLA-A2/hAFP158 complex, including humanized versions and polypeptides capable of specific binding to the complex. These claims encompass engineered TCR proteins suitable for use in immunotherapy against hAFP-expressing tumors.
Stated Advantages
The mTCRs provide high-affinity recognition of the hAFP158 epitope, potentially increasing antitumor efficacy compared to prior human TCRs.
Using murine TCRs can improve surface expression and replace endogenous human TCRs more effectively, enhancing engineered T cell functionality.
The availability of multiple distinct mTCR sequences increases the chances of finding optimal TCRs with high efficacy and low toxicity.
The engineered human T cells expressing these mTCRs can specifically recognize, respond to, and kill hAFP-positive tumor cells in vitro and eradicate tumors in vivo.
Documented Applications
Treatment of hepatocellular carcinoma by adoptive transfer of human T cells engineered to express the disclosed mTCRs targeting hAFP158.
Genetically engineering autologous human T cells with mTCR genes specific for hAFP158 for immunotherapy against hAFP-expressing tumors.
Use of soluble mTCRs or labeled polypeptides for detecting heptacellular carcinoma cells expressing HLA-A2/hAFP158 complex.
Development of immunodetection kits comprising antibodies or mTCR polypeptides for diagnostic applications related to hAFP-expressing cancers.
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