HERV-E reactive T cell receptors and methods of use
Inventors
Childs, Richard W. • Nishimura, Michael I. • Cherkasova, Elena A.
Assignees
Loyola University Chicago • US Department of Health and Human Services
Publication Number
US-11779603-B2
Publication Date
2023-10-10
Expiration Date
2037-06-30
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed herein are T cell receptors (TCRs) capable of binding an antigen expressed by renal cell carcinoma cells. In some examples, the TCRs include an α chain (such as SEQ ID NO: 2) and a β chain (such as SEQ ID NO: 3). Also disclosed herein are vectors including nucleic acids encoding the disclosed TCR α and/or β chains. Further disclosed are modified T cells expressing the TCRs. In some examples, the modified T cells are prepared by transducing T cells with a vector including nucleic acids encoding the TCR α chain and the TCR β chain. In some embodiments, methods include treating a subject with RCC, by obtaining a population of T cells, transducing the population of T cells with a vector including a nucleic acids encoding the TCR α chain and the TCR β chain, and administering a composition comprising the modified T cells to the subject.
Core Innovation
The invention disclosed relates to T cell receptors (TCRs) that recognize antigens expressed by renal cell carcinoma (RCC) cells, specifically recognizing a human endogenous retrovirus-E (HERV-E) antigen. The TCRs include an α chain and a β chain with sequences exemplified by SEQ ID NOs: 2 and 3 for nucleic acids, and SEQ ID NOs: 4 and 5 for amino acid chains. Vectors encoding these TCR chains are also disclosed, along with modified T cells expressing the TCRs, prepared by transducing T cells with vectors encoding the α and β chains, optionally including a truncated CD34 protein for selection.
The problem addressed is the lethality of metastatic RCC, which despite advances using targeted inhibitors and immune checkpoint inhibitors, generally has a mean survival of less than a year. There remains a need for effective therapies to treat RCC, particularly metastatic or advanced clear cell RCC (ccRCC), for which this invention aims to provide a novel immunotherapeutic approach using T cells engineered to express RCC-reactive TCRs.
The invention details methods for treating subjects with RCC by obtaining T cells from the subject or a donor, activating and transducing these cells with vectors encoding the HERV-E recognizing TCR α and β chains, expanding the modified cells ex vivo, and administering them to the subject. The TCRs are HLA-A11 restricted and specific to a HERV-E antigenic peptide expressed by RCC cells. The vectors may be retroviral vectors, for example, a SAMEN vector encoding both TCR chains and truncated CD34 for selectable marker purposes.
Claims Coverage
The patent claims cover three main inventive features centered around a vector, host cells comprising the vector, and specific configurations of these host cells. The following extracts the main inventive features of the independent claims.
Vector comprising the nucleic acid sequence of SEQ ID NO: 6
The vector includes the nucleic acid sequence of SEQ ID NO: 6 encoding the TCR α and β chains reactive to HERV-E antigen and the truncated CD34 marker for modified T cell expression and selection.
Isolated host cell comprising the vector
Host cells are isolated and comprise the vector encoding the HERV-E reactive TCR α and β chains, enabling expression of these receptors for therapeutic or vector production purposes.
Host cell further comprising viral protein-encoding nucleic acids or being a packaging cell
Host cells encompass those expressing viral gag, pol, and env proteins or combinations thereof, including PG13 cells, for packaging or producing the recombinant viral vectors carrying the TCR sequences.
The claims primarily cover a specific vector encoding the HERV-E TCR α and β chains along with truncated CD34, host cells containing this vector for therapeutic or recombinant virus production use, and packaging cell lines for producing high-titer viral stocks comprising the vector.
Stated Advantages
Provides a targeted immunotherapy option for RCC, particularly metastatic clear cell RCC, which has a poor prognosis with existing therapies.
Enables generation of T cells with redirected specificity to RCC cells expressing HERV-E antigen, potentially improving treatment efficacy.
Use of truncated CD34 as a selectable marker allows for efficient enrichment and identification of transduced T cells.
Potentially reduces off-target effects given the tumor-specific expression of the HERV-E antigen targeted by the TCR.
Documented Applications
Treatment of subjects with renal cell carcinoma (RCC), including metastatic and clear cell RCC, using autologous or donor-derived T cells transduced with vectors encoding HERV-E reactive TCRs.
Generating recombinant producer cell lines for producing viral vectors encoding the HERV-E reactive TCRs for therapeutic T cell modification.
Use in clinical protocols and trials for adoptive T cell therapy involving TCR transduced T cells targeting RCC expressing HERV-E antigens, particularly in HLA-A11 positive subjects.
Interested in licensing this patent?