Human immunodeficiency virus-specific T cell receptors
Inventors
Rhode, Peter • Connors, Mark • MIGUELES, Stephen
Assignees
Immunitybio Inc • US Department of Health and Human Services
Publication Number
US-12325734-B2
Publication Date
2025-06-10
Expiration Date
2040-01-15
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Abstract
Engineered TCR molecules specific to retroviral peptide/HLA complexes guide direct killing and/or enable robust immune responses against HIV infected cells. In a first aspect, a TCR fusion polypeptide comprises a TCR variable alpha (Vα) domain, a TCR variable beta domain (Vβ) and a TCR constant region domain (C), wherein the TCR fusion polypeptide is specific for HIV peptides.
Core Innovation
The invention discloses engineered T cell receptor (TCR) molecules that are specific for human immunodeficiency virus (HIV) peptide/HLA complexes. These TCR fusion polypeptides comprise a TCR variable alpha (Vα) domain, a variable beta (Vβ) domain, and a constant region domain (C), optionally linked by a linker molecule. The TCRs can be single chain fragments such as single chain variable fragments (scFv), and are specific for HIV peptides presented in context of HLA class I or class II molecules, including HLA-A, HLA-B, or HLA-C.
The problem being solved is that while combined antiretroviral therapy (cART) can reduce HIV replication, it does not eliminate integrated and transcriptionally silent HIV provirus in latently infected cells, which serve as viral reservoirs causing resurgence after therapy withdrawal. These reservoirs are stable and evade current therapies, which leads to persistent infection and associated comorbidities. Therefore, there is a need for novel therapeutic approaches that specifically target HIV peptides presented by HLA molecules on infected cells.
The engineered TCR molecules guide direct killing of HIV-infected cells and/or enable robust immune responses against these cells. The invention further covers multimeric forms of TCR fusion polypeptides, nucleic acid sequences encoding them, immune signaling domains linked to TCRs, as well as isolated cells modified to express these TCR fusion polypeptides. Methods of treatment include administering TCR polypeptides, nucleic acids, or modified cells to prevent or treat HIV infection.
Claims Coverage
The claims cover seven main inventive features, including polypeptides, nucleic acids, isolated cells, and methods of using engineered TCRs specific for HIV peptides, particularly focusing on TCR sequences and their functional domains.
Single chain TCR polypeptide with HIV specificity
A polypeptide comprising a single chain T cell receptor (scTCR) with variable alpha (Vα) and beta (Vβ) domains and a constant region domain (C), wherein the Vα and Vβ domains each have at least 85% sequence identity to specific scTCR sequences (SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, or 18), and the complementarity determining regions (CDRs) of these domains have 100% identity to the respective CDRs of the scTCR.
Polypeptide further comprising CD3 or CD28 signaling domains
The polypeptide of the single chain TCR further includes immune signaling domains selected from CD3 or CD28 signaling domains.
Nucleic acid encoding the scTCR polypeptide
A polynucleotide sequence encoding the scTCR polypeptide specific for HIV peptides as described, including sequences selected from SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, or 17.
Nucleic acid optionally encoding immune or functional domains
The nucleic acid sequence further encodes an immune signaling domain, transmembrane domain, cytoplasmic domain, biologically active domain, or combinations thereof, including cytokines, checkpoint inhibitors, antigen specific antibody domains, enzymes, or combinations thereof.
Isolated cells comprising nucleic acids encoding the TCR polypeptides
An isolated cell comprises one or more polynucleotides encoding the TCR polypeptides described herein; such cells can be autologous cells.
Method of targeting HIV infected cells with scTCR
A method of targeting staining or therapeutic agents to HIV infected cells by administering an effective amount of scTCR polypeptides specific to HIV peptides.
The claims encompass engineered single chain TCR polypeptides specific for HIV peptides with defined sequence identities, nucleic acid compositions encoding these polypeptides including optional immune effector domains, isolated cells modified to express these TCRs, and methods of treating or targeting HIV infected cells through administration of these compositions.
Stated Advantages
The engineered TCR molecules guide direct killing and/or enable robust immune responses against HIV-infected cells.
The TCRs specifically recognize HIV peptide/HLA complexes, enabling targeting of latently infected cells that current therapies cannot eliminate.
The TCR fusion polypeptides can be soluble or membrane-bound and can comprise additional immune signaling or biologically active domains to enhance therapeutic efficacy.
Documented Applications
The engineered TCRs are applied in therapeutic approaches to treat HIV infection by targeting HIV peptide/HLA complexes presented on antigen presenting cells and CD4+ T cells.
The isolated cells modified to express HIV-specific TCRs can be used in adoptive cell therapies where T cells are isolated, engineered, expanded, and reinfused into subjects to treat HIV infection.
The TCR polypeptides, nucleic acids, or cells can be administered in combination with standard anti-retroviral therapies such as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or protease inhibitors.
The TCR fusion polypeptides are useful in methods for detecting HIV peptide/HLA complexes on infected cells, which can aid in diagnostics or monitoring of infection.
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