T cell receptors with improved pairing
Inventors
Bunk, Sebastian • Maurer, Dominik • FRITSCHE, Jens • Wagner, Claudia • ALTEN, Leonie • HOFFGAARD, FRANZISKA • FERBER, MATHIAS
Assignees
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Publication Number
US-12297252-B2
Publication Date
2025-05-13
Expiration Date
Abstract
The present invention relates to modified T cell receptor (TCR) α or β chains, or heterodimers comprising the same, wherein in the variable domain of said modified α or β chain, an amino acid at position 44 according to the IMGT numbering is substituted by another suitable amino acid in order to improve pairing of desired chains.
Core Innovation
The invention relates to modified T cell receptor (TCR) α or β chains, or fragments thereof, and modified TCR α/β heterodimers that include substitutions at position 44 in the IMGT Framework 2 (FR2) region. The substitutions are configured to improve correct α/β pairing and reduce TCR mispairing with endogenous chains, while maintaining the ability to bind to an antigen–MHC complex.
In particular, the modification comprises substitution pairs at the αQ44/W44/E44 positions combined with βQ44/R44/E44 positions, including αQ44K/βQ44E, αW44K/βQ44E, αE44K/βQ44E, αQ44K/βR44E, αW44K/βR44E, or αH44K/βR44E. The described embodiments include selected position 44 substitution pairs with variable-domain sequence identity constraints and allowed α44/β44 substitution pairs to support correct pairing.
The disclosure further describes related nucleic acid and vector constructs and T-cell engineering approaches to express the modified TCRs, and therapeutic uses against neoplastic, inflammatory, infectious, and autoimmune diseases. The document discusses improved functional recognition in specific contexts including MAG-003/HLA-A*02 and PRAME-004 contexts and reduced graft-versus-host disease risk via increased correctly paired heterodimers.
Claims Coverage
The partial claims provided include two independent claims. Each independent claim requires a modified or recombinant TCR with maintained antigen–MHC binding and specifies an α44/β44 substitution motif as an inventive feature.
Maintained antigen–MHC binding with α44/β44 substitution pair TCR modification
A modified T cell receptor (TCR) comprising an α modified α chain or fragment comprising a variable domain and a modified β chain or fragment comprising a variable domain that maintains the ability to bind to an antigen–MHC complex, wherein the modification comprises a substitution pair selected from αQ44K/βQ44E, αW44K/βQ44E, αE44K/βQ44E, αQ44K/βR44E, αW44K/βR44E, or αH44K/βR44E.
Recombinant TCR with αQ44K/βQ44E motif
A recombinant TCR comprising an α chain or fragment comprising a variable domain and a β chain or fragment comprising a variable domain that maintains the ability to bind to an antigen–MHC complex, wherein the α chain and the β chain comprise the amino-acid pair motif αQ44K/βQ44E.
Across the independent claims, the inventive concept is a modified or recombinant TCR that retains antigen–MHC binding while introducing specific α44/β44 substitution pairs, with explicit allowed pair options in one claim and a fixed αQ44K/βQ44E motif in the other.
Stated Advantages
Improved correct α/β pairing and reduced TCR mispairing with endogenous chains.
Reduced graft-versus-host disease risk via increased correctly paired heterodimers.
Maintains the ability to bind to an antigen–MHC complex while incorporating position 44 substitutions.
Documented Applications
Therapeutic uses against neoplastic diseases.
Therapeutic uses against inflammatory diseases.
Therapeutic uses against infectious diseases.
Therapeutic uses against autoimmune diseases.
Functional recognition contexts including MAG-003/HLA-A*02 and PRAME-004 contexts.
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