Varied T cell repertoire bearing intact TCR/CD3 complexes required to observe maximal therapeutic anti-tumor effects of CD3 Fab fragments when binding to T cells

Abstract A cognate antigen engagement of TCR induces a conformation change in the CD3 complex (CD3Δc) that is required for productive T cell activation. CD3Δc fails when TCRs interact with poorly immunogenic antigens, like many tumor-associated-antigens (TAAs), which do not active cells. Anti-CD3 monovalent Fab fragments (Mono-Fabs) bound to mimic CD3Δc, producing “co-potentiation” associated weak antigens enhances activation, neither stimulating non-engaged cells, nor interrupting responses strong antigens. Previously, we showed co-potentiation can be exploited as novel immunotherapeutic principle by reducing melanoma burden B6 mice treated anti-CD3 Mono-Fabs. signaling initiation requires exposure conserved sequence cytosolic domain CD3ɛ rich prolines (PRS) enables recruitment adaptor protein Nck. The mutation cysteines CXXC motif extracellular inhibits transmission across transmembrane defects and PRS accessibility. Here, using syngeneic lines Yumm 1.7 Yummer1.7, differ number somatic mutations they carry, mouse strains either wild or mutated motifs CD3ɛ, have established need tumor cells carry potential neoantigens, more varied repertoire responding intact TCR/CD3 complexes observe full anti-tumor effects Mono-Fab treatments. MU Start-up funds NIH, NCI, U01 CA244314 NIAID, R01 AI097187