Immunoglobulin constant domains as targets for T-cell receptor-based treatment of multiple myeloma.

Despite major progress with chimeric antigen receptor (CAR) T-cell therapy, multiple myeloma (MM) remains largely incurable, and most patient relapse. To broaden therapeutic options and overcome antigen escape, we explored T-cell receptor (TCR)-based targeting of intracellular antigens derived from immunoglobulin (Ig) heavy chain constant domains. Using HLA class-I peptidomics, we identified nine IgG- or IgA- derived peptides presented by common HLA alleles (HLA-A*01:01, HLA-A*02:01, HLA-A*03:01, and HLA-B*07:02). High-avidity T-cell clones recognizing four of these epitopes were isolated from HLA-mismatched healthy donors. Transfer of these immunoglobulin-specific TCRs into donor T cells conferred potent and selective recognition of IgG- or IgA-expressing MM cell lines while sparing antigen-negative cells. Safety profiling confirmed strict HLA-restricted specificity without cross-reactivity toward other HLA alleles, non-B-lineage tumor cell lines, or healthy tissues, except for depletion of isotype-matched B cells. Immunoglobulin-TCR T cells efficiently lysed patient-derived MM cells ex vivo and eradicated established IgA- or IgG-expressing MM tumors in murine xenograft models. Mechanistic studies revealed that dendritic cells could cross-present immunoglobulin peptides at high serum concentrations, potentially enhancing T-cell activation in vivo. Importantly, subtype-specific depletion of B cells implies that immunoglobulin-TCR T-cell therapy could partly preserve humoral immunity, reducing the need for antibody replacement compared with pan-B-cell depletion strategies. Collectively, these findings establish immunoglobulin heavy chain constant domains as promising targets for TCR-based cellular immunotherapy in MM and potentially other Ig-producing malignancies or autoantibody-mediated autoimmune diseases.