{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:34:56Z","timestamp":1792121696535,"version":"4.4.0"},"reference-count":37,"publisher":"American Society of Hematology","issue":"16","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Despite major progress with chimeric antigen receptor T-cell therapy, multiple myeloma (MM) remains largely incurable and most patients relapse. To broaden therapeutic options and overcome antigen escape, we explored T-cell receptor (TCR)\u2013based targeting of intracellular antigens derived from immunoglobulin heavy chain constant domains. Using HLA class-I peptidomics, we identified 9 immunoglobulin G (IgG)\u2013 or IgA-derived peptides presented by common HLA alleles (HLA-A\u221701:01, HLA-A\u221702:01, HLA-A\u221703:01, and HLA-B\u221707:02). High-avidity T-cell clones recognizing 4 of these epitopes were isolated from HLA-mismatched healthy donors. The transfer of these immunoglobulin-specific TCRs into donor T cells conferred potent and selective recognition of IgG- or IgA-expressing MM cell lines, sparing antigen-negative cells. Safety profiling confirmed strict HLA-restricted specificity without cross-reactivity toward other HLA alleles, non\u2013B-lineage tumor cell lines, or healthy tissues, except for the 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\u2013B-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 immunoglobulin-producing malignancies or autoantibody-mediated autoimmune diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025032234","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:00:16Z","timestamp":1787590816000},"page":"1998-2012","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["Immunoglobulin constant domains as targets for T-cell receptor\u2013based treatment of multiple myeloma"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9268-3141","authenticated-orcid":false,"given":"Miranda H.","family":"Meeuwsen","sequence":"first","affiliation":[{"name":"1Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9861-7276","authenticated-orcid":false,"given":"Anne K.","family":"Wouters","sequence":"additional","affiliation":[{"name":"1Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5469-2258","authenticated-orcid":false,"given":"Johannes C.","family":"Wellershoff","sequence":"additional","affiliation":[{"name":"1Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9507-2530","authenticated-orcid":false,"given":"Tassilo L. 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