{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:04:33Z","timestamp":1790229873631,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Antibody recruiters are an innovative class of immunotherapeutics, comprising a tumor-binding module and an antibody-binding module to redirect endogenous antibodies toward target cells. Recruited antibodies can then induce Fc-dependent effector functions to lyse tumor cells. The clinical success of CD38-directed monoclonal antibodies daratumumab and isatuximab has established CD38 as a validated target for the treatment of multiple myeloma (MM). Since daratumumab treatment can result in antigen loss or mutation of the binding site, novel immunotherapeutics should explore different binding mechanisms for maximum efficacy. Here, we report the generation of CD38-specific trimeric antibody recruiters (CD38-STARs) using nanobodies, single variable immunoglobulin domains isolated from camelid heavy-chain antibodies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We genetically fused two different CD38-specific nanobodies against distinct CD38 epitopes to a human immunoglobulin \u03ba light chain-specific nanobody to generate two CD38-STARs (E2-E3-STAR and E3-E2-STAR) with biparatopic antigen-binding modules. We analyzed their CD38 binding characteristics and the capacity for simultaneous engagement of CD38 and IgG, IgM, or IgA. We evaluated the induction of complement-dependent cytotoxicity (CDC) against various CD38-expressing tumor cell lines\n                      <jats:italic>in vitro<\/jats:italic>\n                      and against primary MM patient cells\n                      <jats:italic>ex vivo<\/jats:italic>\n                      , comparing the CD38-STARs with monoparatopic bispecific antibody recruiters (BARs).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both CD38-STARs engaged CD38 by simultaneously binding two epitopes that are distinct from the epitope bound by daratumumab, resulting in improved avidity compared to monoparatopic CD38-specific BARs. CD38-STARs demonstrated concurrent binding to CD38 and human IgG, IgM, or IgA. CD38-STARs induced higher CDC against various CD38-expressing tumor cell lines\n                      <jats:italic>in vitro<\/jats:italic>\n                      compared to monoparatopic BARs or daratumumab.\n                      <jats:italic>Ex vivo<\/jats:italic>\n                      , CD38-STARs mediated significant CDC induction against primary myeloma cells, whereas monoparatopic BARs failed to achieve significant killing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Biparatopic targeting of CD38 using CD38-STARs represents a promising strategy for the treatment of MM, including the rare cases in which daratumumab fails to bind due to CD38 mutations.<\/jats:p>\n                  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Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Hagen","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anya","family":"Duttmann","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marten","family":"Dannenberg","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie","family":"K\u00e4mereit","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Ahrens","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Al-Bazaz","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristoffer","family":"Riecken","sequence":"additional","affiliation":[{"name":"Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Fehse","sequence":"additional","affiliation":[{"name":"Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf (UKE)","place":["Hamburg, Germany"]},{"name":"German Center for Child and Adolescent Health (DZKJ), Partner Site Hamburg","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Weisel","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bannas","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Department of Diagnostic and Interventional Radiology, Albertinen Hospital","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich","family":"Koch-Nolte","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca Julius","family":"Pape","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Hambach","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf","place":["Hamburg, 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