Jörn C Albring, Karin Frebel, Anika Wohlgemuth, Christian Schwöppe, Stephan Hailfinger, Georg Lenz, Matthias Stelljes

Comparison of antibody-based immunotherapeutics for malignant hematological disease in an experimental murine model

  • Hematology

Antibody-based immunotherapies have revolutionized leukemia and lymphoma treatment, with animal studies being crucial in evaluating effectiveness and side effects. By targeting the evolutionary conserved Slamf7 immune receptor, which is naturally expressed by the murine multiple myeloma cell line MPC-11, we have developed a syngeneic mouse model for direct comparison of three immunotherapies: monoclonal antibodies (mAb), bispecific T cell engagers (BiTE), and CAR T cells (CART), all targeting Slamf7. Slamf7-BiTE is a bispecific single-chain antibody consisting of α-Slamf7 and α-CD3 Fv fragments joined through a Gly-Ser linker, and Slamf7-CART comprises the α-Slamf7 Fv fragment fused to the msCD8α transmembrane and msCD28, 4-1BB and CD3ζ intracellular signaling domains. Slamf7-BiTE and Slamf7-CART effectively killed MPC-11 cells in vitro, independently of Slamf7-mediated inhibitory signaling by self-ligation. After chimerizing the constant region of the rat-anti-mouse Slamf7 antibody to mouse Fc-IgG2a for enhanced effector functions, Slamf7-mAb triggered antigen-specific antibody-dependent cellular cytotoxicity (ADCC) by binding to Fcγ receptor IV. In vivo, all three immunotherapies showed anti-tumor effects against Slamf7-expressing targets. Unlike Slamf7-mAb, Slamf7-BiTE led to considerable side effects in test animals, including weight loss and general malaise, which were also observed to a lesser extent following Slamf7-CART infusion. In allogeneic transplant, Slamf7-BiTE and Slamf7-CART maintained activity compared to the non-transplant setting, while Slamf7-mAb displayed enhanced anti-myeloma activity. In summary, our model faithfully replicates treatment efficacy and side effects detected following human immunotherapy. It aids in developing and improving immunotherapies, and may help devise novel approaches to mitigate undesired effects in steady state and allogeneic stem cell transplantation.

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