From Molecular Precision to Clinical Practice: A Comprehensive Review of Bispecific and Trispecific Antibodies in Hematologic Malignancies

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Abstract
Multispecific antibodies have redefined the immunotherapeutic landscape in hematologic malignancies. Bispecific antibodies (BsAbs), which redirect cytotoxic T cells toward malignant targets via dual antigen engagement, are now established components of treatment for diseases such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma (MM). Clinical trials of agents like blinatumomab, glofitamab, mosunetuzumab, and teclistamab have demonstrated deep and durable responses in heavily pretreated populations. Trispecific antibodies (TsAbs), although still investigational, represent the next generation of immune redirection therapies, incorporating additional tumor antigens or co-stimulatory domains (e.g., CD28, 4-1BB) to mitigate antigen escape and enhance T-cell persistence. This review provides a comprehensive evaluation of BsAbs and TsAbs across hematologic malignancies, detailing molecular designs, mechanisms of action, therapeutic indications, resistance pathways, and toxicity profiles including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, and infections. We further discuss strategies to mitigate adverse effects and resistance, such as antigen switching, checkpoint blockade combinations, CELMoDs, and construct optimization. Notably, emerging platforms such as tetrafunctional constructs, checkpoint-integrated multispecifics, and protease-cleavable masking designs are expanding the therapeutic index of these agents. Early clinical evidence also supports the feasibility of applying multispecific antibodies to solid tumors. Finally, we highlight the transformative role of artificial intelligence (AI) and machine learning (ML) in multispecific antibody development, including antigen discovery, biomarker-driven treatment selection, toxicity prediction, and therapeutic optimization. Together, BsAbs and TsAbs illustrate the convergence of molecular precision, clinical innovation, and AI-driven personalization, establishing a new paradigm for immune-based therapy across hematologic and potentially solid tumor malignancies.

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