The evolving landscape of antibody-based cancer therapies: From monospecific to multi-specific and beyond

The landscape of antibody-based cancer therapies has evolved dramatically since the first monoclonal antibody (mAb) was approved for cancer treatment three decades ago. Advances in recombinant DNA and molecular engineering have transformed monospecific mAbs into multi-specific and multi-modal constructs, revolutionizing oncology. Unlike traditional mAbs, next-generation antibodies, including bispecific antibodies, antibody-drug conjugates (ADCs), and radionuclide-antibody conjugates (RACs), enable synergistic targeting of tumor-associated antigens (TAAs), immunomodulatory receptors, and immune cell engagement while delivering cytotoxic payloads. These constructs enhance specificity, tumor penetration, and therapeutic efficacy while minimizing off-target toxicity. Multi-specific antibodies, designed to bind multiple antigens or distinct epitopes, leverage structural innovations like IgG-like formats for stability and non-IgG-like formats for rapid clearance and improved tissue penetration. ADCs and RACs deliver potent chemotherapeutic or radiotherapeutic agents directly to tumor cells, offering dual therapeutic-diagnostic potential and reducing systemic toxicity compared to conventional treatments. This review explores the structural diversity, mechanisms of action, therapeutic targets, and clinical applications of these advanced antibody formats across different cancer indications. It highlights how multi-modal approaches overcome resistance and enhance synergy with immunotherapies targeting both innate and adaptive immune cells and molecules, aligning with personalized medicine paradigms. By integrating cutting-edge molecular engineering with clinical insights, this review highlights the transformative potential of antibody-based therapies in reshaping cancer treatment and improving patient outcomes.