Beyond Conventional Monoclonals: Novel Antibody Formats and Derivatives as the Next Frontier in Cancer Therapy

Abstract – Background: Monoclonal antibodies (mAbs) and their derivatives represent a central pillar of contemporary oncology, with expanding complexity in molecular design and clinical application. Beyond unconjugated mAbs, bispecific antibodies (bsAbs), trispecific antibodies (tsAbs), and antibody-drug conjugates (ADCs) introduce additional pharmacological dimensions that directly impact efficacy, toxicity, and resistance. BsAbs were developed as pharmacological matchmakers to simultaneously engage tumor antigens and immune receptors, physically bridging effectors and malignant cells to promote immunological synapse formation. TsAbs extend this concept by enabling coordinated engagement of three targets. ADCs exploit mAb specificity to deliver highly potent, otherwise intolerable cytotoxic payloads directly into tumor cells, expanding the therapeutic window in hematologic and solid tumors. Summary: Clinical performance is tightly linked to molecular architecture: bsAb/tsAb activity depends on valency, target geometry, and Fc configuration, whereas ADC efficacy reflects a tripartite pharmacology integrating target engagement, intracellular payload release, and bystander cytotoxicity. Despite their remarkable potency, antibody-based platforms remain vulnerable to resistance, which may arise through target-dependent mechanisms, including antigen downregulation and epitope masking, or target-independent processes, such as altered intracellular trafficking, lysosomal dysfunction, payload efflux, and adaptive survival signaling. Key Message: A comprehensive understanding of antibody architecture, target biology, pharmacokinetic/pharmacodynamic behavior, toxicity profiles, and resistance mechanisms is essential to optimize treatment selection and sequencing. Collectively, mAbs, bsAbs/tsAbs, and ADCs provide the mechanistic and technological basis for next-generation platforms, including peptide-drug conjugates and antibody-radionuclide conjugates.