Antibody–Drug Conjugates: An Integrative Translational and Evidence Framework

Abstract

Background

This thesis examined how antibody–drug conjugates (ADCs) can be designed to maximize benefit while minimizing toxicity. It focused on B cell maturation antigen (BCMA)-directed ADCs in multiple myeloma, late-phase ADCs in solid tumors, and disialoganglioside GD2-targeted ADC strategies for osteosarcoma. The aim was to define principles that improve ADC therapeutic index and to develop a grounded “prime and target” strategy for osteosarcoma.

Methods

Two workstreams were undertaken: (i) a systematic synthesis of efficacy and safety data for BCMA-directed ADCs in relapsed/refractory multiple myeloma, interpreted alongside phase II/III ADC trials in solid tumors; and (ii) preclinical evaluation of a GD2-targeted naxitamab–DM1 ADC in orthotopic osteosarcoma models, including priming with doxorubicin and tazemetostat (TA).

Results

BCMA-directed ADCs, particularly belantamab mafodotin, produced meaningful responses but were limited by ocular and hematologic toxicities, which may be reduced through rational combinations, extended dosing intervals, and structured ophthalmic care. In solid tumors, ADC benefit was linked to biomarker strategies and proactive management of class-specific toxicities, including interstitial lung disease and ocular events. In preclinical studies, the naxitamab–DM1 ADC induced on-target mitochondrial apoptosis, suppressed tumor growth, and reduced pulmonary metastases, with greater activity after TA-mediated GD2 upregulation. Brief subcytotoxic doxorubicin exposure increased pro-apoptotic ceramides and, with TA, created a primed tumor state in which sequential doxorubicin–TA–ADC treatment achieved the greatest tumor control without added cardiotoxicity.

Conclusions

These findings provide a translational framework for safer ADC use and establish a grounded “prime and target” paradigm for GD2-directed ADC therapy in osteosarcoma, informing future biomarker development, ADC engineering, and clinical trial design.