Next Generation Antibody Drug Conjugates: Molecular Design Innovations and Overcoming Resistance

Abstract

Antibody drug conjugates (ADCs) represent the relevant merger between targeted therapy and cytotoxic pharmacology, which supports the targeted destruction of cancerous cells as a result of antibody-mediated identification of antigens attached to tumors. This effect is also central to the engineering of antibodies, linker stability, and an additional benefit of payload design based on the requirements of target sites, which have generally increased the precision and safety of ADCs in cancer biology. Nonetheless, the issues of resistant mechanisms, non-homogeneous expression of antigens, and inefficient intracellular delivery keep affecting their clinical performance.

We selected a systematic review of the recent developments in next-generation ADC development in this review, with a particular focus on site-specific conjugation innovations, adaptive linker technologies, and dual-payload structures to surpass tumor heterogeneity and drug resistance. Furthermore, we discussed the newly emerging artificial intelligence (AI) based molecular modeling and computational optimization that assist in the creation of potential ADCs by enhancing payload-antibody integration. As a set, these interdisciplinary advances augment the ability of ADCs to be translational by shedding light on the realization of more efficient, adaptive, and patient-centered therapeutic solutions in oncology.