Advanced Antibody-Drug Conjugates Design: Innovation in Linker Chemistry and Site-Specific Conjugation Technologies.

Antibody-drug conjugates (ADCs) represent a promising class of targeted cancer therapies, with the potential to improve treatment precision because of their unique mechanism of selectively delivering cytotoxic payloads (PLs) to tumor cells. ADCs combine a monoclonal antibody directed against a tumor-associated antigen with a potent cytotoxic PL via a covalent linker which connects the PL to the antibody. Several ADCs have been approved for clinical use in oncology, including Mylotarg, Adcetris, Kadcyla, Besponsa, Polivy, Lumoxiti, Padcev, Enhertu, Trodelvy, Aidixi, Zynlonta, Tivdak, Elahere, Datroway, and Emrelis. This review focuses on recent advances in linker chemistry and site-specific conjugation technologies, which are critical for optimizing ADC design and improving therapeutic indices. The development of next-generation ADCs has focused on overcoming challenges related to linker stability, efficiency of target antigen internalization, and pharmacokinetics. Traditional conjugation methods, such as lysine or cysteine conjugation, have been widely used but are associated with inherent issues of heterogeneity and instability. Advances in linker chemistry, such as the development of novel cleavable linkers, have significantly contributed to the clinical success of ADCs. In this review, different linker components are discussed, including chemical handles for conjugation, spacers to improve hydrophobicity, and triggers for PL release. In addition, innovative conjugation strategies are highlighted, which enhance ADC homogeneity and stability. The site-specific conjugation and therapeutic performance benefits of technologies such as THIOMAB, SMARTag, microbial transglutaminase, glycan remodeling, and AJICAP are discussed. The toxicity profiles of ADCs and strategies are also addressed to mitigate off-target effects and systemic toxicity. Overall, this review provides a comprehensive overview of the current state of linker and conjugation technologies in ADC development.