Dual payloads

Drug-linker conjugates are central to dual-payload antibody-drug conjugate (ADC) design because they enable the controlled attachment of two distinct payloads to a single antibody while maintaining conjugate homogeneity and defined drug-to-antibody ratios (DARs)^[1]. Mechanistically, dual-payload ADCs use linker architectures and orthogonal conjugation strategies to deliver two payloads with distinct mechanisms of action into the same tumor cell, creating a unified delivery platform that differs from combinations of single-payload ADCs or ADC-plus-chemotherapy approaches^[1][2]. Site-specific conjugation methods, including multifunctional linkers, canonical and non-canonical amino acid approaches, and enzyme-mediated technologies, have been developed to precisely control payload placement and payload ratios, thereby supporting manufacturability and physicochemical stability^[1]. In cancer models, dual-payload ADCs are being investigated to address low antigen expression, tumor heterogeneity, payload resistance, and disease relapse by simultaneously engaging complementary cytotoxic mechanisms within targeted cells^[1][2]. Compared with conventional single-payload ADC formats, homogeneous dual-payload constructs provide a distinct strategy for combining mechanistically different payload classes within one molecular entity^[1][2]. For experimental applications, advanced linker designs and site-selective conjugation technologies have enabled the synthesis of homogeneous dual-payload ADCs with defined DAR profiles, low aggregation, and stable physicochemical properties, supporting continued evaluation of next-generation ADC platforms^[3].

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