Here we report PAC-XL, a precision antibody conjugate linking the PI3K/mTOR inhibitor BGT226 to cetuximab through a ß-glucuronidase-cleavable benzyl-ammonium carbamate (BAC) linker. Unlike conventional linkers, the BAC chemistry enabled a homogeneous, high drug-to-antibody ratio (DAR=8) conjugate that preserved EGFR binding, antigen-mediated uptake, lysosomal trafficking, plasma stability, and enzyme-dependent payload release. PAC-XL induced EGFR/PI3K/mTOR-dependent cytotoxicity and in xenografts, PAC-XL outperformed cetuximab, BGT226, and alpelisib, including complete regressions, while reducing hyperglycemia.

Drug conjugates and prodrugs commonly rely on endogenous triggers to release bioactive compounds. However, the heterogeneous nature and restricted distribution of these triggers can limit their therapeutic potential. Developing alternative chemical strategies for controlled drug release therefore offers exciting opportunities for therapeutic innovation. This presentation will highlight recent advances in the field, with a particular focus on emerging chemical approaches that enable drug release independently of endogenous triggers.

Off-site toxicity is a major obstacle in drug development.  The precise spatial and temporal control afforded by photomedicine can not only significantly minimize off-site toxicity and widen the therapeutic index, but also markedly expand the range of druggable targets. Examples include photoimmunotherapy (i.e., photosensitizer conjugates) and photo-caging (photoactivation of prodrugs), with clinical applications in dermatology and oncology.  Beyond their therapeutic applications, these innovations serve as powerful tools for chemical biology.

Cyclic amphipathic peptides are efficient carriers for cytotoxic payloads, but their conjugates behave very differently depending on how the drug is attached. This talk examines conjugation chemistry and linker choice for cyclic peptides containing tryptophan and arginine, using anthracycline conjugates built on these scaffolds to compare serum stability and release kinetics and to show how these differences translate into cellular uptake, potency against drug-resistant lines, and sparing of healthy cardiomyocytes.

Precision degrader antibody conjugates (DACs) are an emerging modality that integrates the selectivity of antibody-directed delivery with targeted protein degradation. Here, we describe the discovery of dual SMARCA2/4 degrader payloads with potent degradation and antiproliferative activity together with linker technologies suitable for DAC applications. Conjugation of these payload–linker constructs to antibodies targeting diverse tumor antigens generated DACs with robust, antigen-dependent activity.