S. Thayumanavan

Linker Chemistry in Antibody-Drug Conjugates: Current Strategies, Clinical Pharmacokinetic Analyses, and Linker-Free Outlooks.

With the increasing cancer incidence and death tolls worldwide, antibody-drug conjugates (ADCs) have emerged as a promising platform to selectively deliver cytotoxic payloads to cancerous tissues. This platform has the potential to spare patients from off-target effects compared to traditional chemotherapy. Despite the clinical success of some ADCs, many in the pipeline did not even reach the clinical stage. We turn our attention to their linker chemistry that connects the antibody and the drug molecules together. Despite their small size, linkers play a key role in governing the payload release kinetics and location. In this Viewpoint, we collect and discuss a plethora of linkers employed in ADC development, specifically focusing on advancements in antibody modification and linker cleavage chemistries. The choice of linker chemistry has evolved over time, going from stochastically attached non-stimuli-responsive to site-specifically modified cleavable linkers. Then we correlate the linker technologies to their pharmacokinetic outcomes in clinics, followed by a discussion of the upcoming "linker-free" technology for more facile and efficient antibody-conjugated targeted delivery.

Expanding the Repertoire of Lysosomal Degradation of Membrane Proteins: A Generalizable Strategy Using Multivalent Antibody−Polymer Chimeras

Targeted protein degradation enables the removal of undesired proteins via proteasomal or lysosomal pathways without genomic alteration. Existing lysosomal strategies rely on chimeras that concurrently engage the protein of interest (POI) and a receptor that inherently directs bound proteins to the lysosome. We posit here that multivalent noncovalent interactions can trigger endosomal uptake and lysosomal degradation of specific membrane proteins in combination with an ancillary membrane protein, where the ancillary protein does not need to possess endogenous lysosome-directing characteristics. We demonstrate this relaxation of the ancillary protein characteristics using antibody–polymer conjugates, namely Polymeric Lysosome-Targeting Chimeras (PolyTACs), bearing ligands that polyvalently bind to membrane proteins. Using membrane carbonic anhydrase and PD-L1 as examples, we show the possibility of expanding the repertoire of lysosomal degradation of membrane POIs, which in turn opens up opportunities for new therapeutic possibilities.

Enzyme Activation of Triggerable Polymeric Lysosome Targeting Chimeras