Molecular Targeted Therapy:Reversible-Covalent Ligands and Linker-Payload (dis)Connections

Hetero-bifunctional constructs, especially antibody-drug conjugates (ADCs), combine two molecular entities to selectively deliver drugs and improve therapeutic efficacy, and they are now being explored beyond oncology, including autoimmune and infectious diseases. Alongside ADCs, drug conjugates to smaller tumor-targeting ligands (e.g., synthetic small molecules or peptides) are also attracting attention, as they may overcome pharmacokinetic limits of large IgG antibodies, showing faster and more selective tumor accumulation.
This lecture will illustrate the pros and cons of antibodies and small molecules as drug delivery carriers, especially describing how aldehyde tags could be generally exploited as electrophilic warheads to engage Lys residues in various protein targets, ideally reducing the binding strength gap between small ligands antibodies.
Besides the targeting units, the lecture will describe the state-of-the-art of linker-payload modules, i.e., the fragments devoted to the carrier conjugation to the pharmaceutically active drug and its selective release in the tumor site. Here, the role of self-immolative spacers will be introduced, with focus on pyrrolidine-carbamate constructs and their application to a rapid and efficient release of alcohol-bearing drugs.