RESEARCH

LINKERS FOR NEXT-GENERATION ANTIBODY-DRUG CONJUGATES

Cancer chemotherapy is seeing the beginning of a new era with the emergence of antibody-drug conjugates (ADCs), a novel class of drug delivery systems. ADC chemical linkers connect therapeutic antibodies and highly potent antitumor drug molecules (payloads). The linker component is important because its chemical and physicochemical properties affect ADC potency, in vivo stability, and tolerability. To advance this promising molecular class, we have been committed to developing novel ADC linkers. For example, we have developed branched chemical linkers that enable facile and quantitative installation of multiple payloads on single therapeutic antibodies. We have demonstrated that this multiloading linker actually increases ADC potency. Another recent finding in our lab is acidic tripeptide linkers with incredibly high in vivo stability, such as a glutamic acid-valine-citrulline (Glu-Val-Cit or EVCit) linker. Unlike valine-citrulline dipeptide linkers, which are commonly used for ADC construction but unstable in mouse plasma, our EVCit linker is much more stable in mouse models while retaining a drug release mechanism by enzymatic cleavage in lysosomes. Further improvement of these linker technologies are underway in our lab. We are also developing a variety of ADCs using our technology platform and antibodies targeting novel tumor antigens in collaboration with cancer biologists and immunologists.

QUORUM SENSING-GUIDED ANTIBACTERIAL THERAPY

The accessory gene regulator (agr) of Staphylococcus aureus coordinates various pathogenic events and is recognized as a promising therapeutic target for virulence control. S. aureus utilizes autoinducing peptides (AIPs), cyclic-peptide signaling molecules, to mediate the agr-based quorum sensing system. Despite the high potency of synthetic AIP analogues in agr inhibition, the potential of AIP molecules as a delivery vehicle for antibacterial agents remains unexplored. We have found that truncated AIP scaffolds can be fused with fluorophore and cytotoxic photosensitizer molecules without compromising their high agr inhibitory activity, binding affinity to its receptor, or cell specificity. Strikingly, a photosensitizer-AIP conjugate exhibited 16-fold greater efficacy in a S. aureus cell-killing assay than a non-targeting analogue. We are currently investigating whether this strategy can be used to deliver other drug classes.