The Kay Lab specializes in protease-resistant mirror-image (D) peptide drugs, which have increased drug half-life compared to natural L-peptides and reduced host-immune response due to their evasion of MHC presentation. Cholesterol-conjugated PIE12-trimer is a D-peptide HIV entry inhibitor with promising non-human primate efficacy and phase I clinical trial results, but its relatively small size (~9 kDa) leaves it vulnerable to kidney filtration, resulting in a shorter half-life than long-lasting biologics or depot-formulated small molecules. As with all HIV monotherapies, it is ultimately susceptible to viral resistance due to HIV’s high mutation rate. Monoclonal antibodies (mAb) and antibody-drug conjugates (ADC) have seen an increase in therapeutic use due to their high specificity and long half-lives. For HIV, broadly neutralizing antibodies (bNAbs) as a class can bind to a variety of conserved viral envelope epitopes to block infection, but their breadth and potency are not yet sufficient on their own to control or prevent disease. Here, I describe the development of an antibody-D-peptide conjugate (ADpC) comprised of PIE12-trimer and a bNAb in a heterochiral “single-molecule cocktail” that we predict will broadly and potently neutralize HIV with a long half-life to support very infrequent dosing. I am synthesizing this ADpC using sortase-mediated conjugation. Sortase ligates a specific C-terminal sequence motif (LPXTG) to an N-terminal poly-glycine on a second peptide. The bNAb and PIE12-trimer will be connected via a flexible polyethylene glycol (PEG) linker. This ADpC will provide a combination therapy in a single molecule with significant potential therapeutic and pharmacokinetic benefits for patients.
