Generation of antibody-drug conjugates by proximity-based sortase-mediated ligation - there has been growing interest in the use of antibody drug conjugates (adcs) for the treatment of cancer as…

Generation of antibody-drug conjugates by proximity-based sortase-mediated ligation - there has been growing interest in the use of antibody drug conjugates (adcs) for the treatment of cancer as mounting data suggests an increase in anti-tumor effectiveness and reduced toxicity, compared with the administration of unlabeled antibodies in combination with chemotherapy. Recent evidence has shown that differentially labeled antibodies, i.e. labeled at different locations and with different numbers, can have distinct therapeutic and pharmacokinetic properties and some subpopulations can show little, if any, therapeutic activity yet account for most of the toxicity. Therefore, there has been a movement towards the development of site- specific adcs, which are precisely labeled with drugs at pre-defined locations. We have recently developed two new approaches for the preparation of highly uniform adcs, one site-specific bioconjugation approach, proximity-based sortase-mediated protein ligation (PBS-PL), whereby sortase is used to ligate drugs to a peptide tag that has been introduced into the antibody backbone, and one region- specific bioconjugation approach, proximity-based sortase isopeptide ligation (PBS-IL), which allows for the labeling of native antibodies with reduced variability compared with current lysine/cysteine residue labeling approaches. Both methods produce adcs in high yields, are compatible with glycosylated IGG, and offer unlimited flexibility in antibody-drug linker chemistry. Therefore, we believe that these technologies will provide new, favorable approaches for the production of adcs that will be of interest to the pharmaceutical industry. In this proposal, we have partnered with integral molecular and the university of pennsylvania to develop adcs against claudin-18 (cldn 18.2). CLD18.2 is ectopically expressed in several cancers including pancreatic cancer, which is the focus of this proposal. Outcomes for pancreatic cancer patients are poor with a 5-year survival of…