ALPHATHERA — Department of Health and Human Services STTR Phase I: 103

Description

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 The two ADCs that are currently approved by the FDA brentuximab vedotin Adcetris and ado trastuzumab emtansine T DM Kadcyla are both heterogeneous mixtures in terms of both the location of the drug and the number of drugs per IgG 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 Currently there are four general approaches for the generation of site specific ADCs These include the introduction of cysteine tags into the genetic code of IgG the use of unnatural amino acids the addition of peptide tags that are recognized and modified with enzymes e g formylglycine generating enzyme or transglutaminase and glycan modifications e g via glycotransferase While each approach has its own unique advantages shortcomings can include low product yields inefficient drug conjugation unstable and or hydrophobic antibody drug linker chemistry or incompatibility with glycosylated antibodies We propose to further develop a new site specific bioconjugation approach Proximity Based Sortase Ligation PBSL that can produce ADCs in high yields allows different drugs to be site specifically added to the heavy and or light chains is compatible with glycosylated IgG and offers unlimited flexibility in antibody drug linker chemistry Therefore we believe that this technology will provide a new favorable approach for the production of site specific ADCs that will be of interest to the pharmaceutical industry The specific aims for this proposal are Aim Use PBSL to produce site specific anti prostate specific membrane antigen PSMA MMAE ADCs and characterize their properties Aim Evaluate the binding and efficacy of site specific anti PSMA MMAE ADCs in vitroThe overall goal of this proposal is to develop a new site specific bioconjugation technology that enables the highly efficient production of antibody drug conjugates in high yields