Homogeneous ADCs Bearing Two Different Payloads Show Strong Synergy In Tumor Killing
Poster Oct 28, 2014
Lisha Allen, Yi Mi, Muhammad Abbas, Wolfgang Richter, and Sean Hu
Using engineered microbial transglutaminase (mTGase), we are able to conjugate any given toxin with an amine group to any mAB without the need of antibody re-engineering. Such a simple and quick site-specific conjugation method has enabled us to screen out endosome escaping & non-cleavable (EENC) linkers. These EENC linkers need an optimal length to achieve the highest ADC activity. ADCs made with EENC linkers are highly stable in human, rat and mouse plasma and potent. When two different payload toxins were conjugated site-specifically to one mAB molecule, the homogeneous hybrid ADC (DAR 2) prepared shows synergy towards tumor cell killing while mixtures of the respective two homogeneous ADCs (DAR 2) bearing the same toxins do not. The pM Ic50 in assay and high in-vivo potency challenges the widely accepted ADC concept of an activation pathway via lysosomal destruction to release free toxin. On the contrary, our data imply that ADC can be directly active after escaping from an endosome and as a result of multiple interactions of the different payloads, make the new ADCs more potent.
Human papillomavirus (HPV) vaccine rates continue to be low in the United States. Young women ages 18-26 years are eligible for catch-up vaccination but previous research shows that relationships status and percieved risk may be barriers to HPV vaccination. The purpose of this quantitative study was to assess the association between relationship status and perceived risk for HPV among young adult women.READ MORE