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HOMOGENEOUS ADCs BEARING TWO DIFFERENT PAYLOADS SHOW STRONG SYNERGY IN TUMOR KILLING
EP22456
Poster Title: HOMOGENEOUS ADCs BEARING TWO DIFFERENT PAYLOADS SHOW STRONG SYNERGY IN TUMOR KILLING
Submitted on 28 Oct 2014
Author(s): Lisha Allen, Yi Mi, Muhammad Abbas, Wolfgang Richter, and Sean Hu
Affiliations: Dophen Biomed and TUBE Pharmaceuticals GmbH
This poster was presented at World ADC Summit 2014 San Diego
Poster Views: 4,079
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Poster Information
Abstract: 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.Summary: We presented a one-pot reaction to prepare site-specific ADCs using available mABs on hand without re-engineering. We have identified a novel non-cleavable linker, which increases not only ADC stability, but also potency. We also demonstrate synergy in cancer cell killing of hybrid ADC loaded with two different toxinsReport abuse »
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