Development of a novel antibody-drug conjugate for treating T-cell lymphoma.

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Abstract T-cell lymphomas comprise up to 15% of all Non-Hodgkin’s lymphoma. These complex clusters of blood cancers are very aggressive with poor (<50%) five-year survival. The inherent molecular heterogeneity of these cancers impedes therapeutics development and as a result, targeted therapeutics with durable responses against these blood cancers are alarmingly few. In pilot studies, we identified a cell surface protein that is present on all T-cell lymphoma patient specimens examined, suggesting that it could be a novel therapeutic target. We thus developed an antibody-drug conjugate (ADC) specific for this new target and found that this ADC is highly effective in selectively killing T lymphoma cells in vitro and shrinking already developed tumors in vivo in a preclinical model of T-cell lymphoma. We have also sequenced and humanized the monoclonal antibody (mAb) used in our pilot studies to generate the mouse version of the ADC. Even though both the parent mAb and the humanized mAbs showed picomolar affinities against the target, we noticed a ~2 –fold drop of humanized mAb affinity. In this Phase I application, Shennong Biotech and Cleveland Clinic will collaborate to develop both the humanized and chimeric ADCs, test their treatment efficacies, and explore their safety profiles in two preclinical models of T-cell lymphoma. These studies will identify the ADC for future development and provide the required proof-of-concept to advance it into Phase II studies with the ultimate goal of producing a much-needed new drug for patients with T cell lymphoma.