Activation and mutation of the NOTCH signaling pathway is oncogenic in many tissue types and the target of multiple anti-cancer therapies currently in clinical development. Initial therapeutic strategies designed to target the NOTCH pathway have focused on inhibition of aberrant signaling, but can have undesirable side-effects or insufficient anti-tumor activity. Antibody drug conjugates (ADCs) are an emerging therapeutic modality that equips antibodies with potent cytotoxic payloads that can be directly delivered to tumor cells. Anti-NOTCH3 ADCs exhibited robust anti-tumor activity and induce prolonged tumor regressions in preclinical models of breast, lung and ovarian cancer regardless of their ability to block signaling. Furthermore, anti-NOTCH3 ADC treatment was able to regress OVCAR3 ovarian tumor xenografts that were refractory to a platinum-based agent or relapsed anti-VEGF therapy. The safety and efficacy of the non-inhibitory anti-NOTCH3 ADC, PF-06650808, is currently being examined in a Ph1 clinical trial.<br/>

Therapeutic targeting the NOTCH3 receptor with antibody drug conjugates

251st National Meeting (2016)

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