Efficacy and safety of a human anti-CD70 antibody-MGBA conjugate
Abstract Number: 4061
Author Block:
Pina M. Cardarelli, David J. King, Jon Terrett, Sanjeev Gangwar, Lewis Cohen, Chin Pan, Chetana Rao, Shrikant Deshpande, Rangan Vangipuram, David Passmore, Diann Blanset. Medarex, Inc., Sunnyvale, CA
Antibody-drug conjugates with DNA minor-groove binding alkylating (MGBA) agents are a novel class of antibody conjugates with attractive properties for development. CD70 has been demonstrated to be highly expressed in renal cancer with a prevalence of over 75% in both primary and metastatic disease. CD70 is also highly expressed in both B and T cell derived lymphomas, whereas expression in normal tissues is extremely low. An anti-CD70 MGBA conjugate has been designed and produced in monomeric form, using a human anti-CD70 antibody isolated from a transgenic mouse and a synthetic MGBA. The resulting conjugate is capable of potent and selective cell killing of CD70 positive cells. Activity of the conjugate has been demonstrated across multiple subcutaneous renal cancer xenograft models in SCID mice, including 786-O, Caki-1 and A498. Therapy has been demonstrated to be dose dependent in a series of studies in each model. Tumor regression is observed in all models using single-dose treatment and efficacy can be clearly demonstrated at low doses, down to 5nmol/kg. In addition, efficacy has also been demonstrated in multiple lymphoma xenograft models, including Raji and Daudi. Safety studies have been carried out in a number of species including non-human primates. Cynomolgus monkeys were studied as the anti-CD70 antibody cross-reacts with cynomolgus CD70, allowing a realistic assessment of anticipated toxicity in man. Doses up to 800nmol/kg are well tolerated in monkeys, suggesting a large potential therapeutic window. These studies support the role of CD70 as a viable ADC target for renal carcinoma and other CD70 expressing cancers. |
