[Lani]

Clinical Experience with Agonistic Death-Receptor Monoclonal Antibodies

Presently there are several agonistic monoclonal antibodies against DR4 and DR5; our humanized antibody against DR5 (CS-1008), the Human Genome Science (HGS) fully human antibodies (HGS-ETR1 anti-DR4, HGS-ETR2 and HGS-TR2J anti-DR5), the Genentech Apomab fully human anti-DR5 antibody,[18] the Amgen AMG 655[19] and Novartis LBY135[20] anti-DR5 antibodies. The results of a Phase I trial of mapatumumab (HGS-ETR-1) have been reported. This dose-escalation trial utilized doses of 0.01–10 mg/kg intravenously and 10 mg/kg every 2 weeks, which was safely tolerated in 11 patients with a plasma half-life of 18.8 days. Preliminary reports of Phase I trials of anti-DR5 monoclonal antibodies in patients with advanced metastatic cancer have been reported.[6,18] These trials have demonstrated that these agents are well-tolerated, have attractive pharmacokinetics with plasma half-life of less than 12 days and limited single agent antitumor efficacy with prolonged stable disease as the best antitumor effect. A Phase II trial of mapatumumab in patients with advanced non-Hodgkin's lymphoma has recently reported objective response in three out of 40 patients (8%), all of whom had follicular lymphoma.[21] A Phase I trial of this agent in combination with gemcitabine and cisplatin was reported as safe with further Phase II trials warranted.[22] Thus, humanized and human monoclonal antibodies to DR4 and -5 are rapidly being developed with future efficacy trials of these agents in combination with chemotherapy underway