Subcutaneous Administration of AME-133 Demonstrated Significant Dose Dependent B-Cell Depletion in Cynomolgus Monkeys (Macaca fascicularis)

Abstract

2475 Introduction: Anti-CD20 antibodies like rituximab are traditionally administered by the intravenous routes although clinical trials by subcutaneous routes have been initiated. AME-133 is a monoclonal anti-CD20 antibody, has been engineered to be more potent than rituximab. It has 10–20 fold higher binding affinity for the CD20 epitope and approximately 6-fold greater potency in ADCC assays relative to rituximab. The higher potency may provide benefit to patients with low affinity FcgIIIRa and enable subcutaneous administration (patient convenience). In addition, AME-133 has been engineered to be potentially safer than rituximab; AME-133 is humanized to reduce immunogenicity and the CDC activity has been diminished to potentially reduce side effects associated with tumor lysis syndrome. Phase I/II clinical studies of AME-133 in rituximab pretreated/relapsed, patients with low affinity FcγIIIRa, follicular non-Hodgkin's lymphoma (NHL) in the US and in Japan have shown excellent safety profile and response rate (RR) greater than 30%. As a prelude to investigating the clinical efficacy and safety of AME-133 in subcutaneous formulation, a safety/PK study was conducted in cynomolgus monkeys. Objective: The objective of this study was to evaluate the systemic toxicity and pharmacokinetics of AME-133 in cynomolgus monkeys at three different dose levels when administered subcutaneously once each week for 14 consecutive weeks. In addition, the effect of AME-133 on B-cell depletion was evaluated. Study Design: A total of 48 naive cynomolgus monkeys (24 male and 24 female) were randomly assigned to four dose groups of AME-133 administered subcutaneously once weekly (0.0 mg/kg (vehicle), 0.6 mg/kg, 1.9 mg/kg and 6.0 mg/kg). Within the dose groups, there were two (6 week and 14 week) dosing schedules. In the 6 week dosing schedule, two-third of animals were sacrificed immediately after 6 weeks, and one-third of animals were sacrificed after 4 to 8 weeks of recovery period. In the 14 week dosing schedule, two-third of animals were sacrificed immediately after 14 weeks, and one-third of animals were sacrificed after 4 to 8 weeks of recovery period. Results: There was no AME-133 related toxicity. All dose levels of AME-133 substantially depleted B-cells in peripheral blood. The extent and duration of B-cell depletion was dose-dependent (Figure 1). B-cell depletion was not affected by gender of the animal. All dose levels of AME-133 substantially depleted the B-cells in peripheral blood beginning with the first post-dose time point (4 hours after infusion). The mid and high doses resulted in delayed return to normal during recovery in cynomolgus monkeys in 14 week dosing schedule. Conclusion: This study in cynomolgus monkeys showed AME-133 caused no toxicity, well absorbed and rapidly depleted circulating B-cells when administered subcutaneously. The No Observed Adverse Effect Level (NOAEL) is 6.0 mg/kg, the highest administered dose. These preliminary results justify further investigation of AME-133v administered subcutaneously in follicular lymphoma and other B-cell malignancies. Disclosures: No relevant conflicts of interest to declare.