Comparison of B Cell Depletion Mediated by Intravenous (IV) Rituxan® and Rituxan Given Subcutaneous (SC) In Cynomolgus Monkeys

Abstract 3980

Rituximab (MabThera)® is a chimeric mouse/human monoclonal antibody recognizing the B cell specific trans-membrane protein CD20. Rituximab's CD20 specific binding facilitates the prolonged depletion of both malignant and endogenous CD20+ B cells. Rituximab is currently FDA approved for monotherapy and combinatorial therapies in the treatment of multiple forms of Non Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL) and Diffuse Large B cell Lymphomas (DLBCL), as well as for the treatment of moderate to severe rheumatoid arthritis patients who are refractory to TNF antagonists (in combination with methotrexate, MTX). As with most large protein based biologics, the proto-typical route of administration of rituximab is by intravenous (IV) infusion. Following delivery to the circulation, rituximab distributes into both primary and secondary lymphoid tissues throughout the body. This distribution is essential to full target coverage of CD20+ cells and therefore critical for the efficacy in targeting those cells for depletion. For other monoclonal antibodies in other clinical settings, the conversion from IV to SC administration has resulted in an improved tolerability with less infusion-related reactions, shorter administration times, an increased patient-convenience and an improved cost-effectiveness. These advantages are anticipated for the SC administration of rituximab as well.

Here we describe the results of an IV/SC pharmacokinetic/pharmacodynamic (PKPD) cynomolgus monkey study comparing the traditional IV infusion of rituximab to a novel SC dosing route of rituximab administration using an SC formulation of rituximab containing recombinant human hyaluronidase (rHuPH20). rHuPH20 transiently degrades the local interstitial matrix component, hyaluronan, at the SC injection site, acting as a permeation enhancer and allowing SC administration of high volumes. Cynomolgus monkeys were treated twice, one week apart, with the rituximab SC formulation or with IV rituximab (2 × 10 mg/kg IV or SC). CD20 target coverage and depth of distal lymph node B-cell depletion was measured 7 days later, while the prolonged target coverage and duration of peripheral blood B-cell depletion was evaluated over an extended two month period. The results indicate similar rituximab trough concentrations in serum as well as similar B-cell depletion efficacy in both peripheral blood and distal secondary lymphoid tissue after IV and SC dosing. In conclusion, the results of the study suggest that the SC versus IV dosing routes do not influence the non-clinical efficacy in this B cell depletion model given that similar trough concentrations of rituximab are reached with both administration routes.