THU0104 Nonclinical Assessments Demonstrating the Similarity of the Proposed Biosimilar PF-05280586 and Rituximab
Authors: S. I. Hurst, A. M. Ryan, C.-K. Ng, S. A. Ploch, G. L. Finch, M. W. Leach
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rituximab is a genetically-engineered chimeric mouse/human IgG1 cytolytic monoclonal antibody (mAb) targeting the CD20 antigen present on the surface of B cells and is approved for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and moderate-to-severe rheumatoid arthritis. PF-05280586 is being developed as a potential biosimilar to rituximab. <h3>Objectives</h3> hese studies were designed to evaluate whether PF-05280586 and rituximab-EU (MabThera<sup>®</sup>) were similar using structural, in vitro functional, and in vivo pharmacokinetic, and pharmacodynamic assessments. <h3>Methods</h3> Structural similarity was determined by peptide mapping. Functional similarity was confirmed using an in vitro complement-dependent cytotoxicity (CDC) assay using Ramos cells. Groups of adult cynomolgus monkeys were administered PF-05280586 or rituximab-EU as an intravenous (IV) bolus injection via the saphenous vein. In the single-dose (SD) study, animals received one dose of either mAb at 0, 2, 10 or 20 mg/kg on Day 1 and were observed for 92 days. In the repeat-dose (RD) study, animals received weekly injections (5 doses) of either mAb at 0 or 20 mg/kg and were either necropsied following the last dose or after observation for 92 days. In both studies, assessments included mortality, clinical parameters, pharmacokinetics (PK), pharmacodynamics (PD), and detection of anti-drug antibodies (ADA). In the RD study, complete macroscopic and microscopic evaluations were also performed. <h3>Results</h3> The peptide map of PF-05280586 was similar to that of rituximab-EU and the dose-response curves of the 2 mAbs in the CDC assay were superimposable. In vivo, the PK profiles of the two mAbs were similar (table). In the RD study, emesis was observed infrequently in 6/14 and 7/14 animals receiving 20 mg/kg/dose of PF-05280586 or rituximab-EU, respectively; there was no mortality. In both studies, there was initial depletion of B lymphocytes on Day 4. In the SD study, steady repletion was observed over the 92 day observation period. In the RD study, repletion was incomplete at the end of the 92 day observation period. In the SD study, all animals receiving PF-05280586 or rituximab-EU were positive for ADA from Day 29 through Day 92. In the RD study, 79% and 43% of animals receiving PF-05280586 or rituximab-EU, respectively, were positive for ADA. During the recovery phase, detectable ADA were similar for PF-05280586 and rituximab-EU. <h3>Conclusions</h3> PF-05280586 showed structural, functional, PK, PD, and ADA similarity to rituximab-EU. Both drugs were well tolerated. The results support the development of PF-05280586 as a proposed biosimilar to rituximab. <h3>Acknowledgements</h3> The authors acknowledge the medical writing assitance of Dr. Mukund Nori, PhD, MBA, CMPP, UBC Scientific Solutions, in the preparation of this abstract. <h3>Disclosure of Interest</h3> S. Hurst Employee of: Pfizer Inc., A. Ryan Employee of: Pfizer Inc., C.-K. Ng Employee of: Pfizer Inc., S. Ploch Employee of: Covance Laboratories, Inc., G. Finch Employee of: Pfizer Inc., M. Leach Employee of: Pfizer Inc.