دورية أكاديمية

Distinct in vitro binding properties of the anti-CD20 small modular immunopharmaceutical 2LM20-4 result in profound and sustained in vivo potency in cynomolgus monkeys.

التفاصيل البيبلوغرافية
العنوان: Distinct in vitro binding properties of the anti-CD20 small modular immunopharmaceutical 2LM20-4 result in profound and sustained in vivo potency in cynomolgus monkeys.
المؤلفون: Nickerson-Nutter, Cheryl1, Tchistiakova, Lioudmila1, Seth, Nilufer P.1, Kasaian, Marion1, Sibley, Barbara1, Olland, Stephane1, Zollner, Richard1, Brady, William A.1, Mohler, Kendall M.1, Baum, Peter1, Wahl, Alan1, Herber, Deborah1, Vugmeyster, Yulia1, Wensel, David1, Wolfman, Neil M.1, Gill, Davinder1, Collins, Mary1, Dunussi-Joannopoulos, Kyri1
المصدر: Rheumatology. Jun2011, Vol. 50 Issue 6, p1033-1044. 12p. 1 Diagram, 1 Chart, 5 Graphs.
مصطلحات موضوعية: *ANIMAL experimentation, *AUTOIMMUNE diseases, *B cells, *DOSE-response relationship in biochemistry, *FLOW cytometry, *IMMUNOPHENOTYPING, *IMMUNOSUPPRESSIVE agents, *MICROSCOPY, *GENETIC mutation, *PRIMATES, *REGRESSION analysis, *RESEARCH funding, *RHEUMATOID arthritis, *EXPERIMENTAL therapeutics, *DRUG development, *EQUIPMENT & supplies, *PHARMACODYNAMICS, *THERAPEUTICS
مصطلحات جغرافية: MASSACHUSETTS
الشركة/الكيان: UNITED States. Food & Drug Administration
مستخلص: Objectives. To characterize the in vitro binding and effector function properties of CD20-directed small modular immunopharmaceutical (SMIP) 2LM20-4, and to compare its in vivo B-cell depletion activity with the mutated 2LM20-4 P331S [no in vitro complement-dependent cytotoxicity (CDC)] and rituximab in cynomolgus monkeys.Methods. Direct binding is examined in flow cytometry, confocal microscopy, scatchard and lipid raft assays. Effector function assays include CDC and Fc-mediated cellular toxicity. In the 6-month-long in vivo B-cell depletion study, single i.v. dosages of 1 or 10 mg/kg of anti-CD20 proteins were administered to monkeys and B-cell counts were monitored in peripheral blood, bone marrow and lymph nodes.Results. 2LM20-4 has lower saturation binding to human primary B cells and recruits fewer CD20 molecules into lipid rafts compared with rituximab; however, it induces higher in vitro CDC. In competitive binding, 2LM20-4 only partially displaces rituximab, suggesting that it binds to a fraction of CD20 molecules within certain locations of the plasma membrane as compared with rituximab. In monkeys, 2LM20-4 had more sustained B-cell depletion activity than rituximab in peripheral blood and had significantly more profound and sustained activity than 2LM20-4 P331S and rituximab in the lymph nodes.Conclusions. SMIP 2LM20-4, which binds to a fraction of CD20 molecules as compared with rituximab, has more potent in vitro CDC, and more potent and sustained B-cell depletion activity in cynomolgus monkeys. Our work has considerable clinical relevance since it provides novel insights related to the emerging B-cell depletion therapies in autoimmune diseases. [ABSTRACT FROM PUBLISHER]
قاعدة البيانات: Academic Search Index
الوصف
تدمد:14620324
DOI:10.1093/rheumatology/keq423