Differential in vivo effects of rituximab on two B-cell subsets in cynomolgus monkeys.
Cynomolgus monkeys (Macaca fascicularis) are widely used animal models in biomedical research and have been used to study new therapeutics aimed at B-cell depletion. We have recently identified two different B-cell subsets in cynomolgus monkey, with the CD20lowCD40highCD21+ subset being phenotypically closer to human B cells and having a similar responsivness to anti-CD20 mAb, rituximab, in in vitro depletion assays. Here, we show that similar to in vitro findings CD20highCD40lowCD21- and CD20lowCD40highCD21+ cynomolgus monkey B cells differ significantly in their in vivo susceptibility to rituximab, as the low dose of 0.05 mg/kg of rituximab resulted in more than 70% depletion of the former B-cell subset and virtually no depletion of the latter B-cell subset. Our data suggest that for the B-cell-targeting anti-CD20 therapeutics, depletion of CD20lowCD40highCD21+ subset rather than depletion of all cynomolgus monkey B cells is more relevant to dose-efficacy projections for humans. In addition, we show that differential cell surface expression of CD80/CD86 costimulatory molecules on the two different cynomolgus monkey B-cell subsets is similar to that identified in rhesus monkeys, suggesting that our in vivo study may be relevant to other monkey models.
Vugmeyster
Yulia
Y
Bioanalytical Research and Development Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. yulia@gene.com
Howell
Kathy
K
McKeever
Kathleen
K
Combs
Daniel
D
Canova-Davis
Eleanor
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D008212:Lymphocyte Depletion; D008252:Macaca fascicularis; D008297:Male; D017464:Receptors, Complement 3d / Q000276:immunology; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D017464:Receptors, Complement 3d; D000069283:Rituximab