title: Depletion of B cells by a humanized anti-CD20 antibody PRO70769 in Macaca fascicularis.
abstract: PRO70769 is a humanized IgG1 monoclonal antibody against the CD20 molecule that is present on normal and malignant B cells. PRO70769 is being evaluated for treatment of B-cell-mediated diseases and is in a phase 1 trial for rheumatoid arthritis. As part of the preclinical toxicology evaluation, B-cell depletion profiles and safety of PRO70769 were assessed in cynomolgus monkeys. Animals were administered drug (IV) on days 1 and 15 with 10, 50, or 100 mg/kg PRO70769 and killed 2 weeks after the second dose and after a 3-month recovery period. In a parallel study, animals were not necropsied but instead were retreated with a second cycle of PRO70769 administered under an identical regimen. PRO70769 suppressed B cells in the blood to undetectable levels and significantly reduced B cells in lymphoid tissues. Splenic B cells were depleted to a greater extent compared with lymph node B cells. A second cycle of treatment resulted in a greater extent of depletion in lymphoid tissues compared with the depletion observed after one cycle of treatment; however, residual B cells in lymphoid tissues were still detectable, even at the highest dose. The rate of B-cell recovery in peripheral blood appeared similar between one and two cycles of treatment. Upon depletion there was a change in the profile of lymph node B-cell subsets. After recovery, B-cell subsets were reconstituted to normal levels. Depletion of CD20-expressing cells and lymphoid follicular atrophy were the only treatment-related effects.
authors.affiliation: Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vugmeyster
authors.forename: Joseph
authors.initials: J
authors.lastname: Beyer
authors.forename: Kathy
authors.initials: K
authors.lastname: Howell
authors.forename: Dan
authors.initials: D
authors.lastname: Combs
authors.forename: Paul
authors.initials: P
authors.lastname: Fielder
authors.forename: Jihong
authors.initials: J
authors.lastname: Yang
authors.forename: Ferhan
authors.initials: F
authors.lastname: Qureshi
authors.forename: Bryan
authors.initials: B
authors.lastname: Sandlund
authors.forename: Ly
authors.initials: L
authors.lastname: Kawaguchi
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dummer
authors.forename: Henry
authors.initials: H
authors.lastname: Lowman
authors.forename: Kathleen
authors.initials: K
authors.lastname: McKeever
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20 / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology; D008212:Lymphocyte Depletion; D008252:Macaca fascicularis; D013154:Spleen / Q000166:cytology
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D007074:Immunoglobulin G; C504235:PRO70769 monoclonal antibody