Depletion of B cells by a humanized anti-CD20 antibody PRO70769 in Macaca fascicularis.
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.
Vugmeyster
Yulia
Y
Genentech, Inc., South San Francisco, California 94080, USA.
Beyer
Joseph
J
Howell
Kathy
K
Combs
Dan
D
Fielder
Paul
P
Yang
Jihong
J
Qureshi
Ferhan
F
Sandlund
Bryan
B
Kawaguchi
Ly
L
Dummer
Wolfgang
W
Lowman
Henry
H
McKeever
Kathleen
K
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
D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D007074:Immunoglobulin G; C504235:PRO70769 monoclonal antibody