Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody.
We evaluated the dose requirements for sustained in vivo activity of ofatumumab, a human anti-CD20 antibody under development for the treatment of B cell-mediated diseases. In a mouse xenograft model, a single dose, resulting in an initial plasma antibody concentration of 5 microg/ml, which was expected to result in full target saturation, effectively inhibited human B-cell tumour development. Tumour growth resumed when plasma concentrations dropped below levels that are expected to result in half-maximal saturation. Notably, tumour load significantly impacted antibody pharmacokinetics. In monkeys, initial depletion of circulating and tissue residing B cells required relatively high-dose levels. Re-population of B-cell compartments, however, only became detectable when ofatumumab levels dropped below 10 microg/ml. We conclude that, once saturation of CD20 throughout the body has been reached by high initial dosing, plasma concentrations that maintain target saturation on circulating cells (5-10 microg/ml) are probably sufficient for sustained biological activity. These observations may provide a rationale for establishing dosing schedules for maintenance immunotherapy following initial depletion of CD20 positive (tumour) cells.
Genmab, Utrecht, The Netherlands.
Wim K
WK
Bleeker
Martin E
ME
Munk
Wendy J M
WJ
Mackus
Jeroen H N
JH
van den Brakel
Marielle
M
Pluyter
Martin J
MJ
Glennie
Jan G J
JG
van de Winkel
Paul W H I
PW
Parren
D000818:Animals; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000628:therapy; D016393:Lymphoma, B-Cell / Q000628:therapy; D008252:Macaca fascicularis; D051379:Mice; D016513:Mice, SCID; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; C527517:ofatumumab