Complement activation in circulation and central nervous system after rituximab (anti-CD20) treatment of B-cell lymphoma.
Rituximab (IDEC-C2B8, Mabthera, Rituxan), a chimeric monoclonal antibody against the B-cell specific CD20-antigen, has been demonstrated to be effective in the treatment of non-Hodgkin's B-cell lymphoma (B-NHL). Previous in vitro studies have shown that direct complement-dependent cytotoxicity (CDC), ADCC and apoptosis are important in the rituximab-induced killing of lymphoma cells. It is, however, unknown whether rituximab penetrates the blood-brain barrier. Therefore, we studied rituximab levels and complement (C) activation in blood and cerebrospinal fluid (CSF) following intravenous rituximab therapy in a patient with relapsing non-Hodgkin's lymphoma with central nervous system (CNS) involvement. Longitudinal samples from blood and CSF were taken at 13 time-points during the treatment period. The results show that the C cascade becomes activated in blood during the first mAb infusion (C3a-desArg concentration rose from 55 to 138 microg/ml during the first 2 hours). After the first infusion the proportions of lymphocytes positive for the CD19- and CD20-antigens in the peripheral blood were reduced from 41% and 35%, respectively, to a level of 2% (for both). In CSF the rituximab concentration increased after successive infusions, but remained below 0.55 microg/ml (compared to a Cmax of 400 microg/ml in peripheral blood). Although a minor and delayed C activation response was seen in the CSF the treatment did not clear CD20-positive cells away from the CNS. Thus, it appears that an intact blood-brain barrier restricts the entry of rituximab into the CNS. Possible options to circumvent this would be dose escalation or intrathecal rituximab treatment.
Harjunpää
A
A
The Department of Bacteriology and Immunology Haartman Institute, University of Helsinki, Finland. Seppo.Meri@helsinki.fi
Wiklund
T
T
Collan
J
J
Janes
R
R
Rosenberg
J
J
Lee
D
D
Grillo-López
A
A
Meri
S
S
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D001775:Blood Circulation / Q000276:immunology; D001812:Blood-Brain Barrier; D002490:Central Nervous System / Q000276:immunology; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects*; D015926:Complement C3a / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; C044541:complement C3a, des-Arg-(77)-; D000069283:Rituximab; D015926:Complement C3a