Pharmacokinetics and biodistribution of a monoclonal antibody to Cryptococcus neoformans capsular polysaccharide antigen in a rat model of cryptococcal meningitis: implications for passive immunotherapy.
Several investigators have developed monoclonal antibodies against the capsular polysaccharide of Cryptococcus neoformans which have potential therapeutic applications. Using a rat model of C. neoformans meningitis, we studied the biodistribution and pharmacokinetics of a murine anticryptococcal capsular monoclonal antibody (mAb 2H1) after intravenous and intracisternal administration. After intravenous administration of 125I-labelled 2H1 to infected rats, there was no detectable localization of 125I in the brain or cerebrospinal fluid by either gamma-camera imaging of the whole animal or organ scintillation counting. In contrast, direct intracisternal instillation of 2H1 to infected rats resulted in persistent intracranial activity. In addition, the whole body half-life of intravenously administered radio labelled mAb 2H1 was significantly reduced in infected rats compared with uninfected rats. Our observations suggest that if high central nervous system (CNS) levels of mAb are needed to achieve a therapeutic effect in human C. neoformans meningoencephalitis, direct administration of mAb into the cerebrospinal fluid or modification of the mAb to increase penetration into the CNS may be required. Furthermore, higher or more frequent dosing of mAb may be required to maintain therapeutic levels in the presence of infection. This study demonstrates the usefulness of the rat as an experimental system for studying issues related to cryptococcosis.
Goldman
D L
DL
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Casadevall
A
A
Zuckier
L S
LS
D000818:Animals; D000908:Antibodies, Fungal / Q000008:administration & dosage / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000946:Antigens, Fungal / Q000276:immunology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000276:immunology*; D006207:Half-Life; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D016919:Meningitis, Cryptococcal / Q000378:metabolism / Q000628:therapy*; D008657:Metabolic Clearance Rate; D011134:Polysaccharides / Q000276:immunology*; D011877:Radionuclide Imaging; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D012588:Scintillation Counting; D014018:Tissue Distribution
D000908:Antibodies, Fungal; D000911:Antibodies, Monoclonal; D000946:Antigens, Fungal; D007457:Iodine Radioisotopes; D011134:Polysaccharides