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Antimicrobial Agents and Chemotherapy, March 2005, p. 952-958, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.952-958.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phase I Evaluation of the Safety and Pharmacokinetics of Murine-Derived Anticryptococcal Antibody 18B7 in Subjects with Treated Cryptococcal Meningitis

Robert A. Larsen,1* Peter G. Pappas,2 John Perfect,3 Judith A. Aberg,4 Arturo Casadevall,5 Gretchen A. Cloud,2 Robert James,6 Scott Filler,7 and William E. Dismukes2

University of Southern California, Los Angeles, California,1 University of Alabama at Birmingham, Birmingham, Alabama,2 Duke University Medical Center, Durham, North Carolina,3 Washington University School of Medicine, St. Louis, Missouri,4 Albert Einstein College of Medicine, Bronx, New York,5 Rho Federal Systems Division, Inc., Chapel Hill, North Carolina,6 Harbor-UCLA Research and Education Institute, Torrance, California7

Received 16 June 2004/ Returned for modification 15 September 2004/ Accepted 21 November 2004

A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drug-associated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.

* Corresponding author. Mailing address: Department of Medicine (Infectious Diseases), 2020 Zonal Ave., IRD Room 632, MC 9520, University of Southern California, Los Angeles, CA 90033. Phone: (323) 226-7556. Fax: (323) 226-2775. E-mail: rlarsen{at}usc.edu.

Antimicrobial Agents and Chemotherapy, March 2005, p. 952-958, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.952-958.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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