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Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis.

Publication ,  Journal Article
Larsen, RA; Pappas, PG; Perfect, J; Aberg, JA; Casadevall, A; Cloud, GA; James, R; Filler, S; Dismukes, WE
Published in: Antimicrob Agents Chemother
March 2005

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.

Duke Scholars

Published In

Antimicrob Agents Chemother

DOI

ISSN

0066-4804

Publication Date

March 2005

Volume

49

Issue

3

Start / End Page

952 / 958

Location

United States

Related Subject Headings

  • Microbiology
  • Mice
  • Meningitis, Cryptococcal
  • Immunization, Passive
  • Humans
  • HIV Infections
  • Cryptococcus neoformans
  • Area Under Curve
  • Antigens, Fungal
  • Antibodies, Monoclonal
 

Citation

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Larsen, R. A., Pappas, P. G., Perfect, J., Aberg, J. A., Casadevall, A., Cloud, G. A., … Dismukes, W. E. (2005). Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis. Antimicrob Agents Chemother, 49(3), 952–958. https://doi.org/10.1128/AAC.49.3.952-958.2005
Larsen, Robert A., Peter G. Pappas, John Perfect, Judith A. Aberg, Arturo Casadevall, Gretchen A. Cloud, Robert James, Scott Filler, and William E. Dismukes. “Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis.Antimicrob Agents Chemother 49, no. 3 (March 2005): 952–58. https://doi.org/10.1128/AAC.49.3.952-958.2005.
Larsen RA, Pappas PG, Perfect J, Aberg JA, Casadevall A, Cloud GA, et al. Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis. Antimicrob Agents Chemother. 2005 Mar;49(3):952–8.
Larsen, Robert A., et al. “Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis.Antimicrob Agents Chemother, vol. 49, no. 3, Mar. 2005, pp. 952–58. Pubmed, doi:10.1128/AAC.49.3.952-958.2005.
Larsen RA, Pappas PG, Perfect J, Aberg JA, Casadevall A, Cloud GA, James R, Filler S, Dismukes WE. Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis. Antimicrob Agents Chemother. 2005 Mar;49(3):952–958.

Published In

Antimicrob Agents Chemother

DOI

ISSN

0066-4804

Publication Date

March 2005

Volume

49

Issue

3

Start / End Page

952 / 958

Location

United States

Related Subject Headings

  • Microbiology
  • Mice
  • Meningitis, Cryptococcal
  • Immunization, Passive
  • Humans
  • HIV Infections
  • Cryptococcus neoformans
  • Area Under Curve
  • Antigens, Fungal
  • Antibodies, Monoclonal