Monoclonal antibody-mediated toxicity in Cryptococcus neoformans infection: Mechanism and relationship to antibody isotype

Antibody reagents represent an alternative for the therapy of human cryptoc occosis, and monoclonal antibody 18B7 (IgG1) is a candidate for phase I tri al in humans with cryptococcosis. However, antibody administration to mice with established Cryptococcus neoformans infection has been reported to pro duce acute lethal toxicity (ALT), The present study confirmed this phenomen on and investigated the mechanism of ALT. ALT was associated with hemoconce ntration, hypotension, and circulatory collapse; however, toxicity could be prevented by platelet-activating factor inhibitor, rat antibody to Fc rece ptor, or IgM before IgG1. Significant isotype-specific differences were fou nd in ALT, which can be interpreted as consistent with the hypothesis that there are distinct Fc receptors for murine IgG1 and IgG3. The IgM and IgG3 isotype preference in antibody responses to polysaccharide antigens in mice may translate to a lack of toxicity of antigen-antibody complexes during t he course of infections with encapsulated pathogens.