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Monoclonal antibody-mediated toxicity in Cryptococcus neoformans infection: mechanism and relationship to antibody
1Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
Antibody reagents represent an alternative for the therapy of human cryptococcosis, and monoclonal antibody 18B7 (IgG1) is a candidate for phase I trial in humans with cryptococcosis. However, antibody administration to mice with established Cryptococcus neoformans infection has been reported to produce acute lethal toxicity (ALT). The present study confirmed this phenomenon and investigated the mechanism of ALT. ALT was associated with hemoconcentration, hypotension, and circulatory collapse; however, toxicity could be prevented by platelet-activating factor inhibitor, rat antibody to Fc receptor, or IgM before IgG1. Significant isotype-specific differences were found 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 the course of infections with encapsulated pathogens.
Insights
Monoclonal antibody therapy for cryptococcosis can cause acute lethal toxicity (ALT) in mice, linked to circulatory collapse. This toxicity is preventable and linked to specific antibody isotypes, suggesting distinct Fc receptor interactions.
Area of Science:
- Immunology
- Infectious Diseases
- Pharmacology
Background:
- Antibody reagents, including monoclonal antibodies like 18B7 (IgG1), are being explored for treating human cryptococcosis.
- Previous studies indicated that administering antibodies to mice with established Cryptococcus neoformans infections can result in acute lethal toxicity (ALT).
Purpose of the Study:
- To confirm the phenomenon of ALT in mice with cryptococcosis following antibody administration.
- To investigate the underlying mechanisms responsible for ALT.
- To explore strategies for preventing ALT during antibody-based cryptococcosis therapy.
Main Methods:
- Experimental induction of cryptococcosis in mice followed by administration of monoclonal antibody 18B7 (IgG1).
- Monitoring for signs of acute lethal toxicity (ALT), including hemoconcentration, hypotension, and circulatory collapse.
- Evaluation of preventative measures such as platelet-activating factor inhibitors, Fc receptor antibodies, and alternative antibody isotypes (IgM, IgG3).
Main Results:
- The study confirmed that antibody administration in mice with established cryptococcosis leads to ALT.
- ALT was characterized by hemoconcentration, hypotension, and circulatory collapse.
- Toxicity was successfully prevented by platelet-activating factor inhibitor, Fc receptor antibodies, or by administering IgM or IgG3 isotypes before IgG1.
Conclusions:
- Significant isotype-specific differences in ALT were observed, supporting the hypothesis of distinct Fc receptors for murine IgG1 and IgG3.
- The findings suggest that the preference for IgM and IgG3 isotypes in murine antibody responses to polysaccharide antigens may prevent toxicity from antigen-antibody complexes during infections with encapsulated pathogens.