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Mouse-human immunoglobulin G1 chimeric antibodies with activities against Cryptococcus neoformans
S L Zebedee1, R K Koduri, J Mukherjee
1R. W. Johnson Pharmaceutical Research Institute, San Diego, California 92121.
Antimicrobial Agents and Chemotherapy
|July 1, 1994
Summary
Passive antibody therapy using human immunoglobulin G1 (IgG1) shows promise for treating Cryptococcus neoformans infections. Chimeric antibodies like ch18B7 demonstrated enhanced efficacy against fungal pathogens and improved survival rates in mice.
Area of Science:
- Immunology
- Infectious Diseases
- Microbiology
Background:
- Passive antibody administration is a potential therapeutic strategy for human Cryptococcus neoformans infections.
- Developing human antibody derivatives with reduced immunogenicity and extended half-lives is crucial for effective therapy.
Purpose of the Study:
- To assess the efficacy of the human immunoglobulin G1 (IgG1) constant region against C. neoformans.
- To engineer murine antibody derivatives with improved properties for human application.
Main Methods:
- Generation of two mouse-human IgG1 chimeric antibodies from protective murine monoclonal antibodies (2D10 and 18B7).
- Evaluation of antibody binding affinity, phagocytosis promotion, and fungistatic/fungicidal activity.
- Assessment of therapeutic efficacy in a murine model of cryptococcosis.
Main Results:
- The 18B7 mouse-human IgG1 chimeric antibody (ch18B7) exhibited higher binding affinity than its murine counterpart (m18B7).
- Both ch18B7 and ch2D10 promoted phagocytosis of C. neoformans by human microglial cells and macrophages.
- ch18B7 and m18B7 enhanced fungal killing by macrophages and significantly prolonged survival in infected mice.
Conclusions:
- The human IgG1 constant chain is effective in mediating antifungal activity against C. neoformans.
- ch18B7 represents a promising candidate for passive antibody therapy in human cryptococcosis.