Mouse-human immunoglobulin G1 chimeric antibodies with activities against Cryptococcus neoformans.
Passive antibody administration is a potentially useful approach for the therapy of human Cryptococcus neoformans infections. To evaluate the efficacy of the human immunoglobulin G1 (IgG1) constant region against C. neoformans and to construct murine antibody derivatives with reduced immunogenicities and longer half-lives in humans, two mouse-human IgG1 chimeric antibodies were generated from the protective murine monoclonal antibodies 2D10 (IgM) and 18B7 (IgG1). The 2D10 mouse-human IgG1 chimeric antibody (ch2D10) had significantly lower binding affinity than its parent murine antibody (m2D10), presumably because of a loss of avidity contribution on switching from IgM to IgG. The 18B7 mouse-human IgG1 chimeric antibody (ch18B7) had higher affinity for cryptococcal polysaccharide antigen than its parent murine antibody (m18B7). ch18B7 and ch2D10 promoted phagocytosis of C. neoformans by primary human microglial cells and the murine J774.16 macrophage-like cell line. ch18B7 and m18B7 enhanced fungistatic or fungicidal activity of J774.16 cells and prolonged the survival of lethally infected mice. We conclude that the human IgG1 constant chain can be effective in mediating antifungal activity against C. neoformans. ch18B7 or similar antibodies are potential candidates for passive antibody therapy of human cryptococcosis.
R. W. Johnson Pharmaceutical Research Institute, San Diego, California 92121.
S L
SL
Zebedee
R K
RK
Koduri
J
J
Mukherjee
S
S
Mukherjee
S
S
Lee
D F
DF
Sauer
M D
MD
Scharff
A
A
Casadevall
D000818:Animals; D000908:Antibodies, Fungal / Q000096:biosynthesis / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology*; D001483:Base Sequence; D002460:Cell Line; D003453:Cryptococcosis / Q000276:immunology / Q000517:prevention & control; D003455:Cryptococcus neoformans / Q000276:immunology* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010587:Phagocytosis / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology
D000908:Antibodies, Fungal; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins