title: Exchanging murine and human immunoglobulin constant chains affects the kinetics and thermodynamics of antigen binding and chimeric antibody autoreactivity.
abstract: Mouse-human chimeric antibodies composed of murine variable (V) and human (C) chains are useful therapeutic reagents. Consequently, we investigated whether heterologous C-regions from mice and humans affected specificity and affinity, and determined the contribution of C(H) glycosylation to antigen binding. The interaction of a 12-mer peptide mimetic with monoclonal antibody (mAb) 18B7 to Cryptococcus neoformans glucuronoxylomannan, and its chimeric (ch) and deglycosylated forms were studied by surface plasmon resonance. The equilibrium and rate association constants for the chAb were higher than for mAb 18B7. V region affinity was not affected by C(H) region glycosylation whereas heterologous C region of the same isotype altered the Ab binding affinity and the specificity for self-antigens. Structural models displayed local differences that implied changes on the connectivity of residues. These findings suggest that V region conformational changes can be dictated by the C(H) domains through an allosteric effect involving networks of highly connected amino acids.
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors: Marcela
authors: M
authors: Torres
authors: Narcis
authors: N
authors: Fernandez-Fuentes
authors: András
authors: A
authors: Fiser
authors: Arturo
authors: A
authors: Casadevall
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000937:Antigen-Antibody Reactions; D000941:Antigens / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006031:Glycosylation; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry* / Q000276:immunology; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology; D013816:Thermodynamics
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D007136:Immunoglobulins; D011993:Recombinant Fusion Proteins