Molecular basis for nonanaphylactogenicity of a monoclonal anti-IgE antibody.
IgE Abs mediate allergic responses by binding to specific high affinity receptors (FcepsilonRI) on mast cells and basophils. Therefore, the IgE/FcepsilonRI interaction is a target for clinical intervention in allergic disease. An anti-IgE mAb, termed BSW17, is nonanaphylactogenic, although recognizing IgE bound to FcepsilonRI, and interferes with binding of IgE to FcepsilonRI. Thus, BSW17 represents a candidate Ab for treatment of IgE-mediated disorders. By panning BSW17 against random peptide libraries displayed on phages, we defined mimotopes that mimic the conformational epitope recognized on human IgE. Two types of mimotopes, one within the Cepsilon3 and one within the Cepsilon4 domain, were identified, indicating that this mAb may recognize either a large conformational epitope or eventually two distinct epitopes on IgE. On the basis of alignments of the two mimotopes with the human IgE sequence, we postulate that binding of BSW17 to the Cepsilon3 region predominantly blocks binding of IgE to FcepsilonRI, leading to neutralization of IgE. Moreover, binding of BSW17 to the Cepsilon4 region may explain how BSW17 recognizes FcepsilonRI-bound IgE, and binding to this region may also interfere with degranulation of IgE sensitized cells (basophils and mast cells). As a practical application of these findings, mimotope peptides coupled to a carrier protein may be used for the development of a peptide-based anti-allergy vaccine by induction of anti-IgE Abs similar to the current approach of using humanized nonanaphylactogenic anti-IgE Abs as a passive vaccine.
Rudolf
M P
MP
Institute of Immunology and Allergology, Inselspital, University of Bern, Bern, Switzerland.
Zuercher
A W
AW
Nechansky
A
A
Ruf
C
C
Vogel
M
M
Miescher
S M
SM
Stadler
B M
BM
Kricek
F
F
D000595:Amino Acid Sequence; D000707:Anaphylaxis / Q000276:immunology* / Q000378:metabolism; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001435:Bacteriophages / Q000737:chemistry / Q000276:immunology; D001666:Binding Sites, Antibody; D001667:Binding, Competitive / Q000276:immunology; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000737:chemistry / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology* / Q000494:pharmacology; D007139:Immunoglobulin epsilon-Chains / Q000737:chemistry / Q000378:metabolism; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D019151:Peptide Library; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000939:Epitopes; D007127:Immunoglobulin Constant Regions; D007139:Immunoglobulin epsilon-Chains; D010446:Peptide Fragments; D019151:Peptide Library; C026408:anti-IgE antibodies; D007073:Immunoglobulin E