The carboxyl terminal amino acid residues of Pseudomonas aeruginosa exotoxin A involved in cell toxicity and pathogenesis, characterized by a neutralizing human monoclonal antibody.
Human monoclonal antibody HI-1A4 (IgG3, lambda) neutralized a toxicity caused by pseudomonal exotoxin A (Ex-A) in cell culture and in vivo, and was effective in experimental Pseudomonas aeruginosa infections in mice. HI-1A4 inhibited an Ex-A catalyzed ADP-ribosylation of elongation factor 2 but did not inhibit an incorporation of toxin into a target cell at all. One molecule of HI-1A4 neutralized at least 2 molecules of Ex-A. HI-1A4 retained its binding activity at pH 4.0. The epitope region for HI-1A4 was demonstrated to be a carboxyl terminal end of amino acid residues 591-613 of Ex-A. HI-1A4 might bind to Ex-A carboxyl terminal region outside a target cell, be incorporated into cells as a complex with Ex-A, and inhibit the intracellular function in which the carboxyl terminal part of Ex-A was involved, resulting in the interruption of intoxication of Ex-A.
Ohtsuka
H
H
Biotechnology Laboratory, Sumitomo Chemical Co., Ltd., Hyogo, Japan.
Higuchi
A
A
Nomura
N
N
Horigome
K
K
Kohzuki
T
T
Nakamori
Y
Y
Noguchi
H
H
D016475:3T3 Cells; D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001427:Bacterial Toxins; D002352:Carrier Proteins; D002470:Cell Survival / Q000187:drug effects*; D002872:Chromosome Deletion; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000032:analysis; D005098:Exotoxins / Q000235:genetics / Q000276:immunology / Q000633:toxicity*; D005798:Genes, Bacterial; D006801:Humans; D007167:Immunotherapy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000302:isolation & purification / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D011956:Receptors, Cell Surface; D011950:Receptors, Cholinergic / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology / Q000633:toxicity; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D002352:Carrier Proteins; D000939:Epitopes; D005098:Exotoxins; D010446:Peptide Fragments; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011956:Receptors, Cell Surface; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C027553:Pseudomonas exotoxin binding protein, mouse