title: Multi-valent human monoclonal antibody preparation against Pseudomonas aeruginosa derived from transgenic mice containing human immunoglobulin loci is protective against fatal pseudomonas sepsis caused by multiple serotypes.
abstract: Pseudomonas aeruginosa is a serious human pathogen in a variety of patient groups including those with burns, hospitalized in intensive care, cystic fibrosis and neutropenia. Since there is no vaccine available, passive antibody prophylaxis against protective epitopes is an alternative strategy to prevent P. aeruginosa infection. However, immunoglobulin derived from multiple donors has variable anti-pseudomonas antibody titers, and human Mab are difficult to make from patient samples. We previously reported the use of XenoMouse mice, Ig-inactivated transgenic mice reconstituted with human immunoglobulin loci, to generate human Mab against a single serotype of P. aeruginosa lipopolysaccharide O-specific side chain (PS). We now report the creation of a panel of anti-PS human IgG2 Mab against nine additional O-specific side chain P. aeruginosa serotypes. The majority of the Mab were highly opsonic for uptake and killing of homologous P. aeruginosa by human PMN in the presence of human complement, and all the Mab protected cyclophosphamide-induced neutropenic mice from fatal P. aeruginosa sepsis with homologous serotypes. DNA sequence analysis showed that the Mab used V(H)3, V(H)4, V(H)5 and V(H)6 and Vkappa2, 3 and 4 variable region genes consistent with the heterogeneity of P. aeruginosa LPS O-side chain structure. We conclude that human Mab made in these transgenic mice against common pathogenic serotypes of P. aeruginosa are opsonic and highly protective, and that a high titer, multi-valent human Mab preparation against the majority of circulating O-side chain serotypes of P. aeruginosa could be used as prophylaxis against invasive infections in selected patient groups.
authors.affiliation: Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Zengzu
authors.initials: Z
authors.lastname: Lai
authors.forename: Rhonda
authors.initials: R
authors.lastname: Kimmel
authors.forename: Sheryl
authors.initials: S
authors.lastname: Petersen
authors.forename: Sharon
authors.initials: S
authors.lastname: Thomas
authors.forename: Gerald
authors.initials: G
authors.lastname: Pier
authors.forename: Binyam
authors.initials: B
authors.lastname: Bezabeh
authors.forename: Robin
authors.initials: R
authors.lastname: Luo
authors.forename: John R
authors.initials: JR
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003520:Cyclophosphamide; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D007136:Immunoglobulins / Q000235:genetics* / Q000276:immunology; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008970:Molecular Weight; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications; D011552:Pseudomonas Infections / Q000276:immunology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D018805:Sepsis / Q000382:microbiology / Q000517:prevention & control
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D003520:Cyclophosphamide