Human Monoclonal Antibodies againstPseudomonas aeruginosaLipopolysaccharide Derived from Transgenic Mice Containing Megabase Human Immunoglobulin Loci Are Opsonic and Protective against Fatal Pseudomonas Sepsis

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Abstract
Pseudomonas aeruginosais a significant human pathogen, and no vaccine is commercially available. Passive antibody prophylaxis using monoclonal antibodies (MAb) against protectiveP. aeruginosaepitopes is an alternative strategy for preventingP. aeruginosainfection, but mouse MAb are not suitable for use in humans. Polyclonal human antibodies from multiple donors have variable antibody titers, and human MAb are difficult to make. We used immunoglobulin-inactivated transgenic mice reconstituted with megabase-size human immunoglobulin loci to generate a human MAb against the polysaccharide (PS) portion of the lipopolysaccharide O side chain of a common pathogenic serogroup ofP. aeruginosa, 06ad. The anti-PS human immunoglobulin G2 MAb made from mice immunized with heat-killedP. aeruginosawas specific for serogroup 06ad pseudomonas. The MAb was highly opsonic for the uptake and killing ofP. aeruginosaby human polymorphonuclear leukocytes in the presence of human complement. In addition, 25 μg of the MAb protected 100% of neutropenic mice from fatalP. aeruginosasepsis. DNA sequence analysis of the genes encoding the MAb revealed VH3 and Vκ2/A2 variable-region genes, similar to variable-region genes in humans immunized with bacterial PS and associated with high-avidity anti-PS antibodies. We conclude that human MAb toP. aeruginosamade in these transgenic mice are highly protective and that these mice mimic the antibody response seen in humans immunized with T-cell-independent antigens such as bacterial PS.

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