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Infection and Immunity, April 2001, p. 2223-2229, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2223-2229.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Sonali Hemachandra,1 Kulwant Kamboj,1 Janna Copfer,1 Gerald Pier,2 Larry L. Green,3 and John R. Schreiber1,4,*

Division of Infectious Diseases, Department of Pediatrics, Rainbow Babies and Children's Hospital,1 and Department of Pathology, Case Western Reserve University School of Medicine,4 Cleveland, Ohio 44106; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 021152; and Abgenix, Inc., Fremont, California 945553

Received 31 October 2000/Returned for modification 14 December 2000/Accepted 4 January 2001

Pseudomonas aeruginosa is a significant human pathogen, and no vaccine is commercially available. Passive antibody prophylaxis using monoclonal antibodies (MAb) against protective P. aeruginosa epitopes is an alternative strategy for preventing P. aeruginosa infection, 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 of P. aeruginosa, 06ad. The anti-PS human immunoglobulin G2 MAb made from mice immunized with heat-killed P. aeruginosa was specific for serogroup 06ad pseudomonas. The MAb was highly opsonic for the uptake and killing of P. aeruginosa by human polymorphonuclear leukocytes in the presence of human complement. In addition, 25 µg of the MAb protected 100% of neutropenic mice from fatal P. aeruginosa sepsis. DNA sequence analysis of the genes encoding the MAb revealed VH3 and Vkappa 2/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 to P. aeruginosa made 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.

* Corresponding author. Mailing address: Division of Infectious Diseases, Rainbow Babies and Children's Hospital, 11100 Euclid Ave., Cleveland, OH 44106. Phone: (216) 844-3645. Fax: (216) 844-8362. E-mail: jrs3{at}po.cwru.edu.

Infection and Immunity, April 2001, p. 2223-2229, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2223-2229.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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