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Infection and Immunity, February 2002, p. 612-619, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 70.2.612-619.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Human Stx2-Specific Monoclonal Antibodies Prevent Systemic Complications of Escherichia coli O157:H7 Infection

Jean Mukherjee,1 Kerry Chios,1 Dianne Fishwild,2 Deborah Hudson,2 Susan O'Donnell,2 Stephen M. Rich,1 Arthur Donohue-Rolfe,1 and Saul Tzipori1*

Tufts University School of Veterinary Medicine, North Grafton, Massachusetts,1 Medarex, San Jose, California2

Received 2 May 2001/ Returned for modification 7 August 2001/ Accepted 12 November 2001

Hemolytic-uremic syndrome (HUS) is a serious complication predominantly associated with infection by enterohemorrhagic Escherichia coli (EHEC), such as E. coli O157:H7. EHEC can produce Shiga toxin 1 (Stx1) and/or Shiga toxin 2 (Stx2), both of which are exotoxins comprised of active (A) and binding (B) subunits. In piglets and mice, Stx can induce fatal neurological symptoms. Polyclonal Stx2 antiserum can prevent these effects in piglets infected with the Stx2-producing E. coli O157:H7 strain 86-24. Human monoclonal antibodies (HuMAbs) against Stx2 were developed as potential passive immunotherapeutic reagents for the prevention and/or treatment of HUS. Transgenic mice bearing unrearranged human immunoglobulin (Ig) heavy and {kappa} light chain loci (HuMAb___Mouse) were immunized with formalin-inactivated Stx2. Thirty-seven stable hybridomas secreting Stx2-specific HuMAbs were isolated: 33 IgG1{kappa} A-subunit-specific and 3 IgG1{kappa} and 1 IgG3{kappa} B-subunit-specific antibodies. Six IgG1{kappa} A-subunit-specific (1G3, 2F10, 3E9, 4H9, 5A4, and 5C12) and two IgG1{kappa} B-subunit-specific (5H8 and 6G3) HuMAbs demonstrated neutralization of >95% activity of 1 ng of Stx2 in the presence of 0.04 µg of HuMAb in vitro and significant prolongation of survival of mice given 50 µg of HuMAb intraperitoneally (i.p.) and 25 ng of Stx2 intravenously. When administered i.p. to gnotobiotic piglets 6 or 12 h after infection with E. coli O157:H7 strain 86-24, HuMAbs 2F10, 3E9, 5H8, and 5C12 prolonged survival and prevented development of fatal neurological signs and cerebral lesions. The Stx2-neutralizing ability of these HuMAbs could potentially be used clinically to passively protect against HUS development in individuals infected with Stx-producing bacteria, including E. coli O157:H7.

* Corresponding author. Mailing address: Tufts University School of Veterinary Medicine, Division of Infectious Diseases, 200 Westboro Rd., Building 20, North Grafton, MA 01536. Phone: (508) 839-7955. Fax: (508) 839-7977. E-mail: Saul.Tzipori{at}tufts.edu.

Editor: J. D. Clements

Infection and Immunity, February 2002, p. 612-619, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 70.2.612-619.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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