Antibodies fused to innate immune molecules reduce initiation of Cryptosporidium parvum infection in mice.
At present no completely effective treatments are available for Cryptosporidium parvum infections in humans and livestock. Based on previous data showing the neutralizing potential of a panel of monoclonal antibodies developed against C. parvum, and based on the fact that innate immune peptides and enzymes have anticryptosporidial activity, we engineered several of these antibodies into antibody-biocide fusion proteins. We hypothesized that the combination of high-affinity antibody targeting with innate immune molecule-mediated killing would result in a highly effective new antiprotozoal agent. To test this hypothesis, we expressed antibody-biocide fusion proteins in a mammalian cell culture system and used the resulting products for in vitro and in vivo efficacy experiments. Antibody-biocide fusion proteins efficiently bound to, and destroyed, C. parvum sporozoites in vitro through a membrane-disruptive mechanism. When antibody-biocide fusion proteins were administered orally to neonatal mice in a prophylactic model of cryptosporidiosis, the induction of infection was reduced by as much as 81% in the mucosal epithelium of the gut, as determined on the basis of histopathological scoring of infectious stages. Several versions of antibody fusion proteins that differed in antigen specificity and in the biocide used had strong inhibitory effects on the initiation of infection. The results lay the groundwork for the development of a new class of antimicrobials effective against Cryptosporidium.
Imboden
Michael
M
ioGenetics LLC, 3591 Anderson Street, Madison, WI 53704, USA. michael_imboden@iogenetics.com
Riggs
Michael W
MW
Schaefer
Deborah A
DA
Homan
E Jane
EJ
Bremel
Robert D
RD
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000235:genetics; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000235:genetics; D000913:Antibodies, Protozoan / Q000008:administration & dosage* / Q000235:genetics; D003457:Cryptosporidiosis / Q000276:immunology* / Q000517:prevention & control*; D016785:Cryptosporidium parvum / Q000276:immunology; D007113:Immunity, Innate; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D034101:Sporozoites / Q000276:immunology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000913:Antibodies, Protozoan; D011993:Recombinant Fusion Proteins