Antibodies Fused to Innate Immune Molecules Reduce Initiation ofCryptosporidium parvumInfection in Mice

Abstract

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.

IL‐18 Cytokine Levels Modulate Innate Immune Responses and Cryptosporidiosis in Mice

“…It has been shown that anti‐ Cryptosporidium antibodies fused to LL‐37, resulted in a decrease in infection (Imboden et al. ) . It may be possible that rIL‐18 could also be used at an early stage to increase effector molecules such as certain AMPs (e.g.…”

Novel Bumped Kinase Inhibitors Are Safe and Effective Therapeutics in the Calf Clinical Model for Cryptosporidiosis

“…For the present study, BKIs were first chosen from a panel of >500 BKIs on the basis of their anti-CpCDPK1 activity, pharmacodynamic/ pharmacokinetic properties, bioavailability, nontoxicity, and ability to inhibit C. parvum growth in vitro. BKIs were prescreened in the neonatal mouse infection model, previously shown to have positive predictive value for efficacy in calves [43,46]. Finally, 3 BKIs (BKI-1294, BKI-1517, and BKI-1553) were evaluated in the calf model of cryptosporidiosis, to ascertain the ability to decrease or eliminate infection and reduce clinical symptoms.…”

Cryptosporidiosis-an overview

“…In addition, studies using B-cell-deficient mice indicate that B-cells are not essential for either resistance to C. parvum infection or recovery from infection[98],[111],[118].…”