Ferroquine (FQ, SSR97193) is currently the most advanced organo-metallic drug candidate and about to complete phase II clinical trials as a treatment for uncomplicated malaria. This ferrocene-containing compound is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. This article focuses on the discovery of FQ, its antimalarial activity, the hypothesis of its mode of action, the current absence of resistance in vitro and recent clinical trials.

Ferroquine (FQ or SR97193) is a novel antimalarial drug candidate, currently in development at Sanofi-Aventis. In contrast to conventional drugs, FQ is the first organometallic drug: a ferrocenyl group covalently flanked by a 4-aminoquinoline and a basic alkylamine. FQ is able to overcome the CQ resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. After fifteen years of effort, it is now possible to propose a multifactorial mechanism of action of FQ by its capacity to target lipids, to inhibit the formation of hemozoin and to generate reactive oxygen species.

After the demonstration of blocking antibodies during rat experimental schistosomiasis, the existence of such factors was investigated in human schistosomiasis. The depletion, in sera from S. mansoni-infected patients, of a given isotype (IgM) either by protein A-Sepharose (PAS) absorption or by fast protein liquid chromatography (FPLC) induced a significant increase in IgG-mediated killing of S. mansoni schistosomula by human eosinophils. Inhibition experiments showed that IgM-enriched fractions (PAS effluents) were able to inhibit eosinophil-dependent cytotoxicity mediated by IgG fractions (total sera or PAS eluates). Both IgG and IgM antibodies from infected human sera immunoprecipitated antigens of 30,000-40,000 Mr in the labeled detergent extracts of schistosomulum surface. The specificity of IgG and IgM for the 38,000 Mr antigen was suggested by competition experiments using two radiolabeled mAbs (IPLSm1, IPLSm3) directed against this antigen. Moreover, crossinhibition between IgG and IgM antibodies for the Mr 38,000 antigen could be directly demonstrated. The in vivo relevance of such IgM blocking antibodies in the context of human immunity to schistosomiasis was evaluated in two groups of children classified as resistant or susceptible to posttreatment reinfection. IgM antibodies specifically directed against the 38,000 Mr antigen were measured by a capture assay. The mean levels of IgM antibodies were significantly higher in the susceptible than in the resistant group both before and after treatment. These results are consistent with the idea that immunity to schistosomiasis could be attributable not only to the existence of antibodies with defined effector function, but also to the absence of blocking antibodies. The description of the existence in human schistosomiasis of antibody isotypes blocking the effector response against defined surface targets might lead to a new understanding of the mechanisms regulating immunity to reinfection against schistosomes and possibly other parasites.

SUMMARY: A total of 129 children were treated forSchistosoma mansoniinfections, and followed for intensity of reinfection at3-monthly intervals over a 21-month period. Blood samples were taken before treatment and at 5 weeks and 6, 12 and 18 months after treatment. This paper presents a statistical analysis of the relationship between various immune responses and subsequent reinfection. Responses analysed were: blood eosinophil levels; IgE antibodies against schistosomulum antigens; IgG antibodies mediating eosinophil-dependent killing of schistosomula; antibodies inhibiting the binding to schistosomulum antigens of two rat monoclonal antibodies that also recognize egg antigens; the levels of anti-adult worm and of anti-egg (total, IgM and IgG) antibodies; and IgM anti-schistosomulum antibodies. Results for each assay were well correlated for each of the five separate blood samples. None of the assays were predictive of resistance to reinfection, butsusceptibilityto reinfection was strongly correlated with results in the preceding blood samples for total anti-egg antibodies and the inhibition of binding of one of the two monoclonal antibodies. Further analysis also revealed a correlation between reinfection intensities and both IgM anti-schistosomulum antibodies and IgM and IgG anti-egg antibodies. These results are consistent with the hypothesis that early infections elicit the development, in response to egg antigens, of antibodies that block immune mechanisms directed against schistosomula. Blocking antibodies may be IgM, but might also be of an ineffective IgG isotype. The existence of such antibodies in young children would explain the slow development of immunity in the face of a range of detectable, potentially protective immune responses.