Abstract
High systemic drug toxicity and increasing prevalence of drug resistance hampers efficient treatment of human African trypanosomiasis (HAT). Hence, development of new highly specific trypanocidal drugs is necessary. Normal human serum (NHS) contains apolipoprotein L-I (apoL-I), which lyses African trypanosomes except resistant forms such as Trypanosoma brucei rhodesiense1. T. b. rhodesiense expresses the apoL-I–neutralizing serum resistance–associated (SRA) protein2, endowing this parasite with the ability to infect humans and cause HAT. A truncated apoL-I (Tr-apoL-I) has been engineered by deleting its SRA-interacting domain, which makes it lytic for T. b. rhodesiense1. Here, we conjugated Tr-apoL-I with a single-domain antibody (nanobody) that efficiently targets conserved cryptic epitopes of the variant surface glycoprotein (VSG) of trypanosomes3 to generate a new manmade type of immunotoxin with potential for trypanosomiasis therapy. Treatment with this engineered conjugate resulted in clear curative and alleviating effects on acute and chronic infections of mice with both NHS-resistant and NHS-sensitive trypanosomes.
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Acknowledgements
We thank A. Beschin for comments on the manuscript and V. Flamand for measurement of AST values. This work was supported by grants from the Foundation for Scientific Research-Flanders (FWO-Vlaanderen) performed in frame of an Interuniversity Attraction Poles Program – Belgian Science Policy, by the Vrije Universiteit Brussel–Research grants (Geconcerteerde Onderzoekers Acite and Onderzoeksraad). S.M. is postdoctoral fellow for FWO-Vlaanderen and B.V. is Research Fellow at the Belgian FNRS.
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Supplementary Fig. 1
Analysis of trypanosomes that reappeared at day 60 in mice receiving two doses of NbAn33–Tr-apoL-I around the second peak of parasitemia. (PDF 292 kb)
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Baral, T., Magez, S., Stijlemans, B. et al. Experimental therapy of African trypanosomiasis with a nanobody-conjugated human trypanolytic factor. Nat Med 12, 580–584 (2006). https://doi.org/10.1038/nm1395
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DOI: https://doi.org/10.1038/nm1395
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