Experimental therapy of African trypanosomiasis with a nanobody-conjugated human trypanolytic factor.
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 rhodesiense. T. b. rhodesiense expresses the apoL-I-neutralizing serum resistance-associated (SRA) protein, 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. rhodesiense. 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 trypanosomes 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.
Baral
Toya Nath
TN
Department of Cellular and Molecular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Laboratorium voor Cellulaire en Moleculaire Immunologie, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussel, Belgium. tbaral@vub.ac.be
Magez
Stefan
S
Stijlemans
Benoît
B
Conrath
Katja
K
Vanhollebeke
Benoit
B
Pays
Etienne
E
Muyldermans
Serge
S
De Baetselier
Patrick
P
D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D000922:Immunotoxins / Q000627:therapeutic use*; D008075:Lipoproteins, HDL / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D014344:Trypanocidal Agents / Q000276:immunology / Q000627:therapeutic use*; D016833:Trypanosoma brucei rhodesiense / Q000276:immunology / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000276:immunology; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000235:genetics / Q000276:immunology*
C108666:APOL1 protein, human; D000913:Antibodies, Protozoan; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D007143:Immunoglobulin Heavy Chains; D000922:Immunotoxins; D008075:Lipoproteins, HDL; D014344:Trypanocidal Agents; D014643:Variant Surface Glycoproteins, Trypanosoma