Baral Toya Nath, Magez Stefan, Stijlemans Benoît, Conrath Katja, Vanhollebeke Benoit, Pays Etienne, Muyldermans Serge, De Baetselier Patrick
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.
Nat Med. 2006 May;12(5):580-4. doi: 10.1038/nm1395. Epub 2006 Apr 9.
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.
高全身药物毒性和耐药性患病率的增加阻碍了人类非洲锥虫病（HAT）的有效治疗。因此，开发新型高特异性杀锥虫药物是必要的。正常人血清（NHS）含有载脂蛋白L-I（apoL-I），它能裂解非洲锥虫，但对诸如布氏罗得西亚锥虫等耐药形式无效。布氏罗得西亚锥虫表达apoL-I中和血清抗性相关（SRA）蛋白，赋予这种寄生虫感染人类并导致HAT的能力。通过删除其与SRA相互作用的结构域构建了截短的apoL-I（Tr-apoL-I），这使其对布氏罗得西亚锥虫具有裂解作用。在此，我们将Tr-apoL-I与一种单域抗体（纳米抗体）偶联，该纳米抗体能有效靶向锥虫变异表面糖蛋白（VSG）的保守隐蔽表位，以产生一种具有治疗锥虫病潜力的新型人工免疫毒素。用这种工程偶联物进行治疗对耐NHS和对NHS敏感的锥虫感染的小鼠急性和慢性感染均产生了明显的治愈和缓解效果。
