Experimental therapy of African trypanosomiasis with a nanobody-conjugated human trypanolytic factor
Experimental therapy of African trypanosomiasis with a nanobody-conjugated human trypanolytic factor
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DOI：
10.1038/nm1395
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发表时间：
2006-05-01
期刊：
影响因子：
82.9
通讯作者：
De Baetselier, Patrick
中科院分区：
文献类型：
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作者：
Baral, Toya Nath;Magez, Stefan;De Baetselier, Patrick
高全身性药物毒性和耐药性的增加阻碍了非洲人锥虫病（HAT）的有效治疗。因此，开发新的高度特异性的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），可裂解非洲锥虫，但耐药形式（如布氏锥虫罗得西亚）除外（1）。T. B.罗德西亚疟原虫表达apoL-I中和血清抗性相关（SRA）蛋白（2），赋予该寄生虫感染人类并引起HAT的能力。通过缺失与SRA相互作用的结构域，设计了一个截短的apoL-I（Tr-apoL-I），使其对T. B. Rhodesiense（1）.在这里，我们将Tr-apoL-I与有效靶向锥虫变体表面糖蛋白（VSG）的保守隐蔽表位的单域抗体（纳米抗体）结合（3），以产生一种新的具有锥虫治疗潜力的人造免疫毒素。用这种工程化缀合物治疗对NHS抗性和NHS敏感性锥虫的小鼠的急性和慢性感染产生明确的治疗和缓解作用。
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(1). T. b. rhodesiense expresses the apoL-I neutralizing serum resistance-associated (SRA) protein(2), 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(1). 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(3) 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.