Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
Kirby Institute, University of New South Wales, Kensington, NSW, Australia.
Front Immunol. 2021 Nov 11;12:749891. doi: 10.3389/fimmu.2021.749891. eCollection 2021.
Broadly neutralising antibodies (bNAbs) may play an important role in future strategies for HIV control. The development of anti-drug antibody (ADA) responses can reduce the efficacy of passively transferred bNAbs but the impact of ADA is imperfectly understood. We previously showed that therapeutic administration of the anti-HIV bNAb PGT121 (either WT or LALA version) controlled viraemia in pigtailed macaques with ongoing SHIV infection. We now report on 23 macaques that had multiple treatments with PGT121. We found that an increasing number of intravenous doses of PGT121 or human IgG1 isotype control antibodies (2-4 doses) results in anti-PGT121 ADA induction and low plasma concentrations of PGT121. ADA was associated with poor or absent suppression of SHIV viremia. Notably, ADA within macaque plasma recognised another human bNAb 10E8 but did not bind to the variable domains of PGT121, suggesting that ADA were primarily directed against the constant regions of the human antibodies. These findings have implications for the development of preclinical studies examining multiple infusions of human bNAbs.
广泛中和抗体（bnAbs）可能在未来的 HIV 控制策略中发挥重要作用。抗药性抗体（ADA）的产生会降低被动转移的 bnAbs 的疗效，但 ADA 的影响尚未完全了解。我们之前曾表明，抗 HIV bnAb PGT121（WT 或 LALA 版本）的治疗性给药可控制感染 SHIV 的长尾猕猴的病毒血症。我们现在报告了 23 只接受多次 PGT121 治疗的猕猴。我们发现，静脉内给予 PGT121 或人 IgG1 同种型对照抗体（2-4 剂）的次数增加，导致抗 PGT121 ADA 的诱导和 PGT121 的血浆浓度降低。ADA 与 SHIV 病毒血症的抑制不良或缺失有关。值得注意的是，猕猴血浆中的 ADA 识别另一种人类 bnAb 10E8，但不结合 PGT121 的可变区，这表明 ADA 主要针对人类抗体的恒定区。这些发现对正在研究多次输注人类 bnAbs 的临床前研究具有重要意义。
