近日，美国国立卫生研究院Joseph P. Casazza等研究人员完成AAV8递送广谱中和抗体在成人艾滋病患者中安全性和耐受性的临床试验。2022年4月11日，《自然—医学》杂志在线发表了这项成果。

研究人员向8名成年HIV感染者注射了重组的双顺反腺相关病毒（AAV8）载体，该载体编码了有效的广谱中和HIV-1抗体VRC07的轻链和重链（AAV8-VRC07）。在这个1期的剂量递增临床试验（NCT03374202）中，所有参与者都保持有效的抗逆转录病毒治疗（病毒载量（VL）<50拷贝/毫升）。AAV8-VRC07以每公斤5×10¹⁰、5×10¹¹和2.5×10¹²个载体基因组的剂量进行肌肉注射。这项研究的主要目的是评估AAV8-VRC07的安全性和耐受性；确定体内VRC07生产的药代动力学和免疫原性；并描述针对AAV8-VRC07载体及其产品的免疫反应。次要终点是评估AAV8-VRC07对CD4 T细胞计数和VL的临床效果，并评估参与者体内产生的VRC07的持久性。

在这个队列中，AAV8-VRC07的IM注射是安全和良好的耐受性。在1-3年的随访中，CD4 T细胞计数或VL没有发生临床上的显著变化。在接受AAV8-VRC07的参与者中，VRC07的浓度在注射该产品的6周（P=0.008）和52周（P=0.016）后有所增加。所有八个人都产生了可测量数量的血清VRC07，其中三个人的最大VRC07浓度>1微克每毫升。在四个人中，VRC07的血清浓度在长达3年的随访中一直稳定在最大浓度附近。

在探索性分析中，体内产生的VRC07的中和活性与体外产生的VRC07相似。8名参与者中有3人显示出针对VRC07的Fab部分的非独特型抗药性抗体（ADA）反应。这种ADA反应似乎减少了这三个参与者中两个人的血清VRC07的产生。这些数据代表了一个概念的证明，即腺相关病毒载体可以在体内持久地产生具有生物活性的、难以诱导的广义中和性抗HIV抗体（bnAb），这可以为抗击传染病增加宝贵的新工具。

据介绍，腺相关病毒载体介导的编码bnAb的DNA转移，为试图通过疫苗接种或重复输注bnAb来诱导保护提供了一种替代方法。

附：英文原文

Title: Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial

Author: Casazza, Joseph P., Cale, Evan M., Narpala, Sandeep, Yamshchikov, Galina V., Coates, Emily E., Hendel, Cynthia S., Novik, Laura, Holman, LaSonji A., Widge, Alicia T., Apte, Preeti, Gordon, Ingelise, Gaudinski, Martin R., Conan-Cibotti, Michelle, Lin, Bob C., Nason, Martha C., Trofymenko, Olga, Telscher, Shinyi, Plummer, Sarah H., Wycuff, Diane, Adams, William C., Pandey, Janardan P., McDermott, Adrian, Roederer, Mario, Sukienik, Avery N., ODell, Sijy, Gall, Jason G., Flach, Britta, Terry, Travis L., Choe, Misook, Shi, Wei, Chen, Xuejun, Kaltovich, Florence, Saunders, Kevin O., Stein, Judy A., Doria-Rose, Nicole A., Schwartz, Richard M., Balazs, Alejandro B., Baltimore, David, Nabel, Gary J., Koup, Richard A., Graham, Barney S., Ledgerwood, Julie E., Mascola, John R.

Issue&Volume: 2022-04-11

Abstract: Adeno-associated viral vector-mediated transfer of DNA coding for broadly neutralizing anti-HIV antibodies (bnAbs) offers an alternative to attempting to induce protection by vaccination or by repeated infusions of bnAbs. In this study, we administered a recombinant bicistronic adeno-associated virus (AAV8) vector coding for both the light and heavy chains of the potent broadly neutralizing HIV-1 antibody VRC07 (AAV8-VRC07) to eight adults living with HIV. All participants remained on effective anti-retroviral therapy (viral load (VL) <50 copies per milliliter) throughout this phase 1, dose-escalation clinical trial (NCT03374202). AAV8-VRC07 was given at doses of 5×1010, 5×1011 and 2.5×1012 vector genomes per kilogram by intramuscular (IM) injection. Primary endpoints of this study were to assess the safety and tolerability of AAV8-VRC07; to determine the pharmacokinetics and immunogenicity of in vivo VRC07 production; and to describe the immune response directed against AAV8-VRC07 vector and its products. Secondary endpoints were to assess the clinical effects of AAV8-VRC07 on CD4 T cell count and VL and to assess the persistence of VRC07 produced in participants. In this cohort, IM injection of AAV8-VRC07 was safe and well tolerated. No clinically significant change in CD4 T cell count or VL occurred during the 1–3 years of follow-up reported here. In participants who received AAV8-VRC07, concentrations of VRC07 were increased 6 weeks (P=0.008) and 52 weeks (P=0.016) after IM injection of the product. All eight individuals produced measurable amounts of serum VRC07, with maximal VRC07 concentrations >1μgml1 in three individuals. In four individuals, VRC07 serum concentrations remained stable near maximal concentration for up to 3 years of follow-up. In exploratory analyses, neutralizing activity of in vivo produced VRC07 was similar to that of in vitro produced VRC07. Three of eight participants showed a non-idiotypic anti-drug antibody (ADA) response directed against the Fab portion of VRC07. This ADA response appeared to decrease the production of serum VRC07 in two of these three participants. These data represent a proof of concept that adeno-associated viral vectors can durably produce biologically active, difficult-to-induce bnAbs in vivo, which could add valuable new tools to the fight against infectious diseases.

DOI: 10.1038/s41591-022-01762-x

Source: https://www.nature.com/articles/s41591-022-01762-x