College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.
Canadian Nuclear Laboratories, Chalk River, ON, Canada.
Nucl Med Biol. 2020 Mar-Apr;82-83:80-88. doi: 10.1016/j.nucmedbio.2020.02.009. Epub 2020 Feb 19.
cART has significantly improved the life expectancy of people living with HIV (PLWH). However, it fails to eliminate the long-lived reservoir of latent HIV-infected cells. Radioimmunotherapy (RIT) relies on antigen-specific monoclonal antibodies (mAbs) for targeted delivery of lethal doses of ionizing radiation to cells. Previously, we have demonstrated that human mAb 2556 against HIV gp41 conjugated with Bismuth radioisotope (t = 46 min, alpha-emitter) selectively killed HIV-infected cells. Actinium (t = 9.92 d, alpha-emitter) and Lutetium (t = 6.7 d, beta-emitter) are two long-lived clinically proven radioisotopes for cancer treatment which might be more effective in killing infected cells systemically and in CNS.
In this study we have conjugated 2556 mAb with Bi, Ac and Lu, and compared their ability to kill HIV-infected human peripheral blood mononuclear cells (PBMCs) and monocytes. PBMCs and monocytes from healthy donors were infected with HIV and treated in vitro with increasing concentrations of Bi (4-20 μCi)-, Ac (20-100 nCi)- and Lu (4-50 μCi)-2556 mAb.
After three days post-treatment of infected PBMCs and monocytes, Bi- and Lu-conjugated 2556 mAb reduced virus production measured by p24 level in a dose-dependent manner, whereas, Ac-2556 showed minimal effect. However, seven days post-treatment all three radioisotopes showed significantly more pronounced reduction of virus replication as compared to control labeled mAb with Ac-2556 showing the least non-specific killing.
These results indicate that RIT holds promise as a novel treatment option for the eradication of HIV-infected cells that merits further study in combination with cART and reactivation drugs.
高效抗逆转录病毒疗法（cART）显著提高了艾滋病毒感染者（PLWH）的预期寿命。然而，它无法消除潜伏的艾滋病毒感染细胞的长期储存库。放射免疫疗法（RIT）依赖于抗原特异性单克隆抗体（mAbs），将致死剂量的电离辐射靶向递送至细胞。此前，我们已经证明，针对 HIV gp41 的人源单克隆抗体 2556 与铋放射性同位素（t = 46 分钟，α发射器）结合，可选择性地杀死感染 HIV 的细胞。锕（t = 9.92 天，α发射器）和镥（t = 6.7 天，β发射器）是两种经过临床验证的用于癌症治疗的长寿命放射性同位素，它们可能更有效地杀伤全身和中枢神经系统中的感染细胞。
在这项研究中，我们将 2556 mAb 与 Bi、Ac 和 Lu 缀合，并比较它们杀死感染 HIV 的人外周血单核细胞（PBMCs）和单核细胞的能力。来自健康供体的 PBMCs 和单核细胞被 HIV 感染，并在体外用递增浓度的 Bi（4-20μCi）-、Ac（20-100nCi）-和 Lu（4-50μCi）-2556 mAb 处理。
在感染的 PBMCs 和单核细胞处理后 3 天，Bi 和 Lu 缀合的 2556 mAb 以剂量依赖性方式减少 p24 水平测量的病毒产量，而 Ac-2556 则显示出最小的效果。然而，在处理后 7 天，所有三种放射性同位素均显示出更显著的病毒复制减少，与对照标记的 mAb 相比，Ac-2556 显示出最小的非特异性杀伤。
这些结果表明，RIT 作为一种新型治疗方法，有望根除 HIV 感染细胞，值得与 cART 和再激活药物联合进一步研究。
