Non-Invasive In Vivo Imaging of CD4 pool in HIV-1 Infected Patients

外周血液中只含有人体内淋巴细胞总数的一小部分。因此，彻底了解T细胞动力学，包括SIV/SIV/HIV介导的T细胞耗尽、T细胞转运和联合抗逆转录病毒治疗(CART)后的免疫重建，需要对淋巴组织进行直接的全身可视化。尽管在过去的几十年里，免疫学家试图使用光学成像技术来解决其中的一些问题，但由于低能光子的衰减和散射，后者无法从深层组织中产生定量信息，因此将其应用于啮齿动物模型。NIAID的科学家已经证明了在非人类灵长类动物中使用完整或碎片的抗CD4单抗分别用单光子伽马或正电子发射器和单光子发射计算机断层扫描(SPECT)或正电子发射断层扫描(PET)相机进行体内成像的可行性。虽然SPECT和PET都记录了健康和SIV/SIV/SHIV CD4耗竭动物之间淋巴组织CD4池的差异，但正如最近报道的那样，PET更高的灵敏度、分辨率和独特的定量成像能力使我们能够量化体内CD4受体的绝对数量(单位组织体积)。Ibalizumab是FDA批准的重组人源化IgG4鼠抗人CD4单抗，静脉注射(IV)治疗多药耐药HIV感染。NIAID团队已经通过去铁胺与正电子发射体-89(89Zr)的结合物成功地标记了Ibalizumab，该正电子发射体的半衰期为78小时，与64Cu(12.7小时半衰期)等其他正电子发射体相比，可以在至少一周内进行连续成像，同时还能获得商业分布和患者调度的便利。他们已经开发并验证了将Ibalizumab与去铁胺(DF-Ibalizumab)结合并与89Zr进行放射性标记以使用现有方法生产89Zr-DF-Ibalizumab的方法和质量控制，最近还制作了健康猕猴和SIV CD4耗竭猕猴全身CD4池的PET图像，质量与NIAID计划中先前开发的PET抗CD4探针生成的图像相似。这项概念验证研究旨在通过一项单点、开放标签、非随机的1期试验，确定GMP开发的89Zr-DF-Ibalizumab在人类体内可视化CD4池的安全性和能力。

The peripheral blood contains only a small fraction of the total number of lymphocytes in the body. Therefore, a thorough understanding of T-cell dynamics, including SIV/SHIV/HIV-mediated T cell depletion, T-cell trafficking and immune reconstitution following combination antiretroviral therapy (cART), requires a direct whole body in vivo visualization of lymphoid tissues. Although in the past decades immunologists have attempted to address some of these questions using optical imaging technologies, the latter are unable to generate quantitative information from deep tissues, due to attenuation and scattering of low energy photons, hence limiting their use to rodent models. NIAID scientists have demonstrated the feasibility of CD4 pool in vivo imaging in non-human primates using intact or fragmented anti-CD4 monoclonal antibodies radiolabeled with single photon gamma or positron emitters, and Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET) cameras, respectively. Although both SPECT and PET document differences in CD4 pools of lymphoid tissues between healthy and SIV/SHIV CD4 depleted animals, PET’s higher sensitivity, resolution and unique quantitative imaging capability allows the quantification of the absolute number of CD4 receptors (per unit volume of tissue), in vivo, as recently reported. Ibalizumab is an FDA-approved recombinant humanized IgG4 mouse anti-human-CD4 monoclonal antibody administered intravenously (IV) for the treatment of multi-drug resistant HIV infection. The NIAID team has successfully radiolabeled Ibalizumab via a deferoxamine conjugate with Zirconium-89 (89Zr), a positron emitter with a 78h half-life that allows serial imaging over at least 1 week with the additional benefit of commercial distribution and ease of patient scheduling as compared to other positron emitters such as 64Cu (12.7h half-life). They have developed and validated the methods and quality control for conjugating Ibalizumab with deferoxamine (DF-Ibalizumab) and radiolabeling with 89Zr to produce 89Zr-DF-Ibalizumab using established methods and have recently produced PET images of the whole-body CD4 pool in healthy and SIV CD4 depleted macaques with quality similar to those generated with previously developed PET anti-CD4 probes in the NIAID program. This proof-of-concept study aims to establish the safety and capability of a GMP developed 89Zr-DF-Ibalizumab to visualize the CD4 pool in humans through a single-site, open-label, non-randomized, phase 1 trial.