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

HIV-1 感染患者 CD4 池的非侵入性体内成像

• 批准号: 10705883
• 负责人: C.K. OSBORNE
• 金额: $ 71.14万
• 依托单位: LEIDOS BIOMEDICAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2027-09-11
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705883
• 关键词: Address; Adult; Adverse event; Age; Animals; Antibodies; Biodistribution; CD4 Antigens; CD4 Lymphocyte Count; Common Terminology Criteria for Adverse Events; Deferoxamine; FDA approved; HIV; HIV Infections; HIV drug resistance; HIV-1; Half-Life; Human; IgG4; Image; Imaging technology; Immunologist; Intravenous; Lymphocyte Count; Lymphoid Tissue; Macaca; Matched Group; Measures; Mediating; Methods; Monoclonal Antibodies; Multi-Drug Resistance; Mus; National Institute of Allergy and Infectious Disease; Patient Schedules; Patients; Photons; Positron; Positron-Emission Tomography; Production; Quality Control; Radioimmunoconjugate; Radiolabeled; Recombinants; Reporting; Resolution; Rodent Model; SIV; Safety; Scientist; Site; Spleen; T-Cell Depletion; T-Lymphocyte; Tissues; Visualization; Zirconium; antiretroviral therapy; attenuation; imaging capabilities; immune reconstitution; immunogenicity; in vivo; in vivo imaging; lymph nodes; nonhuman primate; open label; optical imaging; peripheral blood; phase I trial; programs; quantitative imaging; serial imaging; simian human immunodeficiency virus; single photon emission computed tomography; trafficking; whole body imaging

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.

外周血仅含有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/SHIV/HIV介导的T细胞耗竭，T细胞运输和联合抗逆转录病毒治疗（cART）后的免疫重建，需要淋巴组织的直接全身体内可视化。尽管在过去的几十年中，免疫学家试图使用光学成像技术来解决这些问题中的一些，但由于低能光子的衰减和散射，后者无法从深层组织产生定量信息，因此限制了它们在啮齿动物模型中的使用。NIAID科学家已经证明了在非人类灵长类动物中使用完整或片段化的抗CD 4单克隆抗体进行体内成像的可行性，这些抗体分别用单光子γ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）相机进行放射性标记。尽管SPECT和PET都记录了健康和SIV/SHIV CD 4耗尽动物之间淋巴组织的CD 4库的差异，但PET的更高灵敏度、分辨率和独特的定量成像能力允许在体内定量CD 4受体的绝对数量（每单位体积的组织），如最近报道的。Ibalizumab是FDA批准的重组人源化IgG 4小鼠抗人CD 4单克隆抗体，静脉（IV）给药，用于治疗多重耐药HIV感染。NIAID团队通过去铁胺与锆-89（89 Zr）的结合物成功地放射性标记了Ibalizumab，锆-89是一种具有78小时半衰期的正电子发射体，与其他正电子发射体如64 Cu（12.7小时半衰期）相比，其允许在至少1周内进行连续成像，具有商业分销和易于患者安排的额外益处。他们开发并验证了Ibalizumab与去铁胺（DF-Ibalizumab）结合以及使用89 Zr放射性标记的方法和质量控制，以使用已建立的方法生产89 Zr-DF-Ibalizumab，并且最近在健康和SIV CD 4耗尽的猕猴中产生了全身CD 4池的PET图像，其质量与NIAID计划中先前开发的PET抗CD 4探针产生的图像相似。这项概念验证研究旨在通过一项单中心、开放标签、非随机、I期试验，确定GMP开发的89 Zr-DF-Ibalizumab在人体中可视化CD 4池的安全性和能力。