Alpha Emitter Labeled Anti-T Cell Antibody: Targeting Latent HIV Infected Cells

Alpha 发射体标记的抗 T 细胞抗体：针对潜伏的 HIV 感染细胞

• 批准号: 8842434
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 25.66万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842434
• 关键词: Acceleration; Allogenic; Anti-Retroviral Agents; Antibodies; Antigen Targeting; Antigens; Astatine; Binding; Binding Sites; Biodistribution; Blood; CD3 Antigens; CD4 Positive T Lymphocytes; Canis familiaris; Cell Transplants; Cells; Development; Dose; Flow Cytometry; Gene-Modified; Genetic Transcription; Goals; HIV; HIV-1; Half-Life; Hematopoietic; Human; Image; Immune; Individual; Infection; Infusion procedures; Label; Lead; Length; Linear Energy Transfer; Lymphoid Tissue; Macaca; Macaca mulatta; Maximum Tolerated Dose; Measures; Memory; Methods; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Occupations; Organ; Pancytopenia; Patients; Pharmaceutical Preparations; Phase; Plasma; Probability; Proteins; Radiation; Radioisotopes; Radiolabeled; Reagent; Residual state; Rest; SIV; Source; Specificity; Spleen; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Thymus Gland; Tissues; Toxic effect; Viral; Viral Load result; Virus; Work; Xenograft Model; Xenograft procedure; antibody conjugate; cancer cell; cell killing; chemoradiation; cytokine; cytotoxic; gastrointestinal; in vivo; killings; lymph nodes; meetings; memory CD4 T lymphocyte; mortality; mouse model; nonhuman primate; novel; peripheral blood; public health relevance; radiochemical; radiotracer; success; viral DNA

 DESCRIPTION: Control of HIV-1 infection can be achieved in most patients with combination anti-retroviral therapy (ART). Even with a prolonged period of completely suppressive ART, the viral load increases within weeks to months after discontinuation. The source of re-emergent HIV-1 is found mainly in memory CD4+ T cells which harbor replication-competent but transcriptionally silent pro-viral DNA. Elimination of this latent HIV-1 reservoir is the major impediment to achieving a cure of HIV-1 infection. Strategies to eradicate the latent reservoir by stimulating HIV-1 replication in latently infected cells, either through drug-induced activation of viral transcription or cytokine-induced acceleration of CD4+ cell turnover, have met with limited success. An alternative strategy is to directly target and kill latently infected cells. We hypothesize that memory CD4+ cells can be targeted by monoclonal antibodies (MAb) and killed by radiation in the form of an alpha-emitter without undue toxicity to the patient. We furthr hypothesize that radiolabeled MAb depletion of memory CD4+ cells, followed by measures to protect CD4+ cells during rebound proliferation, would considerably shorten the duration of ART and accomplish a sterilizing cure. Here, we propose to develop the radiolabeled MAb and to study efficacy and toxicity in nonhuman primates. We propose two targeting strategies, one to deplete CD4+ cells that include all memory CD4+ subsets, and a second to broadly target CD3+ cells, which would likely result in a greater depletion of CD4+ cells and for which we have already shown in a canine model to be safe (nontoxic). In the R21 phase, we will produce the radiolabeled MAbs that target macaque and human T cells and characterize binding to target antigen. In Aim 1 we will conjugate 211At to both anti-CD4 and anti-CD3 MAb using a novel method for radiolabeling and validate binding specificity. In Aim 2 we will characterize the radiolabeled MAb in vivo, using a human T-cell xenograft mouse model to ascertain stability of the conjugation and binding to target antigens. The R33 phase will proceed only after the radiolabeled MAb(s) have been validated. Here, we will test the radiolabeled MAbs in rhesus macaques to determine the optimal dose for use in depletion of memory CD4+ T cell subsets. In Aim 3 we will conduct bio distribution studies to determine the dose of radiolabeled MAb that will result in >50% saturation of the target antigens. Then, in Aim 4 we will investigate the toxicity profile of the radiolabeled MAbs and their effects on CD4+ cell subsets in peripheral blood and lymphoid tissues. Finally, we will consider results of the toxicity and efficacy studies to arrive t the optimal dose of each radiolabeled MAb. The immediate goal of our proposal is to develop a highly effective agent to deplete memory CD4+ cells, to be tested further in NHP models of HIV-1 latency. The ultimate goal is to develop a non-toxic agent capable of depleting latently infected cells to a level that, when combined with fully suppressive ART and ongoing reservoir decay, would allow for HIV eradiation within years rather than decades.

 描述：大多数患者通过联合抗逆转录病毒治疗 (ART) 可以控制 HIV-1 感染。即使长期完全抑制 ART，病毒载量也会在停药后数周至数月内增加。重新出现的 HIV-1 的来源主要是在记忆 CD4+ T 细胞中发现的，这些细胞含有具有复制能力但转录沉默的前病毒 DNA。消除这种潜在的 HIV-1 病毒库是治愈 HIV-1 感染的主要障碍。通过刺激潜伏感染细胞中的 HIV-1 复制来根除潜伏病毒库的策略，或者通过药物诱导的激活 病毒转录或细胞因子诱导的 CD4+ 细胞更新加速，取得的成功有限。另一种策略是直接靶向并杀死潜伏感染的细胞。我们假设记忆 CD4+ 细胞可以被单克隆抗体 (MAb) 靶向，并以 α 发射体的形式被辐射杀死，而不会对患者产生过度的毒性。我们进一步假设，放射性标记的 MAb 消除记忆 CD4+ 细胞，然后采取措施在反弹增殖期间保护 CD4+ 细胞，将大大缩短 ART 的持续时间并实现绝育治疗。 在这里，我们建议开发放射性标记的单克隆抗体并研究非人类灵长类动物的功效和毒性。我们提出了两种靶向策略，一种是消耗包括所有记忆 CD4+ 亚群的 CD4+ 细胞，第二种是广泛靶向 CD3+ 细胞，这可能会导致 CD4+ 细胞更大程度的消耗，并且我们已经在犬类模型中证明了这种策略是安全的（无毒的）。在 R21 阶段，我们将生产靶向猕猴和人类 T 细胞的放射性标记单克隆抗体，并表征与靶抗原的结合。在目标 1 中，我们将使用一种新的放射性标记方法将 211At 与抗 CD4 和抗 CD3 MAb 结合并验证结合特异性。在目标 2 中，我们将使用人类 T 细胞异种移植小鼠模型来表征放射性标记的 MAb 体内特征，以确定与靶抗原的缀合和结合的稳定性。 R33 阶段仅在放射性标记的 MAb 得到验证后才会进行。在这里，我们将在恒河猴中测试放射性标记的 MAb，以确定用于消除记忆 CD4+ T 细胞亚群的最佳剂量。在目标 3 中，我们将进行生物分布研究，以确定导致靶抗原饱和度 >50% 的放射性标记 MAb 的剂量。然后，在目标 4 中，我们将研究放射性标记 MAb 的毒性特征及其对外周血和淋巴组织中 CD4+ 细胞亚群的影响。最后，我们将考虑毒性和功效研究的结果，以确定每种放射性标记单克隆抗体的最佳剂量。我们提案的直接目标是开发一种高效的药物来消耗记忆 CD4+ 细胞，并在 HIV-1 潜伏期的 NHP 模型中进行进一步测试。最终目标是开发一种能够消除潜伏感染的无毒制剂 当与完全抑制性 ART 和持续的病毒库衰退相结合时，艾滋病毒将在数年而不是数十年内被根除。