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：HIV-1感染的控制可以在大多数患者中实现联合抗逆转录病毒治疗（ART）。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性CD 4 + T细胞中发现的，这些细胞具有复制能力但转录沉默的前病毒DNA。消除这种潜伏的HIV-1储库是实现治愈HIV-1感染的主要障碍。通过刺激HIV-1在潜伏感染细胞中的复制，或者通过药物诱导的激活， 病毒转录或奎宁诱导的CD 4+细胞更新的加速，已经取得了有限的成功。另一种策略是直接靶向并杀死潜伏感染的细胞。我们假设记忆性CD 4+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毒性。我们进一步假设，放射性标记的单克隆抗体耗尽记忆CD 4+细胞，然后采取措施，以保护CD 4+细胞在反弹增殖，将大大缩短ART的持续时间，并实现灭菌治愈。 在这里，我们建议开发放射性标记的单克隆抗体，并在非人灵长类动物中研究疗效和毒性。我们提出了两种靶向策略，一种是耗尽包括所有记忆CD 4+亚群的CD 4+细胞，第二种是广泛靶向CD 3+细胞，这可能会导致更大程度的CD 4+细胞耗尽，我们已经在犬模型中证明了这是安全的（无毒的）。在R21阶段，我们将产生靶向猕猴和人T细胞的放射性标记的单克隆抗体，并表征与靶抗原的结合。在目标1中，我们将使用放射性标记的新方法将211 At与抗CD 4和抗CD 3 MAb偶联并验证结合特异性。在目标2中，我们将使用人T细胞异种移植小鼠模型在体内表征放射性标记的MAb，以确定缀合和结合靶抗原的稳定性。R33阶段仅在放射性标记MAb验证后进行。在这里，我们将在恒河猴中测试放射性标记的单克隆抗体，以确定用于消除记忆性CD 4 + 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%的放射性标记单克隆抗体的剂量。然后，在目标4中，我们将研究放射性标记的单克隆抗体的毒性特征及其对外周血和淋巴组织中CD 4+细胞亚群的影响。最后，我们将考虑毒性和有效性研究的结果，以确定每种放射性标记单克隆抗体的最佳剂量。我们提案的近期目标是开发一种高效的药物来消耗记忆性CD 4+细胞，并在HIV-1潜伏期的NHP模型中进行进一步测试。最终的目标是开发一种无毒的药物， 如果再加上完全抑制性抗逆转录病毒疗法和持续的储库衰减，将使艾滋病毒在几年内而不是几十年内被消灭。