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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

基本信息

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
项目类别：
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

项目摘要

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.