A Novel Strategy Targeting TfR1 for the Prevention/Treatment of AIDS-related NHL

针对 TfR1 预防/治疗艾滋病相关 NHL 的新策略

• 批准号: 9198980
• 负责人: OTONIEL MARTINEZ-MAZA
• 金额: $ 50.26万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198980
• 关键词: AIDS related cancer; AIDS-Related Lymphoma; AIDS-Related Non-Hodgkin' s Lymphoma; Acquired Immunodeficiency Syndrome; Affinity; Antibodies; Antineoplastic Agents; Avidin; B lymphoid malignancy; B-Cell Activation; B-Lymphocytes; Binding; Cell Line; Cell surface; Cells; Chemicals; Chimeric Proteins; Chronic; Complement; Complement 1q; Complex; DNA lesion; Development; Diagnosis; Dimerization; Dose; Epstein-Barr Virus Infections; Exposure to; Foundations; Goals; Growth; HIV; HIV Infections; HOX protein; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Human Herpesvirus 4; IgG3; Immune; Immune response; Immunoglobulin G; In Vitro; Iron; Lead; Lesion; Lymphomagenesis; Macaca fascicularis; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Multiple Myeloma; Mus; Passive Immunotherapy; Peptides; Persons; Phagocytosis; Pharmaceutical Preparations; Plants; Play; Prevention; Process; Recycling; Role; SCID Mice; Seminal; Signal Transduction; Structure; System; TFRC gene; Therapeutic; Time; Toxic effect; Toxin; Work; Xenograft procedure; antibody-dependent cell cytotoxicity; base; blood treatment; cancer cell; cell transformation; cytotoxicity; deprivation; dimer; economic cost; fighting; gambogic acid; immunoregulation; in vivo; inhibitor/antagonist; mouse model; novel strategies; overexpression; prevent; public health relevance; receptor; receptor mediated endocytosis; tumor; tumor growth; vector

 DESCRIPTION (provided by applicant): HIV infection-associated B-cell hyperactivation plays a central role in the genesis of AIDS-associated non- Hodgkin lymphoma (AIDS-NHL), as it is associated with molecular processes that lead to the seminal molecular lesions for NHL. In our prior work, we observed evidence for HIV-associated B-cell activation, including elevated numbers of B cells overexpressing transferrin receptor 1 (TfR1), a marker of B-cell activation, for several years preceding NHL diagnosis. We have developed an antibody (ch128.1) and an antibody-avidin fusion protein (ch128.1Av), specific for human TfR1. ch128.1Av shows enhanced in vitro cytotoxicity against human malignant B cells overexpressing TfR1, including multiple myeloma (MM) and NHL cells, when compared to the parental antibody without avidin (ch128.1). Cytotoxicity is due to the ability of ch128.1Av, and to a lesser extent ch128.1, to decrease cell-surface TfR1 leading to lethal iron deprivation. ch128.1Av is also a universal delivery system and its cytotoxicity can be enhanced by conjugating it to biotinylated drugs such as the plant toxin saporin; making it a unique molecule capable of a two-pronged attack against malignant cells. However, ch128.1Av alone, or complexed with biotinylated saporin, is not toxic to normal human hematopoietic stem cells due to their lack of TfR1 expression. In addition, the combination of ch128.1Av with non-biotinylated drugs, such as the HOX protein inhibitor peptide HXR9 or the natural chemical compound gambogic acid, results in an additive or synergistic anti-cancer activity against malignant B cells. Importantly, in two disseminated human MM xenograft mouse models, a single low dose of ch128.1Av alone, and even ch128.1, resulted in significant anti-tumor activity. Our central hypothesis is that the overexpressed TfR1 on circulating activated B cells in HIV infection and on malignant AIDS-NHL cells represents a meaningful target for the use of the proposed antibody-based therapeutics, which can be used as a potential treatment for AIDS-NHL, as well as for removing activated B-cells in HIV+ persons in order to prevent the development of AIDS-NHL by "resetting the B-cell clock". Importantly, we have already obtained preliminary results demonstrating that human AIDS-NHL cell lines, and activated (but not resting) human B cells, express high levels of TfR1 and that our anti-TfR1 Abs are efficacious against both malignant and activated B cells in vitro and in meaningful mouse models. We have four specific aims: Aim 1: Define the ability of ch128.1Av and ch128.1 to inhibit/eliminate HIV- and/or EBV-activated B cells in vitro; Aim 2: Define the ability of ch128.1Av and ch128.1 to inhibit/eliminate AIDS-NHL in vitro; Aim 3: Define the toxicity of ch128.1Av and ch128.1 on hematopoiesis, and in general, as well as their ability to inhibit HIV- or EBV-driven B-cell activation in vivo; Aim 4: Define the potential of ch128.1Av and ch128.1 in passive immunotherapy for AIDS-NHL. This project will develop the scientific basis for the use of ch128.1Av and ch128.1 alone, or combined with other drugs, for the prevention and treatment of AIDS-NHL.

 描述（由申请方提供）：HIV感染相关B细胞过度活化在艾滋病相关非霍奇金淋巴瘤（AIDS-NHL）的发生中起核心作用，因为它与导致NHL精液分子病变的分子过程相关。在我们之前的工作中，我们观察到HIV相关B细胞活化的证据，包括在NHL诊断前数年过度表达转铁蛋白受体1（TfR 1）（B细胞活化的标志物）的B细胞数量增加。我们已经开发了一种抗体（ch128.1）和抗体-亲和素融合蛋白（ch128.1Av），特异性针对人TfR 1。与不含抗生物素蛋白的亲本抗体相比，ch128.1 Av显示对过度表达TfR 1的人恶性B细胞（包括多发性骨髓瘤（MM）和NHL细胞）的体外细胞毒性增强（ch128.1）。细胞毒性是由于ch128.1Av的能力，并在较小程度上ch128.1，减少细胞表面TfR 1导致致命的铁剥夺。ch128.1Av也是一种通用的传递系统，其细胞毒性可以通过将其与生物素化药物（如植物毒素皂草素）结合来增强;使其成为一种能够双管齐下攻击恶性细胞的独特分子。然而，单独的ch128.1Av或与生物素化皂草素复合的ch128.1Av对正常人造血干细胞没有毒性，因为它们缺乏TfR 1表达。此外，ch128.1Av与非生物素化药物（例如HOX蛋白抑制剂肽HXR 9或天然化合物藤黄酸）的组合导致针对恶性B细胞的相加或协同抗癌活性。重要的是，在两种弥散性人MM异种移植小鼠模型中，单独使用低剂量的ch128.1Av，甚至ch128.1，都产生了显着的抗肿瘤活性。我们的中心假设是，HIV感染中循环活化B细胞和恶性AIDS-NHL细胞上的过表达TfR 1代表了使用所提出的基于抗体的治疗剂的有意义的靶点，其可用作AIDS-NHL的潜在治疗，以及用于去除HIV+人中的活化B细胞，以通过“重置B细胞时钟”防止AIDS-NHL的发展。重要的是，我们已经获得了初步结果，证明人AIDS-NHL细胞系和活化的（但不是静息的）人B细胞表达高水平的TfR 1，并且我们的研究结果表明， 抗TfR 1 Ab在体外和有意义的小鼠模型中对恶性和活化的B细胞都有效。我们有四个具体目标：目标1：确定ch128.1 Av和ch128.1体外抑制/消除HIV和/或EBV激活的B细胞的能力;目的2：确定ch128.1 Av和ch128.1体外抑制/消除AIDS-NHL的能力;目的3：确定毒性 ch128.1Av和ch128.1对造血作用的影响，以及它们在体内抑制HIV或EBV驱动的B细胞活化的能力;目的4：确定ch128.1Av和ch128.1在AIDS-NHL被动免疫治疗中的潜力。本项目将为ch128.1Av和ch128.1单独使用或与其他药物联合使用预防和治疗AIDS-NHL提供科学依据。