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（由申请人提供）：HIV 感染相关的 B 细胞过度激活在 AIDS 相关非霍奇金淋巴瘤 (AIDS-NHL) 的发生中起着核心作用，因为它与导致 NHL 的重要分子病变的分子过程相关。在我们之前的工作中，我们观察到了与 HIV 相关的 B 细胞激活的证据，包括在 NHL 诊断前几年，过度表达转铁蛋白受体 1 (TfR1)（B 细胞激活标志物）的 B 细胞数量增加。我们开发了一种针对人 TfR1 的抗体 (ch128.1) 和抗体-亲和素融合蛋白 (ch128.1Av)。与不含亲和素的亲本抗体 (ch128.1) 相比，ch128.1Av 对过表达 TfR1 的人类恶性 B 细胞（包括多发性骨髓瘤 (MM) 和 NHL 细胞）表现出增强的体外细胞毒性。细胞毒性是由于 ch128.1Av 以及较小程度的 ch128.1 能够降低细胞表面 TfR1，导致致命的铁缺乏。 ch128.1Av 也是一种通用的递送系统，可以通过将其与植物毒素皂草素等生物素化药物结合来增强其细胞毒性；使其成为一种独特的分子，能够对恶性细胞进行双管齐下的攻击。然而，单独的 ch128.1Av 或与生物素化皂素复合物对正常人造血干细胞没有毒性，因为它们缺乏 TfR1 表达。此外，ch128.1Av与非生物素化药物（例如HOX蛋白抑制剂肽HXR9或天然化合物藤黄酸）的组合可产生针对恶性B细胞的附加或协同抗癌活性。重要的是，在两个播散性人类 MM 异种移植小鼠模型中，单次低剂量的 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 感染中循环激活的 B 细胞和恶性 AIDS-NHL 细胞上过表达的 TfR1 代表了使用所提出的基于抗体的疗法的有意义的靶点，该疗法可用作 AIDS-NHL 的潜在治疗方法，以及去除 HIV+ 患者中激活的 B 细胞，以通过“重置 B 细胞时钟”来预防 AIDS-NHL 的发展。重要的是，我们已经获得了初步结果，证明人类 AIDS-NHL 细胞系和激活的（但不是静止的）人类 B 细胞表达高水平的 TfR1，并且我们的 抗 TfR1 Ab 在体外和有意义的小鼠模型中对恶性和活化的 B 细胞均有效。我们有四个具体目标： 目标 1：确定 ch128.1Av 和 ch128.1 在体外抑制/消除 HIV 和/或 EBV 激活的 B 细胞的能力；目标2：明确ch128.1Av和ch128.1在体外抑制/消除AIDS-NHL的能力；目标 3：定义毒性 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 细胞激活的能力；目标 4：确定 ch128.1Av 和 ch128.1 在 AIDS-NHL 被动免疫治疗中的潜力。该项目将为ch128.1Av和ch128.1单独使用或与其他药物联合用于预防和治疗AIDS-NHL奠定科学基础。