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: 9793985
• 负责人: OTONIEL MARTINEZ-MAZA
• 金额: $ 10.6万
• 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 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9793985
• 关键词: AIDS related cancer; AIDS-Related Lymphoma; AIDS-Related Non-Hodgkin' s Lymphoma; Acquired Immunodeficiency Syndrome; Affinity; Antibodies; Antibody Therapy; 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; 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; Public Health; Recycling; Role; SCID Mice; Seminal; Signal Transduction; Structure; System; TFRC gene; Time; Toxic effect; Toxin; Work; Xenograft procedure; anti-cancer; antibody-dependent cell cytotoxicity; anticancer activity; base; blood treatment; cancer cell; cell transformation; cytotoxicity; deprivation; dimer; economic cost; fighting; gambogic acid; human model; immunoregulation; in vivo; inhibitor/antagonist; mouse model; novel strategies; overexpression; prevent; receptor; receptor mediated endocytosis; tumor; tumor growth; vector

SCIENTIFIC ABSTRACT 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.

科学抽象 HIV感染相关的B细胞过度活化在艾滋病相关的非免疫性疾病的发生中起着重要作用。 霍奇金淋巴瘤（AIDS-NHL），因为它与导致精液 NHL的分子病变。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， 包括过量表达转铁蛋白受体1（TfR1）的B细胞数量增加，转铁蛋白受体1是B细胞免疫缺陷的标志物。 活化，在NHL诊断前几年。我们已经开发了一种抗体（ch128.1）和一种抗人源性抗体（ch128.1）。 抗体-抗生物素蛋白融合蛋白（ch128.1Av），对人TfR1具有特异性。ch128.1Av在体外显示增强 对过表达TfR 1的人恶性B细胞（包括多发性骨髓瘤（MM）和NHL）的细胞毒性 细胞，当与不含抗生物素蛋白的亲本抗体相比时（ch128.1）。细胞毒性是由于 ch128.1Av，以及在较小程度上ch128.1，减少细胞表面TfR1，导致致命的铁剥夺。 ch128.1Av也是一种通用的递送系统，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;使其成为一种独特的分子，能够双管齐下， 攻击恶性细胞。然而，单独的ch128.1Av，或与生物素化皂草素复合， 由于缺乏TfR1表达，对正常人造血干细胞有毒。此外该 ch128.1Av与非生物素化药物的组合，如HOX蛋白抑制剂肽HXR 9或 天然化合物藤黄酸，导致抗肿瘤的相加或协同抗癌活性， 恶性B细胞。重要的是，在两种播散性人MM异种移植小鼠模型中，单次低剂量的 单独的ch128.1Av，甚至ch128.1，导致显著的抗肿瘤活性。我们的核心假设是 在HIV感染的循环活化B细胞和恶性AIDS-NHL细胞上， 代表了使用所提出的基于抗体的治疗剂的有意义的靶标，其可以用作 一种潜在的治疗艾滋病-非霍奇金淋巴瘤，以及消除活化的B细胞在艾滋病毒+的人， 通过“重置B细胞时钟”来预防艾滋病-NHL的发展。重要的是，我们已经获得了 初步结果表明，人类艾滋病-非霍奇金淋巴瘤细胞系，并激活（但不休息）， 人B细胞表达高水平TfR1，我们的抗TfR1抗体对这两种细胞都有效 恶性和活化的B细胞在体外和有意义的小鼠模型。我们有四个具体目标： 目的1：确定ch128.1 Av和ch128.1抑制/消除HIV和/或EBV激活的B细胞的能力， 目的2：确定ch128.1Av和ch128.1在体外抑制/消除AIDS-NHL的能力;目的3：确定 ch128.1Av和ch128.1对造血的毒性，以及它们抑制HIV-1或 EBV驱动的体内B细胞活化;目的4：确定ch128.1Av和ch128.1在被动免疫中的潜力 免疫治疗艾滋病-NHL。该项目将为ch128.1Av的使用奠定科学基础， ch128.1单用或与其他药物联合用于预防和治疗AIDS-NHL。