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细胞过度激活在艾滋病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精液分子损害的分子过程有关。在我们之前的工作中，我们观察到了HIV相关B细胞激活的证据，包括在NHL诊断前几年B细胞过度表达转铁蛋白受体1(TfR1)的数量增加，TfR1是B细胞激活的标志。我们已经研制出针对人TfR1的抗体(ch128.1)和抗体-亲和素融合蛋白(Ch1281Av)。与没有亲和素的亲本抗体(ch128.1)相比，ch1281Av对高表达TfR1的人恶性B细胞(包括多发性骨髓瘤(MM)和非霍奇金淋巴瘤细胞)具有更强的体外细胞毒作用。细胞毒性是由于ch1281Av和较小程度的ch128.1减少细胞表面TfR1导致致命性铁剥夺的能力所致。Ch1281Av也是一种通用的递送系统，通过将其与生物素化药物(如植物毒素Saporin)结合，可以增强其细胞毒性；使其成为能够双管齐下攻击恶性细胞的独特分子。然而，ch1281Av单独或与生物素标记的皂苷复合，由于缺乏TfR1的表达，对正常的人类造血干细胞没有毒性。此外，ch1281Av与非生物素化药物，如HOX蛋白抑制肽HXR9或天然化合物伽马酸相结合，可产生对恶性B细胞的相加或协同抗癌活性。重要的是，在两个播散性人多发性骨髓瘤移植小鼠模型中，单一低剂量的ch1281Av，甚至ch128.1，都能产生显著的抗肿瘤活性。我们的中心假设是，在HIV感染的循环中激活的B细胞和恶性的AIDS-NHL细胞上过表达的TfR1代表了一个有意义的靶点，可以用于拟议的基于抗体的疗法，这种疗法可以被用作艾滋病-NHL的潜在治疗方法，以及用于去除HIV+患者的激活的B细胞，以便通过“重置B细胞时钟”来防止AIDS-NHL的发展。重要的是，我们已经获得了初步结果，表明人类AIDS-NHL细胞株，以及激活的(但不是静止的)人类B细胞，表达高水平的TfR1和我们的 在体外和有意义的小鼠模型中，抗TfR1抗体对恶性和激活的B细胞都是有效的。我们有四个具体目标：目标1：确定ch1281Av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：确定ch1281Av和ch128.1在体外抑制/消除AIDS-NHL的能力；目标3：确定其毒性 目的4：探讨ch1281Av和ch128.1在艾滋病非霍奇金淋巴瘤被动免疫治疗中的应用前景。该项目将为单独使用ch1281Av和ch128.1或与其他药物联合用于预防和治疗AIDS-NHL奠定科学基础。