Oligomannose antigens as conserved immunological targets of Non-Hodgkin lymphomas

寡甘露糖抗原作为非霍奇金淋巴瘤的保守免疫靶点

• 批准号: 10267450
• 负责人: DENONG WANG
• 金额: $ 27.12万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267450
• 关键词: Antibodies; Antigen Targeting; Antigens; Autoantigens; B-Cell Lymphomas; B-Lymphocytes; Blood specimen; Bypass; California; Carbohydrates; Cell Line; Cell surface; Chimeric Proteins; Clinical; Development; Diagnostic; Disadvantaged; Epitopes; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immunoglobulin G; Immunologics; Immunotherapy; In Vitro; Interferon-alpha; Interferons; International; Legal patent; Light; Los Angeles; Lymphoma; Lymphoma cell; Mammalian Cell; Mannose; Modeling; Molecular; Molecular Target; Monoclonal Antibodies; Mus; Neoplasm Circulating Cells; Non-Hodgkin' s Lymphoma; Normal Cell; Patients; Pharmaceutical Preparations; Phenotype; Polymers; Polysaccharides; Property; Proteins; Recombinant Antibody; Recombinant Proteins; Regimen; Relapse; Safety; Side; Technology; Therapeutic; Therapeutic Effect; Tissue Sample; Tissues; Treatment Efficacy; Tumor Subtype; Universities; Work; Xenograft Model; anti-tumor immune response; antibody engineering; antitumor agent; cancer cell; cancer stem cell; design; glycosylation; improved; in vivo; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; neoplasm immunotherapy; neoplastic cell; next generation; non-Hodgkin' s lymphoma patients; novel; overexpression; patient derived xenograft model; polymeric IgG; professor; side effect; systemic toxicity; targeted agent; targeted treatment; treatment response; tumor; tumor microenvironment

PROJECT SUMMARY Non-Hodgkin lymphoma (NHL) is primarily of B-cell origin but is substantially heterogeneous, which makes developing a tumor-specific immunotherapy for it difficult. Recent advances in immune check-point inhibitor- directed and pan-B marker-targeted immunotherapies are alternative strategies to bypass the problem of tumor heterogenicity and have achieved promising therapeutic effects. However, targeting both tumor cells and normal cells remains an intrinsic disadvantage because such treatments may cause undesired and even lethal side effects. Thus, there is an unmet need for new targeting strategies to further advance immunotherapy for NHL. Our tumor glycomics team at SRI International studies immunologically important glycan markers that are potentially useful in diagnostic and/or therapeutic applications. Recently, we found high-mannose autoantigens were overexpressed in tissues of diffuse large B-cell lymphomas (DLBCLs), a major class of aggressive NHL. In addition, we found that several newly established Man9-specific mAbs recognize the cell-surface markers co- expressed by a murine B-lymphoma A20 and the Raji and Ramos human B-lymphoma cell lines (Preliminary Results). Thus, the BMan9 autoantigens are likely evolutionarily conserved and may serve as “pan” markers for B-lymphoma targeting; anti-BMan9 mAbs are, therefore, promising candidates for use in developing targeted immunotherapies to treat major NHL tumor subtypes. Our antibody engineering team at University of California, Los Angeles has developed multiple platforms of recombinant antibodies to improve therapeutic efficacy. Notably, these include humanized polymeric IgGs and immunocytokines. The polymeric IgG platform can be used to trap and eradicate circulating tumor cells and cancer stem cells (CTCs/CSCs) in vivo, and the immunocytokines are designed to direct potent immune- modulating factors, such as interferon-alpha (IFN), to the tumor microenvironment to enhance anti-tumor immune responses and tumor-killing activities. We plan, therefore, to explore this combination of technologies to develop NHL-specific immunotherapies using our new panel of BMan9 -targeting mAbs. Specifically, we will determine if humanized polymeric IgGB-Man9 antibodies identify major subtypes of NHLs in tissues and detect CTCs in the blood samples of NHL patients (Aim 1). We will also assess whether anti-BMan9 IgG antibodies and their IFN fusion proteins offer highly efficient killing of the BMan9 - immune types of NHL cells [in vitro and in the A20 mouse models] (Aim 2). [Additionally, we will extend our effort to explore the BMan9-immunotypes of Patient- Derived xenograft (PDX) models for evaluating the therapeutic potential of the Man9-targeting strategy against human NHLs.] Our team has already identified targeting mAbs and established technologies for producing recombinant proteins, and we expect to develop several promising novel NHL-targeting agents during the proposed R21 period. Our work may also reveal the feasibility of exploring other relatively conserved NHL subtype-specific glycan markers that could advance next-generation precision NHL immunotherapy.

项目摘要 非霍奇金淋巴瘤（NHL）主要是B细胞来源，但基本上是异质的，这使得 由于困难而开发肿瘤特异性免疫疗法。免疫切点抑制剂的最新进展 - 定向和PAN-B标记的免疫疗法是绕过肿瘤问题的替代策略 异质性并达到了有希望的治疗作用。但是，靶向肿瘤细胞和正常 细胞仍然是一场内在的灾难，因为这种治疗可能会导致不希望的甚至致命的一面 效果。这是未满足的新目标策略，以进一步推进NHL的免疫疗法。 我们的SRI国际研究肿瘤糖核科团队免疫学上重要的聚糖标记 在诊断和/或治疗应用中可能有用。最近，我们发现了高曼诺斯自动抗原 在弥漫性大B细胞淋巴瘤（DLBCLS）的组织中过表达，这是一类侵略性NHL类。在 此外，我们发现几个新成立的MAN9特异性mAb识别出细胞表面标记的共同 由鼠B-淋巴瘤A20以及Raji和Ramos人类B淋巴瘤细胞系（初步）表示 结果）。那是Bman9自动抗原可能在进化上保存的，并且可能是 B淋巴瘤靶向；因此，抗BMAN9 mAB是有望在开发目标的候选人 免疫疗法治疗主要NHL肿瘤亚型。 我们在加利福尼亚大学洛杉矶分校的抗体工程团队开发了多个平台 重组抗体以提高热效率。值得注意的是，这些包括人源化聚合物IgG和 免疫细胞因子。聚合物IgG平台可用于捕获和放射性循环肿瘤细胞和 癌症干细胞（CTCS/CSC）在体内，免疫细胞因子旨在导致有效的免疫 调节因子，例如干扰素-alpha（IFN），以增强抗肿瘤的肿瘤微环境 免疫反应和肿瘤活动。因此，我们计划探索这种技术的组合 使用我们新的BMAN9 -argeting mABS开发NHL特异性免疫疗法。具体来说，我们会的 确定人源化聚合物IgGB-MAN9抗体是否鉴定了组织中NHL的主要亚型并检测 NHL患者血液样本中的CTC（AIM 1）。我们还将评估抗BMAN9 IgG抗体和是否 他们的IFN融合蛋白可对BMAN9- NHL细胞的免疫类型提供高效杀死[体外和在 A20鼠标模型]（AIM 2）。 [此外，我们将扩大努力探索患者的BMAN9-免疫型 用于评估针对MAN9靶向策略的治疗潜力的衍生定征（PDX）模型 人类NHLS。]我们的团队已经确定了针对MAB的目标和生产的既定技术 重组蛋白，我们希望在此期间开发几种诺言新颖的NHL靶向剂 拟议的R21期。我们的工作也可能揭示了探索其他相对构成的NHL的可行性 亚型特异性的聚糖标记物可以推进下一代精度NHL免疫疗法。