Targeting CD37 and elucidating its role in B-cell malignancy

靶向 CD37 并阐明其在 B 细胞恶性肿瘤中的作用

• 批准号: 9248911
• 负责人: Kyle A. Beckwith
• 金额: $ 4.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248911
• 关键词: Address; Adhesions; Affect; Animals; Antibodies; Antibody-drug conjugates; Antigen-Presenting Cells; Antimitotic Agents; Antineoplastic Agents; Apoptosis; Apoptotic; B lymphoid malignancy; B-Lymphocytes; Binding; Biological Process; Biology; Blood; C57BL/6 Mouse; Cell Survival; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Complement; Cytotoxic agent; Data; Development; Diagnosis; Disease; Effector Cell; Fc Receptor; Follicular Dendritic Cells; Goals; Homing; Human; IgG1; Immune; Immune system; Impairment; In Vitro; Incidence; Integrin alpha4beta1; Integrins; Investigation; Knockout Mice; Knowledge; Laboratories; Ligands; Ligation; Lymphoid Tissue; MS4A1 gene; Malignant Neoplasms; Mediating; Membrane Proteins; Modeling; Monitor; Monoclonal Antibodies; Monoclonal Antibody CD20; Mus; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Onset of illness; Outcome; Parents; Patients; Peptides; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Proliferating; Proteins; Relapse; Research; Resistance; Role; Signal Transduction; Source; Structure of germinal center of lymph node; Surface; Testing; Therapeutic; Therapeutic antibodies; Tissues; Translating; Transplantation; Treatment Efficacy; United States; Work; adult leukemia; antibody conjugate; base; cancer cell; cytotoxicity; design; immunoregulation; improved; in vivo; insight; killings; kinase inhibitor; leukemia; leukemia/lymphoma; macrophage; mouse model; neoplastic cell; novel therapeutics; plasma cell development; pre-clinical; protein function; public health relevance; rituximab; sound; targeted treatment; therapeutic target; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): Among adult leukemias, chronic lymphocytic leukemia (CLL) has the highest rate of new diagnoses per year in the United States. Therapeutic antibodies like the CD20-targeting rituximab have significantly benefited these patients. However, current treatments are not curative and resistance is common. Therapeutic antibodies that target different surface proteins on the cancer cells may help circumvent resistance and are therefore highly desirable. CD37 is a promising alternative target which is highly expressed in CLL. Very little is known about the function of this protein, but its role in promoting survival of certain non-cancerous cells suggests it could function similarly in leukemia to support disease development or progression. A new CD37-targeting antibody- drug conjugate was recently developed to both retain antibody-derived anti-leukemic mechanisms and also deliver anti-proliferative drug to cancer cells. It is hypothesized that this therapeutic could hel eliminate the proliferating subset of CLL cells that is ultimately responsible for a patient's demise. This therapy recently began clinical trials for non-Hodgkins lymphoma and demonstrates promising pre-clinical activity against human CLL in the laboratory and in a mouse model of CLL. In addition to delivering anti-cancer drug to tumor cells, the antibody portion could potentially contribute to efficacy in two ways: directly killing leukemia and promoting elimination of cancer by the immune system. The degree to which these different mechanisms are responsible for its activity in animals is unknown, and this has not been explored for any other antibody-drug conjugate. The objectives of this research are to determine the mechanisms responsible for the efficacy of this therapeutic, investigate potential combination treatments to improve its elimination of tumor cells, and to better understand the functional role of its target (CD37) in leukemia. Aim 1 establishes a mouse model of CLL that lacks CD37, which is used to study this protein's role in malignancy. Aim 2 will elucidate the mechanism of the CD37-targeting antibody-drug conjugate in mouse CLL and evaluate combination therapies predicted to augment its activity. Our long-term goal is to bring effective CD37-targeted therapeutic strategies to the clinic for treatment of CLL and related malignancies. These investigations will address questions that could affect the clinical use of this and other antibody-drug conjugates, in addition to influencing the design of new therapies belonging to this rapidly expanding class of cancer therapeutics. Furthermore, many aspects of the work are relevant to other therapies targeting CD37, several of which are currently being evaluating in clinical trials.

 描述（由适用提供）：在成人白血病中，慢性淋巴细胞性白血病（CLL）在美国每年的新诊断率最高。 CD20靶向利妥昔单抗等治疗性抗体已显着使这些患者受益。但是，目前的治疗不是当代的，抵抗是常见的。靶向癌细胞上不同表面蛋白的治疗性抗体可能有助于规避耐药性，因此非常需要。 CD37是在CLL中高度表达的承诺替代目标。对这种蛋白质的功能知之甚少，但是它在促进某些非癌细胞存活中的作用表明它在白血病中可以相似地发挥疾病发育或进展。最近开发了一种新的CD37靶向抗体 - 药物结合物，既保留抗体衍生的抗白血病机制，又可以将抗增殖药物提供给癌细胞。假设这种疗法可以治愈最终导致患者灭亡的CLL细胞的增殖子集。该疗法最近开始对非霍奇金斯淋巴瘤进行临床试验，并在实验室和小鼠CLL模型中证明了针对人CLL的临床前活性。除了向肿瘤细胞递送抗癌药物外，抗体部分还可以通过两种方式提高效率：直接杀死白血病并促进免疫系统消除癌症。这些不同的机制对动物的活性负责的程度尚不清楚，并且尚未针对任何其他抗体 - 药物结合物进行探索。这项研究的目标是确定负责该疗法效率的机制，研究潜在的组合治疗以改善其消除肿瘤的方法。 AIM 1建立了缺乏CD37的CLL小鼠模型，该模型用于研究该蛋白质在恶性肿瘤中的作用。 AIM 2将阐明小鼠CLL中CD37靶向抗体 - 药物结合物的机制，并评估预测可增强其活性的组合疗法。我们的长期目标是将有效的CD37靶向治疗策略带到诊所，以治疗CLL和相关的恶性肿瘤。这些研究还将解决可能影响该抗体和其他药物缀合物的临床使用的问题，此外还影响了属于这种快速扩展的癌症治疗类别的新疗法的设计。此外，这项工作的许多方面与针对CD37的其他疗法有关，其中一些目前正在临床试验中评估。