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（由申请人提供）：在成人白血病中，慢性淋巴细胞白血病（CLL）在美国每年的新诊断率最高。靶向 CD20 的利妥昔单抗等治疗性抗体已使这些患者显着受益。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，因此是非常理想的替代靶点。人们对这种蛋白的功能知之甚少，但它在促进某些非癌细胞存活方面的作用表明它在白血病中也能发挥类似的作用，以支持疾病的发生或进展。 - 最近开发出药物缀合物，既保留抗体衍生的抗白血病机制，又向癌细胞输送抗增殖药物。人们重新认识到，这种治疗方法可以帮助消除最终导致癌症的 CLL 细胞的增殖子集。该疗法最近开始针对非霍奇金淋巴瘤进行临床试验，并在实验室和 CLL 小鼠模型中显示出针对人类 CLL 的有希望的临床前活性。可能以两种方式提高功效：直接杀死白血病和促进免疫系统消除癌症。这些不同的机制在动物中发挥作用的程度尚不清楚，并且尚未针对任何其他抗体进行过探索。药品本研究的目的是确定该疗法的功效机制，研究潜在的联合疗法以改善其对肿瘤细胞的消除，并更好地了解其靶点 (CD37) 在白血病 Aim 1 中的功能作用。建立了缺乏 CD37 的 CLL 小鼠模型，用于研究该蛋白在恶性肿瘤中的作用，目标 2 将阐明 CD37 靶向抗体-药物缀合物在小鼠 CLL 中的作用机制。并评估预计可增强其活性的联合疗法，我们的长期目标是将有效的 CD37 靶向治疗策略引入临床，用于治疗 CLL 和相关恶性肿瘤。抗体-药物偶联物，除了影响属于这一快速扩展的癌症治疗类别的新疗法的设计之外，该工作的许多方面与其他针对 CD37 的疗法相关，其中一些疗法目前正在临床试验中进行评估。