CD20-targeted IL-15 immunotherapeutic for B-cell malignancies

针对 B 细胞恶性肿瘤的 CD20 靶向 IL-15 免疫疗法

• 批准号: 8455573
• 负责人: HING C. WONG
• 金额: $ 25.73万
• 依托单位: ALTOR BIOSCIENCE. LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455573
• 关键词: Address; Affinity; Animal Model; Animals; Antibodies; Antibody Therapy; Apoptosis; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Binding; Bone Marrow; Burkitt Lymphoma; Cell Maintenance; Cells; Chemotherapy-Oncologic Procedure; Chimeric Proteins; Chronic Lymphocytic Leukemia; Clinical; Complement; Complement-Dependent Cytotoxicity; Complex; Data; Development; Diagnosis; Dose; Drug Kinetics; Effector Cell; Evaluation; Exhibits; Fc Receptor; Fc domain; Follicular Lymphoma; Goals; HLA Antigens; Human; IgG Receptors; IgG1; Immune; Immune Tolerance; Immune response; Immunization; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; Inbred BALB C Mice; Incidence; Indolent; Interleukin-15; Link; Lymphoma; MS4A1 gene; Malignant Neoplasms; Mediating; Memory; Mus; Non-Hodgkin' s Lymphoma; Outcome; Patients; Pharmaceutical Preparations; Phase; Play; Preparation; Progression-Free Survivals; Refractory Disease; Relapse; Relative (related person); Resistance; Role; SCID Mice; Safety; Scaffolding Protein; Schedule; Site; Small Business Innovation Research Grant; Testing; Therapeutic Agents; Therapeutic Effect; Toxic effect; Toxicology; Treatment Efficacy; Treatment Protocols; Variant; Xenograft Model; Xenograft procedure; antibody-dependent cell cytotoxicity; base; cell killing; comparative; cytokine; cytotoxicity; design; disulfide bond; improved; interleukin-15 receptor; killer T cell; manufacturing process development; mortality; mouse model; neoplastic cell; next generation; novel; preclinical efficacy; preclinical safety; protein complex; receptor; research clinical testing; response; rituximab; scaffold; therapeutic target; tositumomab; tumor

DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) represents a significant clinical challenge in cancer management. Approximately 70,000 new cases of NHL are diagnosed annually in the U.S. and NHL ranks fifth in cancer incidence and mortality. The majority of NHL cases are of B-cell origin and more than 90% express the leukocyte antigen CD20, making these cancers amenable to targeted therapeutic approaches. As a result, B-cell depletion therapies using the anti-CD20 antibody (Ab), rituximab, given alone or in combination with chemotherapy regimens, has been shown to significantly outcome of patients with a range of B-cell malignancies including NHL and chronic lymphocytic leukemia (CLL). However, relapse is a common occurrence in rituximab-treated patients and there remains a need for more durable first-line therapies and more effective options for patients with rituximab-refractory disease. We are using a proprietary protein scaffold comprising IL-15 and IL-15 receptor ¿ (IL-15R¿)/IgG Fc domains to create potent CD20-targeted immunotherapeutic agents. Specifically, we have generated a fusion protein complex (2B8T2M) with single- chain Ab domains derived from rituximab linked to both an IL-15 superagonist variant and an IL-15R¿/Fc fusion. High affinity interactions between the IL-15 and IL-15R¿ fusion proteins result in a stable soluble multivalent complex that retains functional binding activities of the anti-CD20 Ab, IL-15 and Fc components. The IL-15 domain of 2B8T2M is expected to provide potent antitumor immunostimulatory activity against B- lymphoma cells at the tumor site. IL-15 is a critical cytokine for the proliferation and activation of effector natural killer and T cells and plays a maor role in memory T cell maintenance. Based on its potential to elicit long-lasting immune responses, a recent NCI review listed IL-15 as the most promising immunotherapeutic candidate that could potentially cure cancer. The 2B8T2M complex was shown to be capable of directing complement dependent and antibody-dependent cellular cytotoxicity against human lymphoma cells with comparable activity to that seen with rituximab. Surprisingly, the 2B8T2M complex also exhibits higher levels of direct cell killing of human lymphomas than were observed with rituximab. Overall, the anti-lymphoma activity of the 2B8T2M complex exceeded that of the rituximab, suggesting that 2B8T2M is a superior therapeutic agent against CD20+ NHL. Based on these promising results, we intend under this proposal to further characterize efficacy of the CD20-targeted IL-15 fusion protein complexes in well-established B-cell lymphoma xenograft animal models. Additionally, the pharmacokinetic and toxicity profile of the 2B8T2M complex will be evaluated and an optimal treatment regimen against B-cell lymphomas will be developed. Positive results from these studies will allow advancement of 2B8T2M into preclinical efficacy and GLP toxicology studies and product process development/manufacture as part of an SBIR Phase II project. The overall goal is the submission of an IND to support clinical testing of 2B8T2M in patients with NHL and/or CLL. PUBLIC HEALTH RELEVANCE: While anti-CD20 antibody therapy provides patients with B-cell malignancies with significant clinical benefit, indolent lymphomas, such as follicular lymphoma and chronic lymphocytic leukemia (CLL), remain incurable with patients exhibiting relapses and refractory disease, highlighting the need for more effective durable treatment options. Under this Phase I proposal, we intend to evaluate the preclinical efficacy and safety of a novel CD20-targeted immunotherapeutic complex that has the capacity to mediate antibody-directed cytotoxicity against B-cell lymphomas and provide potent, long-lasting IL-15-mediated immunostimulation to effector cells. Positive outcomes from the proposed animal studies would provide justification to advancement of this approach into additional non-clinical studies and product manufacture in preparation for clinical testing in patients with non-Hodgkin lymphomas and CLL.

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）代表了癌症管理中的重大临床挑战。在美国，每年诊断出大约70，000例NHL新病例，NHL在癌症发病率和死亡率中排名第五。大多数NHL病例是B细胞起源的，超过90%表达白细胞抗原CD 20，使这些癌症适合靶向治疗方法。因此，使用抗CD 20抗体（Ab）利妥昔单抗单独或与化疗方案联合使用的B细胞耗竭疗法已被证明对患有一系列B细胞恶性肿瘤（包括NHL和慢性淋巴细胞白血病（CLL））的患者具有显著疗效。然而，复发在利妥昔单抗治疗的患者中是常见的，并且对于利妥昔单抗难治性的患者仍然需要更持久的一线治疗和更有效的选择。 疾病我们正在使用包含IL-15和IL-15受体（IL-15 R）/IgG Fc结构域的专有蛋白质支架来创建有效的CD 20靶向免疫抑制剂。具体地，我们已经产生了融合蛋白复合物（2B 8 T2 M），其具有来自利妥昔单抗的单链Ab结构域，所述单链Ab结构域连接到IL-15超激动剂变体和IL-15 R4/Fc融合体两者。IL-15和IL-15 R？融合蛋白之间的高亲和力相互作用产生稳定的可溶性多价复合物，其保留抗CD 20 Ab、IL-15和Fc组分的功能性结合活性。预期2B 8 T2 M的IL-15结构域在肿瘤部位提供针对B-淋巴瘤细胞的有效抗肿瘤免疫刺激活性。IL-15是一种重要的细胞因子，对效应性自然杀伤细胞和T细胞的增殖和活化起关键作用，并在记忆性T细胞的维持中起重要作用。基于其引发持久免疫应答的潜力，最近的NCI综述将IL-15列为可能治愈癌症的最有希望的免疫候选物。显示2B 8 T2 M复合物能够指导针对人淋巴瘤细胞的补体依赖性和抗体依赖性细胞毒性，其活性与利妥昔单抗相当。令人惊讶的是，与利妥昔单抗相比，2B 8 T2 M复合物也表现出更高水平的对人淋巴瘤的直接细胞杀伤。总体而言，2B 8 T2 M复合物的抗淋巴瘤活性超过利妥昔单抗，表明2B 8 T2 M是一种针对CD 20 + NHL的上级治疗剂。基于这些有希望的结果，我们打算在此提议下进一步表征CD 20靶向IL-15融合蛋白复合物在良好建立的B细胞淋巴瘤异种移植动物模型中的功效。此外，将评价2B 8 T2 M复合物的药代动力学和毒性特征，并开发针对B细胞淋巴瘤的最佳治疗方案。这些研究的积极结果将使2B 8 T2 M进入临床前有效性和GLP毒理学研究以及作为SBIR II期项目一部分的产品工艺开发/生产。总体目标是提交IND，以支持2B 8 T2 M在NHL和/或CLL患者中的临床试验。 公共卫生关系：虽然抗CD 20抗体治疗为B细胞恶性肿瘤患者提供了显著的临床益处，但惰性淋巴瘤（如滤泡性淋巴瘤和慢性淋巴细胞白血病（CLL））仍然无法治愈，患者表现出复发和难治性疾病，突出了对更有效持久治疗选择的需求。在该I期提案中，我们打算评估一种新型CD 20靶向免疫复合物的临床前疗效和安全性，该复合物能够介导针对B细胞淋巴瘤的抗体定向细胞毒性，并为效应细胞提供有效、持久的IL-15介导的免疫刺激。拟定动物研究的阳性结果将为将该方法推进到其他非临床研究和产品生产中提供依据，为非霍奇金淋巴瘤和CLL患者的临床试验做准备。