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)在癌症治疗中是一个重大的临床挑战。在美国，每年约有70,000例新确诊的非霍奇金淋巴瘤病例，在癌症发病率和死亡率方面排名第五。大多数NHL病例是B细胞起源的，超过90%的病例表达白细胞抗原CD20，使这些癌症适合靶向治疗。因此，使用抗CD20抗体(Ab)的美罗华单独或与化疗方案联合使用的B细胞去除疗法，已被证明对包括NHL和慢性淋巴细胞白血病(CLL)在内的一系列B细胞恶性肿瘤患者的疗效显著。然而，复发在接受利妥昔单抗治疗的患者中是常见的，仍然需要更持久的一线治疗和更有效的选择来治疗利妥昔单抗耐药的患者。 疾病。我们正在使用一种包含IL-15和IL-15受体(IL-15R)/Ig G Fc结构域的专利蛋白质支架来创建有效的CD20靶向免疫治疗剂。具体地说，我们已经产生了一个融合蛋白复合体(2B8T2M)，其单链抗体结构域来自利妥昔单抗，与IL-15超级激动剂变异体和IL-15R？/Fc融合。IL-15和IL-15R融合蛋白之间的高亲和力相互作用导致了稳定的可溶性多价复合体，该复合体保留了抗CD20抗体、IL-15和Fc组分的功能结合活性。2B8T2M的IL-15结构域有望对肿瘤部位的B淋巴瘤细胞提供强大的抗肿瘤免疫刺激活性。IL-15是影响效应器、自然杀伤细胞和T细胞增殖和激活的关键细胞因子，在记忆T细胞的维持中起着重要作用。基于其引发持久免疫反应的潜力，最近NCI的一篇综述将IL-15列为最有希望治愈癌症的免疫治疗候选药物。2B8T2M复合物被证明能够引导补体依赖和抗体依赖的细胞对人淋巴瘤细胞的杀伤作用，其活性与利妥昔单抗相当。令人惊讶的是，2B8T2M复合体对人类淋巴瘤的直接细胞杀伤水平也高于利妥昔单抗。总体而言，2B8T2M复合体的抗淋巴瘤活性优于美罗华，提示2B8T2M是一种治疗CD20+NHL的优良药物。基于这些有希望的结果，我们打算在这项建议下，进一步表征CD20靶向的IL-15融合蛋白复合体在已建立的B细胞淋巴瘤异种移植动物模型中的有效性。此外，还将评估2B8T2M复合体的药代动力学和毒性，并将开发针对B细胞淋巴瘤的最佳治疗方案。这些研究的积极结果将使2B8T2M进入临床前疗效和GLP毒理学研究，并作为SBIR第二阶段项目的一部分进行产品工艺开发/制造。总体目标是提交IND，以支持2B8T2M在NHL和/或CLL患者中的临床测试。 公共卫生相关性：虽然抗CD20抗体治疗为B细胞恶性肿瘤患者提供了显著的临床益处，但滤泡性淋巴瘤和慢性淋巴细胞白血病(CLL)等惰性淋巴瘤仍然无法治愈，患者表现出复发和难治性疾病，这突显了需要更有效的持久治疗方案。根据这一第一阶段的建议，我们打算评估一种新型的CD20靶向免疫治疗复合体的临床前有效性和安全性，该复合体能够介导抗体导向的B细胞淋巴瘤细胞毒作用，并为效应细胞提供有效的、持久的IL-15介导的免疫刺激。拟议的动物研究的积极结果将为将这一方法推广到其他非临床研究和产品生产提供理由，为非霍奇金淋巴瘤和CLL患者的临床测试做准备。