IL-15 Superagonist Complex as an Immunotherapeutic for Multiple Myeloma

描述（由申请人提供）：多发性骨髓瘤（MM）是第二大最常诊断的血液恶性肿瘤，2011年美国估计有20,520例新诊断病例和10,610例因MM死亡。MM是一种老年人疾病，诊断时中位年龄为70岁，37%的患者年龄大于75岁。由于正常人口的预期寿命增加，老年MM患者的数量预计将随着时间的推移而增加。MM是一种骨髓（BM）克隆浆细胞恶性肿瘤，以副蛋白血症、破坏性骨病、高钙血症、肾功能衰竭和/或血液功能障碍为特征。虽然MM患者的生存率随着最近的治疗进展而提高，但由于微小残留疾病的持续存在，MM仍然无法治愈。因此，迫切需要新的方式来补充或改善目前的治疗方案。有充分的证据表明，免疫调节药物对MM有效。因此，使用一种有效的免疫疗法是一种有吸引力的方法，可以为MM患者提供持久的免疫应答，甚至可能治愈MM。IL-15是效应NK细胞和CD8*记忆T细胞发育、增殖和激活的必要因素。在实验动物模型中对已建立的肿瘤表现出强大的抗肿瘤活性，并被最近的NCI审查列为12种可能治愈癌症的免疫治疗药物中最有希望的候选产品。我们之前曾报道分离出一种新的IL-15突变体，其生物活性增加了4倍。通过与IL-15受体- IgG1融合蛋白（IL-15R¿/Fc）建立复合物，进一步改善了这种超激动剂IL-15 （IL-15N72D）的药代动力学和生物活性。我们假设静脉注射IL- 15n72d:IL- 15R¿/Fc融合复合物将提供持久、有效和广泛的细胞介导免疫应答，这将导致一种高效且具有潜在治愈性的免疫疗法，用于治疗MM患者。我们最近的研究数据支持了这一点，表明这种IL-15融合复合物确实在免疫能力强的C57BL/6小鼠模型中根除了已建立的5T33骨髓瘤肿瘤。更重要的是，短期治疗提供了持久的免疫效果，完全保护小鼠免受随后的肿瘤细胞再攻击。在本研究中，我们建议开展实验来揭示IL- 15超激动剂对小鼠5T33肿瘤型骨髓瘤的作用机制，并进一步评估IL- 15超激动剂诱导反应的持久性（免疫治疗的一个标志）。这些努力将为临床前研究铺平道路，其中将包括额外的疗效研究，以确定最佳剂量、药代动力学和复合物的毒理学评估，作为SBIR二期项目的一部分，以支持临床开发。我们的最终目标是进入IND阶段，并使用IL- 15N72D:IL- 15r¿/Fc超级激动剂复合物治疗MM患者进行临床试验。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy with an estimated 20,520 newly diagnosed cases and 10,610 deaths due to MM in the United States in 2011. MM is a disease of the elderly with a median age at diagnosis of 70 years and 37% of patients older than 75 years. The number of geriatric MM patients is expected to increase over time because of the increasing life expectancy of the normal population. MM is a malignancy of clonal plasma cells in the bone marrow (BM) characterized by the presence of paraproteinemia, destructive bone disease, hypercalcemia, renal failure, and/or hematological dysfunction. Although survival rates of MM patients have improved by recent therapeutic advances, MM remains incurable due to the persistence of minimal residual disease. Thus, novel modalities complementing or improving current treatment options are desperately needed. There is ample evidence that immunomodulatory drugs are effective against MM. Thus, the use of a potent immunotherapeutic is an attractive approach to provide durable immune responses to or even potentially cure patients with MM. IL-15, a necessary factor for the development, proliferation and activation of effector NK cells and CD8* memory T cells, exhibits potent anti-tumor activities against well-established tumors in laboratory animal models and is listed by a recent NCI review as the most promising product candidate among twelve immunotherapy drugs that could potentially cure cancer. We have previously reported the isolation of a novel IL-15 mutant with a 4-fold increase in biological activity. The pharmacokinetics and biological activity of this superagonistic IL-15 (IL-15N72D) have been further improved by creating a complex with an IL-15 receptor ¿ - IgG1 fusion protein (IL-15R¿/Fc). We postulate that that intravenous administration of the IL-15N72D:IL- 15R¿/Fc fusion complex will provide a durable, potent and broad cell-mediated immune response, which would result in a highly efficacious and potentially curative immunotherapy for the treatment of patients with MM. This is supported by the data from our recent studies, indicating that this IL-15 fusion complex indeed eradicated well-established 5T33 myeloma tumors in an immunocompetent C57BL/6 mouse model. More importantly, short-term treatment provided long-lasting immunological effects that completely protected mice against subsequent tumor cell rechallenge. In this study described here, we propose to carry out experiments to reveal the mechanisms of action and to further evaluate the durability (a hallmark of immunotherapy) of IL- 15 superagonist-induced responses for 5T33 tumor-based myeloma in mice. These efforts will pave the way for pre-clinical studies, which will include additional efficacy studies to determine optimal dosing and pharmacokinetics and toxicology evaluation of the complex, as part of the SBIR Phase II project, to support clinical development. Our ultimate goal is to enter the IND phase and to conduct clinical trials using the IL- 15N72D:IL-15R¿/Fc superagonist complex to treat patients with MM. PUBLIC HEALTH RELEVANCE: In this proposal, we propose to carry out experiments to reveal the mechanisms-of-action and to evaluate the anti-tumor durability (a hallmark of immunotherapy) of a novel interleukin-15 (IL-15) superagonist complex (IL- 15N72D:IL-15R¿/Fc) in the 5T33 tumor-based multiple myeloma model in mice. Positive outcomes from this proposed study would provide justification for clinical development of this complex as a safe, durable, potent and cell-mediated immunotherapy to treat patients with multiple myeloma.