Non-clinical Combination Pharmacology Studies and Phase 1 Clinical Development of IO-202 in Acute Myeloid Leukemia (AML)

IO-202 治疗急性髓系白血病 (AML) 的非临床联合药理学研究和 1 期临床开发

• 批准号: 10079394
• 负责人: Charlene Liao
• 金额: $ 107万
• 依托单位: IMMUNE-ONC THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079394
• 关键词: Acute Myelocytic Leukemia; Adverse event; Affect; Antibodies; Antigen-Presenting Cells; Biological; Blocking Antibodies; Bone Marrow; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Clinical; Clinical Investigator; Combined Modality Therapy; Cytotoxic Chemotherapy; Data; Development; Development Plans; Disease remission; Dose; Dose-Limiting; Drug Kinetics; Engraftment; Feedback; Funding; Grant; Hematopoietic Neoplasms; Human; Immune; Immunity; In Vitro; Individual; Infiltration; Kinetics; Label; Lead; Leukemic Cell; Maximum Tolerated Dose; Mediating; Modeling; Organ; Patient-Focused Outcomes; Patients; Phagocytosis; Pharmacodynamics; Pharmacology Study; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Positioning Attribute; Pre-Clinical Model; Refractory; Relapse; Resistance; Safety; Schedule; Signal Transduction; Small Business Innovation Research Grant; Survival Rate; T-Cell Activation; Therapeutic; Toxic effect; Toxicology; Translating; Work; acute myeloid leukemia cell; antibody-dependent cell cytotoxicity; appropriate dose; cell killing; clinical development; effector T cell; efficacy study; experimental study; first-in-human; improved; in vivo Model; individual patient; inhibiting antibody; leukemia; leukemia treatment; monocyte; mouse model; novel; outcome forecast; pharmacokinetics and pharmacodynamics; pre-clinical; programs; receptor; synergism; targeted treatment; therapeutic candidate; tumor; tumor growth; tumor-immune system interactions

Abstract In this Direct-to-Phase 2 SBIR, Immune-Onc Therapeutics proposes development of IO-202, a safe and active therapy for prolonging the survival of patients with monocytic acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). AML affects 20,000 people in the US each year and has a dismal prognosis, with a 5-year survival rate of approximately 25%. CMML is an established precursor of AML with monocytic differentiation, with approximately 20% of CMML cases progressing to AML. Novel treatments are urgently needed to improve patient outcomes. LILRB4 is an immune-inhibitory receptor whose expression is restricted to normal antigen-presenting cells, where it functions as a negative regulator of immunity; it is upregulated on monocytic subtypes of AML, where it creates an immunosuppressive micro-environment. IO- 202 is an antibody that inhibits LILRB4 signaling; LILRB4 blocking antibodies have resulted in tumor regression, delay in tumor engraftment, and anti-leukemia T-cell activation in preclinical in vivo models of AML, suggesting that IO-202 is a promising therapeutic candidate. The differential in expression levels between normal and AML cells allows us to selectively target the AML cells. We hypothesize that IO-202 will block LILRB4 signaling in leukemic cells in patients with monocytic AML, thereby activating effector T-cells, impeding leukemic engraftment/infiltration and mediating direct leukemic cell killing through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. The aforementioned biological activity is hypothesized to translate into blast count reductions in the bone marrow of patients with AML, leading to complete remissions and prolonged survival. Here, we propose to evaluate the combination therapy of IO-202 with standard cytotoxic chemotherapy, hypomethylating agents and/or targeted therapy in non-clinical AML models (Aim 1). In addition, we aim to characterize the safety, pharmacokinetics and activity of IO-202, an antibody targeting LILRB4, in a first-in-human Phase 1 clinical trial in relapsed/refractory AML and CMML patients. Data from this trial will identify the maximum-tolerated dose (MTD) of IO-202 (Aim 2) and the recommended Phase 2 dose (RP2D) of IO-202 (Aim 3).

摘要 在这份直接进入第2阶段的SBIR中，Immune-Onc Therapeutics建议开发IO-202，一种安全有效的 用于延长患有单核细胞性急性髓性白血病（AML）和慢性粒细胞白血病（CML）的患者的存活的疗法 骨髓单核细胞白血病（CMML）。AML每年影响美国2万人， 预后，5年生存率约为25%。CMML是AML的一种已确定的前体， 单核细胞分化，约20%的CMML病例进展为AML。新的治疗方法 迫切需要改善患者的预后。LILRB 4是一种免疫抑制受体，其表达是 仅限于正常的抗原呈递细胞，在那里它作为免疫的负调节剂发挥作用;它是 在AML的单核细胞亚型上上调，在那里它创造了一个免疫抑制微环境。IO- 202是抑制LILRB 4信号传导的抗体; LILRB 4阻断抗体已导致肿瘤细胞凋亡。 AML临床前体内模型中的消退、肿瘤植入延迟和抗白血病T细胞活化， 这表明IO-202是有希望的治疗候选物。表达水平的差异， 正常细胞和AML细胞之间的差异使我们能够选择性地靶向AML细胞。我们假设IO-202会阻止 单核细胞AML患者的白血病细胞中的LILRB 4信号传导，从而激活效应T细胞， 白血病植入/浸润和通过抗体依赖性细胞介导直接白血病细胞杀伤 细胞毒性和抗体依赖性细胞吞噬作用。上述生物活性是 假设转化为AML患者骨髓中原始细胞计数的减少，导致 完全缓解和延长生存期。在这里，我们建议评估IO-202的联合治疗 在非临床AML中使用标准细胞毒性化疗、低甲基化药物和/或靶向治疗 模型（目标1）。此外，我们的目标是表征IO-202的安全性、药代动力学和活性， 靶向LILRB 4的抗体，在复发性/难治性AML和CMML的首次人体I期临床试验中 患者本试验的数据将确定IO-202的最大耐受剂量（MTD）（目标2）和 IO-202的推荐2期剂量（RP 2D）（目标3）。