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

摘要 在这项直接进入第二阶段的SBIR中，免疫-ONC治疗公司建议开发IO-202，一种安全和有效的 延长单核细胞急性髓系白血病和慢性粒细胞白血病患者生存期的治疗 粒单核细胞白血病(CMML)。AML每年在美国影响2万人，并有令人沮丧的 预后，5年生存率约为25%。CMML是AML的成熟前身，具有 单核细胞分化，大约20%的CMML病例进展为AML。新的治疗方法是 迫切需要改善患者的预后。LILRB4是一种免疫抑制受体，其表达是 仅限于正常的抗原提呈细胞，在那里它作为免疫的负调节因子发挥作用；它是 上调单核细胞亚型的AML，在那里它创造了一个免疫抑制的微环境。IO- 202是一种抑制LILRB4信号的抗体；阻断LILRB4的抗体已导致肿瘤 急性髓系白血病临床前体内模型中的消退、肿瘤植入延迟和抗白血病T细胞激活， 提示IO-202是一种很有前途的治疗候选药物。不同基因表达水平的差异 正常和AML细胞使我们能够选择性地靶向AML细胞。我们假设IO-202将阻塞 LILRB4信号在单核细胞AML患者白血病细胞中的表达，从而激活效应T细胞，从而阻碍 白血病的植入/渗透与抗体依赖细胞介导的白血病细胞直接杀伤 细胞毒性和抗体依赖的细胞吞噬作用。上述生物活性为 假设转化为急性髓系白血病患者骨髓中原始细胞计数的减少，导致 完全缓解并延长存活期。在这里，我们建议评估IO-202的联合治疗 标准细胞毒化疗、去甲基化药物和/或靶向治疗非临床AML 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。 针对LILRB4的抗体，在复发/难治性AML和CMML的人类首个1期临床试验中 病人。这项试验的数据将确定IO-202的最大耐受量(MTD)(目标2)和 IO-202的推荐第二阶段剂量(RP2D)(目标3)。

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).