Early clinical development of a novel IL-7R antibody for treating children with relapsed T-cell leukemia

项目摘要 复发性T细胞急性淋巴细胞白血病（T-ALL）患者的治疗仍然是一个主要的未满足的医疗需求。 儿童的五年存活率仅为21-39%，成人为20%。B细胞ALL（B-ALL）的结局 最近批准的几种二线疗法已经有所改善。相反，在小得多的T-ALL中， 人群（约占ALL的20%），奈拉滨是FDA于2005年批准的最后一种新药， 正在开发中。 Fannin Partners及其子公司Allterum Therapeutics正在开发嵌合单克隆抗体4A 10 靶向IL-7a受体（CD 127），由国家癌症研究所的Scott Durum博士开发。IL7R， 对淋巴细胞发育至关重要，在T-ALL的发展和维持中也起重要作用， 包括复发性疾病。4A 10结合IL 7 R受体，其具有介导抗体介导的IgG 1 Fc区。 依赖性细胞介导的细胞毒性（ADCC）。4A 10已证明稳健 在体外和体内对表达IL 7 R的T-ALL的抗癌活性，包括延长患有 患者来源的T-ALL异种移植物。 得克萨斯州癌症预防和研究所（CPRIT）赠款和种子资金的支持， 我们的生产规模扩大和毒理学工作，我们现在正在努力提交IND。 进一步的赠款资金将使我们能够进行首次人体1期临床试验，以评估安全性， T-ALL患者中4A 10的活性，并评估药效学和肿瘤生物标志物以及与4A 10的相关性 T-ALL患者的活性和耐受性。这些具体目标将使我们（1）确定安全性，最大耐受性 剂量（MTD）和推荐的4A 10作为单一疗法的2期剂量（RP 2D）。 （3）评估4A 10作为单一疗法的活性，（4）探索4A 10作为单一疗法的药代动力学特征， 潜在的生物学和临床活性及安全性的药效学标志物;（5）探讨肿瘤IL-2与肿瘤细胞凋亡的相关性。 7 R表达与临床活动的关系;（6）探讨肿瘤遗传学与生物学和临床活动的相关性 和对4A 10的耐受性。这些目标的完成将使我们能够在以下患者中进行关键性试验： 复发性T-ALL，以及其他ALL亚群和其他IL 7 R表达癌症的其他研究。 众所周知，CD 127是一种高度多态性的基因，并且经历从膜脱落或从细胞膜脱落。 在患者样本中可检测到的可变剪接。可溶性CD 127血浆浓度已被 据报道，在正常个体中随着时间的推移保持稳定，可溶性CD 127的上调可能表明 患者的转移性疾病进展。这个多样性补充项目的长期目标是能够 使用可溶性CD 127作为一种非侵入性生物标志物，可以很容易地从简单的血液测试中检测出来。我们 我们可以利用这些信息，为高可溶性CD 127患者提供临床个体化4A 10治疗，我们希望这些患者 将从4A 10治疗中受益更多。

Project Summary Treatment of patients with relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL) remains a major unmet medical need, with a five-year survival of only 21-39% in children and 20% in adults. Outcomes in B-Cell ALL (B-ALL) have improved, with several recently approved second-line therapies. In contrast, in the much smaller T-ALL population (~20% of ALL), nelarabine was the last new agent approved by FDA, in 2005, and few new therapies are in development. Fannin Partners, with its subsidiary, Allterum Therapeutics, is developing 4A10, a chimeric monoclonal antibody targeting the IL-7a receptor (CD127) developed by Dr. Scott Durum at the National Cancer Institute. The IL7R, critical to lymphocyte development, also plays an important role in the development and maintenance of T-ALL, including in relapsed disease. 4A10 binds the IL7R receptor, with an IgG1 Fc region that mediates antibody- dependent cell-mediated cytotoxicity (ADCC) in addition to inhibiting IL-7 signaling. 4A10 has demonstrated robust anti-cancer activity against IL7R-expressing T-ALL in-vitro and in-vivo, including prolonged survival of mice with patient-derived T-ALL xenografts. Support from a Cancer Prevention and Research Institute of Texas (CPRIT) grant and seed financing, enabled our manufacturing scale-up and toxicological work, and we are now working towards submission of an IND. Further grant funding will enable us to conduct a first-in-human Phase 1 clinical trial to assess the safety and activity of 4A10 in T-ALL patients and assess pharmacodynamic and tumor biomarkers and correlate with 4A10 activity and tolerability in T-ALL patients. These specific aims will allow us (1) determine safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of 4A10 as monotherapy, (2) Determine the pharmacokinetic profile of 4A10 as monotherapy, (3) Assess the activity of 4A10 as monotherapy, (4) Explore potential pharmacodynamic markers of biologic and clinical activity and safety, (5) Explore correlation of tumor IL- 7R expression with clinical activity, and (6) Explore correlation of cancer genetics with biologic and clinical activity and tolerability to 4A10. Completion of these aims will enable us to advance to a pivotal trial in patients with relapsed T-ALL, as well as other studies in additional ALL subpopulations and other IL7R-expressing cancers. It is very well known that CD127 is a highly polymorphic gene and undergoes shedding from the membrane or alternative splicing which is detectable in patient samples. Soluble CD127 plasma concentrations have been reported to remain stable over time in a normal individual, and upregulation of soluble CD127 may indicate metastatic disease progression in patients. The long-term goal of this diversity supplement project is to be able to use soluble CD127 as a noninvasive biomarker which could be easily detected from a simple blood test. We can harness this information to clinically individualize 4A10 therapy for high soluble CD127 patients, who we expect will benefit more from 4A10 treatment.