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

用于治疗儿童复发性 T 细胞白血病的新型 IL-7R 抗体的早期临床开发

基本信息

批准号：
10819043
负责人：
Philip Breitfeld
金额：
$ 8.43万
依托单位：
FANNIN PARTNERS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10819043
关键词：
Acute T Cell Leukemia Adult Alternative Splicing Antibodies Applications Grants B-Cell Acute Lymphoblastic Leukemia Binding Biological Biological Markers Blood Tests Child Clinical Clinical Trials Development Disease Progression Dose Drug Kinetics FDA approved Funding Genes Goals Grant IL7 gene IL7R gene IgG1 In Vitro Individual Interleukin 7 Receptor Lymphocyte Maintenance Malignant Neoplasms Maximum Tolerated Dose Mediating Medical Membrane Monoclonal Antibodies Mus National Cancer Institute Nelarabine New Agents Outcome Patients Phase Phase I Clinical Trials Plasma Play Population Recommendation Recurrent disease Relapse Reporting Research Institute Role Safety Sampling Signal Transduction Survival Rate T-Cell Leukemia Texas Therapeutic Time Toxicology Tumor Markers Up-Regulation Work Xenograft procedure antibody-dependent cell cytotoxicity anticancer activity anticancer research cancer genetics cancer prevention clinical development first-in-human improved in vivo invention manufacturing scale-up novel novel therapeutics parent grant pharmacodynamic biomarker receptor safety assessment tumor

项目摘要

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.

项目概要复发性 T 细胞急性淋巴细胞白血病 (T-ALL) 患者的治疗仍然是一个未得到满足的主要医疗领域儿童的五年生存率仅为 21-39%，成人的五年生存率为 20%。 B 细胞 ALL (B-ALL) 的结果一些最近批准的二线疗法已经有所改善。相比之下，在小得多的 T-ALL 中人群（约占 ALL 的 20%），奈拉滨是 FDA 于 2005 年批准的最后一个新药，并且几乎没有新疗法正在开发中。 Fannin Partners 及其子公司 Allterum Therapeutics 正在开发 4A10，一种嵌合单克隆抗体靶向 IL-7a 受体 (CD127)，由美国国家癌症研究所的 Scott Durum 博士开发。 IL7R，对淋巴细胞发育至关重要，也在 T-ALL 的发育和维持中发挥重要作用，包括疾病复发。 4A10 与 IL7R 受体结合，并具有介导抗体-的 IgG1 Fc 区除了抑制 IL-7 信号传导外，还具有依赖性细胞介导的细胞毒性 (ADCC)。 4A10已表现出稳健的体外和体内针对表达 IL7R 的 T-ALL 的抗癌活性，包括延长小鼠的生存期患者来源的 T-ALL 异种移植物。来自德克萨斯州癌症预防和研究所 (CPRIT) 赠款和种子融资的支持，启用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。进一步的拨款将使我们能够进行首次人体一期临床试验，以评估安全性和 T-ALL 患者中 4A10 的活性并评估药效学和肿瘤生物标志物并与 4A10 相关 T-ALL 患者的活性和耐受性。这些具体目标将使我们能够 (1) 确定安全性、最大耐受性剂量（MTD）和推荐的 4A10 2 期剂量（RP2D）作为单一疗法，（2）确定 4A10 作为单一疗法的药代动力学特征，(3) 评估 4A10 作为单一疗法的活性，(4) 探索生物学和临床活性及安全性的潜在药效学标志物，（5）探索肿瘤IL-的相关性 7R表达与临床活性，以及（6）探索癌症遗传学与生物学和临床活性的相关性和对 4A10 的耐受性。完成这些目标将使我们能够推进一项针对患有以下疾病的患者的关键试验：复发性 T-ALL 以及针对其他 ALL 亚群和其他表达 IL7R 的癌症的其他研究。众所周知，CD127 是一个高度多态性基因，会从细胞膜或细胞膜上脱落。在患者样本中可检测到的选择性剪接。可溶性 CD127 血浆浓度据报道，在正常个体中随时间推移保持稳定，可溶性 CD127 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 CD127 作为非侵入性生物标志物，可以通过简单的血液测试轻松检测到。我们可以利用这些信息对我们期望的高可溶性 CD127 患者进行临床个体化 4A10 治疗将从4A10治疗中获益更多。