Growth plate-targeted IGF1 to treat Turner Syndrome

生长板靶向 IGF1 治疗特纳综合征

• 批准号: 10819340
• 负责人: Timothy Richard Stowe
• 金额: $ 27.46万
• 依托单位: CAVALRY BIOSCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10819340
• 关键词: Acceleration; Address; Adult; Adverse effects; Affect; Affinity; Age; Antibodies; Avidity; Binding; Biodistribution; Biological Assay; Biological Response Modifier Therapy; Biological Sciences; Birth; Bone Growth; Bone Lengthening; Chimeric Proteins; Chondrocytes; Clinical; Clinical Trials; Complement; Congenital chromosomal disease; Dose; Drug Kinetics; Epiphysial cartilage; Extracellular Matrix Proteins; FDA approved; FUS-1 Protein; Failure; Female; Fluorochrome; Foundations; Frequencies; Future; Generations; Genes; Goals; Growth; Half-Life; Height; Hormones; Human; Hyperglycemia; Hypoglycemia; IGF1 gene; In Vitro; Injections; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor-Binding Proteins; Insulin-Like-Growth Factor I Receptor; Intracranial Hypertension; Label; Lead; Liver; Lymphoid Tissue; Measurement; Modification; Mus; Nasopharynx; Normal Range; Osteogenesis; Patients; Pharmaceutical Preparations; Phase; Phenotype; Pre-Clinical Model; Production; Proliferating; Property; Proto-Oncogene Proteins c-akt; Rare Diseases; Recombinant Growth Hormone; Recombinant IGF-I; Safety; Serum; Signal Transduction; Small Business Innovation Research Grant; Somatotropin; Structure; Testing; Toxic effect; Turner' s Syndrome; United States National Institutes of Health; Variant; X Chromosome; arm; bone; candidate identification; clinical development; design; drug candidate; efficacy evaluation; efficacy study; efficacy testing; established cell line; experimental study; growth hormone deficiency; healthy volunteer; high risk; improved; in vivo; innovation; lead candidate; lead optimization; long bone; manufacturability; matrilin 3; mouse model; next generation; pharmacologic; pre-clinical; preclinical study; programs; prototype; public health relevance; r-hGH-M; safety study; skeletal; standard of care; targeted treatment

Turner syndrome (TS) is a rare disorder that occurs at a rate of 1 in 2500 live female births and is caused by partial or complete monosomy of the X chromosome. Among the most common phenotypes in TS patients is short stature, defined as at least 2 standard deviations below mean height for age, which is commonly treated with daily injections of recombinant human growth hormone (GH) as the standard of care. While GH statistically increases adult height, TS patients generally fail to reach their mid-parental height projection or even achieve adult heights within the normal range. Additionally, TS patients are at particularly high risk for adverse effects associated with prolonged GH treatment that include hyperglycemia, intracranial hypertension, growth of the nasopharyngeal lymphoid tissues, insulin resistance, and acromegalic changes. Cavalry Biosciences’ goal is to address the unmet clinical need in safety and efficacy by developing a targeted therapeutic consisting of IGF1 (GH effector that drives bone growth) and an anti-matrilin-3 (MATN3) antibody-based target arm that drives localization to growth plates of long bones. In preclinical studies, prototypes of such a Growth Plate IGF1 (GP- IGF1) biotherapeutics, selectively localized to and increased the size of growth plates in mouse models of GH deficiency. The objective of our Phase 1 proposal is to optimize this prototype molecule into a lead that has PK- PD-efficacy and manufacturability properties that are favorable for clinical advancement. To accomplish this objective, we will pursue two specific aims. In the first aim, we will design and express next-generation GP-IGF1 fusions proteins with modifications that (i) improve MATN3 binding to optimize GP targeting, (ii) alter IGF1’s affinity for IGF1R and/or ability to interact with activity inhibiting IGF-binding proteins, and (iii) optimize pharma- cokinetics (PK). The resulting molecules will be tested for their ability to bind MATN3 and activate IGF1R in vitro and in vivo using assays that we have developed in preliminary studies. Candidate molecules will be assessed for PK and biodistribution properties in mice. In the second aim, we will use preclinical models to evaluate the efficacy and safety of next-gen GP-IGF1 molecules relative to recombinant GH and IGF1. Growth plate height measurements in GH-inhibited mice will be used for initial efficacy testing of the next-gen GP-IGF1 molecules generated through our drug optimization program. Because growth plate height is a surrogate for chondrocyte proliferation and bone growth, these experiments will be complemented with direct measurements of chondro- cyte proliferation and bone formation. Lead molecules will then be murinized for use in longer-term experiments that will critically evaluate (i) the extent to which they accelerate long bone growth and (ii) the potential for adverse effects. At the successful completion of Phase 1, we will have identified a lead compound that has been tested in mice for PK, biodistribution, PD, efficacy, and safety. This will lay the foundation for a Phase 2 application, in which we will conduct the IND-enabling studies that advance our lead molecule to a drug candidate suitable for human testing.

特纳综合征（TS）是一种罕见的疾病，以2500个活着的女性出生中的1次发生，由 X染色体的部分或完整的单子。在TS患者中最常见的表型之一是 身材矮小，定义为年龄平均高度低于平均高度的至少2个标准出发 每天注射重组人类生长马（GH）作为护理标准。而GH统计 提高成人身高，TS患者通常无法达到其中期高度投影，甚至达到 成人高度在正常范围内。此外，TS患者对不良影响的风险特别高 与包括高血糖，颅内高血压在内的延长GH治疗有关 鼻咽淋巴组织，胰岛素耐药性和巨性变化。骑兵生物科学的目标是 通过开发由IGF1组成的靶向疗法来满足安全和效率的未满足临床需求 （驱动骨骼生长的GH效应子）和基于抗体的抗蛋白酶3（MATN3）基于抗体的靶臂 定位以增加长骨的板。在临床前研究中，这种生长板IGF1的原型（GP- IGF1）生物治疗剂，在GH的小鼠模型中有选择地定位于生长板的大小 不足。我们第1阶段建议的目的是将该原型分子优化为具有PK-的铅 有利于临床进步的PD效能和制造特性。实现这一目标 目标，我们将追求两个具体的目标。在第一个目标中，我们将设计并表达下一代GP-IGF1 融合蛋白具有（i）改善MATN3结合以优化GP靶向的修饰蛋白，（ii）改变IGF1 对IGF1R的亲和力和/或与抑制IGF结合蛋白的活性相互作用的能力，以及（iii）优化药物 Cokinetics（PK）。所得分子将测试其结合MATN3并在体外激活IGF1R的能力 并使用我们在初步研究中开发的测定法进行体内。候选分子将进行评估 用于小鼠的PK和生物分布特性。在第二个目标中，我们将使用临床前模型来评估 相对于重组GH和IGF1，下一代GP-IgF1分子的功效和安全性。生长板高度 GH抑制小鼠的测量将用于下一代GP-IgF1分子的初始效率测试 通过我们的药物优化计划产生。因为生长板的高度是软骨细胞的替代物 增殖和骨骼生长，这些实验将通过直接测量软骨的直接测量来完成 阳离子增殖和骨形成。然后将铅分子浸入长期实验中使用 这将严格评估（i）它们在多大程度上加速长骨的生长以及（ii）广告的潜力 效果。在成功完成第1阶段时，我们将确定已测试的铅化合物 在PK的小鼠中，生物分布，PD，效率和安全性。这将为2阶段申请奠定基础 我们将进行辅助研究，以将我们的铅分子推向适合的药物 人类测试。