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，每 2500 名活产女婴中就有 1 人发生这种疾病，由以下原因引起： X 染色体的部分或完全单体性。 TS 患者最常见的表型是 身材矮小，定义为比年龄平均身高至少低 2 个标准差，这是常见的治疗方法 每日注射重组人生长激素（GH）作为护理标准。虽然 GH 统计 随着成年身高的增加，TS 患者通常无法达到父母身高预测的中间值，甚至无法达到 成人身高在正常范围内。此外，TS 患者出现不良反应的风险特别高 与长期 GH 治疗相关，包括高血糖、颅内高压、生长激素生长 鼻咽淋巴组织、胰岛素抵抗和肢端肥大症改变。 Cavalry Biosciences 的目标是 通过开发由 IGF1 组成的靶向治疗药物，解决安全性和有效性方面未满足的临床需求 （驱动骨骼生长的 GH 效应器）和基于抗 matrilin-3 (MATN3) 抗体的靶臂，驱动 定位于长骨生长板。在临床前研究中，这种生长板 IGF1（GP- IGF1) 生物治疗药物，选择性定位并增加 GH 小鼠模型中生长板的大小 不足。我们第一阶段提案的目标是将这个原型分子优化为具有 PK- 的先导分子。 有利于临床进展的 PD 功效和可制造性特性。为了实现这一点 目标，我们将追求两个具体目标。第一个目标是设计并表达下一代GP-IGF1 融合蛋白经过修饰，(i) 改善 MATN3 结合以优化 GP 靶向，(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 动力学（PK）。所得分子将在体外测试其结合 MATN3 和激活 IGF1R 的能力 以及使用我们在初步研究中开发的体内测定法。将评估候选分子 用于小鼠体内的 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 下一代 GP-IGF1 分子相对于重组 GH 和 IGF1 的功效和安全性。生长板高度 GH 抑制小鼠的测量结果将用于下一代 GP-IGF1 分子的初步功效测试 通过我们的药物优化计划生成。因为生长板高度可以替代软骨细胞 增殖和骨骼生长，这些实验将通过软骨的直接测量来补充 细胞增殖和骨形成。然后先导分子将被鼠化以用于长期实验 这将严格评估（i）它们加速长骨生长的程度以及（ii）潜在的不利影响 影响。第一阶段成功完成后，我们将确定一种经过测试的先导化合物 在小鼠中进行 PK、生物分布、PD、功效和安全性。这将为第二阶段应用奠定基础 我们将进行 IND 支持研究，将我们的先导分子发展为适合的候选药物 人体测试。