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名活产女性中就有1人患病，由以下因素引起