SBIR TOPIC 395: IDENTIFICATION OF BI-SPECIFIC ANTIBODIES TO INHIBIT GDF-15 AND ACTIVIN A FOR ANOREXIA-CACHEXIA

SBIR 主题 395：抑制 GDF-15 和激活素 A 治疗厌食症-恶病质的双特异性抗体的鉴定

• 批准号: 10027551
• 负责人: MARGARET JACKSON
• 金额: $ 29.99万
• 依托单位: BYOMASS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2020-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10027551
• 关键词: Activins; Advanced Malignant Neoplasm; Anorexia; Antibodies; Bispecific Antibodies; Body Weight decreased; Cachexia; Cancer Etiology; Cancer Patient; Catabolism; Disease; Exhibits; Fatty acid glycerol esters; Goals; Human; IgG1; In Vitro; Life; Ligands; Mediating; Medical; Metabolism; Modeling; Monoclonal Antibodies; Muscular Atrophy; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patients; Pharmacotherapy; Plasma; Quality of life; Radiation therapy; Safety; Skeletal Muscle; Small Business Innovation Research Grant; Tumor Burden; Tumor-Derived; activin A; appetite loss; bone strength; cancer anorexia; cancer therapy; chemotherapy; clinical candidate; cytokine; human monoclonal antibodies; increased appetite; mortality; overexpression; tumor

Anorexia-cachexia is a debilitating, life-threatening disease, associated with pronounced loss of appetite, skeletal muscle and fat mass. Anorexia-cachexia constitutes a major unmet medical need, as 80% of patients with advanced cancers exhibit cachexia and 20% of mortalities are derived from cachexia rather than tumor burden. Patients are less tolerant to radiotherapy, chemotherapy, pharmacotherapy and surgery. There are no approved treatments representing a high unmet medical need. The etiology of cancer anorexia-cachexia is attributed to abnormal metabolism, induced by tumor-derived cytokines. Patients with elevated plasma levels of tumor-derived GDF-15 and Activin-A are associated with weight loss and poor survival. GDF-15 and Activin-A are causal factors mediating anorexia and muscle wasting, respectively. Overexpressing GDF-15 and Activin-A results in anorexia and muscle atrophy. Blocking endogenous GDF-15 and Activin-A in tumor-induced weight loss models, reverses cachexia and dramatically prolongs survival. The goal is to identify bispecific antibodies against GDF-15 and Activin-A. A successful outcome will be to prioritize 10 diverse leads. The clinical candidate will suppress plasma levels of GDF-15 to <1 ng/mL and Activin-A to <0.4 ng/mL in cancer patients. Suppressing GDF-15 and Activin-A will increase appetite, decrease catabolism, reverse muscle atrophy, increase bone strength and suppress metastatic lesions. Collectively, this unique profile will enable patients to receive optimal anti-cancer therapy to increase survival and quality of life.

厌食-恶病质是一种使人衰弱、危及生命的疾病，与食欲、骨骼肌和脂肪量的明显丧失有关。厌食-恶病质构成了一个主要的未满足的医疗需求，因为 80% 的晚期癌症患者表现出恶病质，20% 的死亡源于恶病质而不是肿瘤负担。患者对放疗、化疗、药物治疗和手术的耐受性较差。没有批准的治疗方法代表着高度未满足的医疗需求。癌症厌食-恶病质的病因归因于肿瘤源性细胞因子诱导的代谢异常。肿瘤源性 GDF-15 和激活素 A 血浆水平升高的患者与体重减轻和生存率低相关。 GDF-15 和激活素 A 分别是介导厌食和肌肉萎缩的致病因素。过度表达 GDF-15 和 Activin-A 会导致厌食和肌肉萎缩。在肿瘤诱导的体重减轻模型中阻断内源性 GDF-15 和激活素 A，可逆转恶病质并显着延长生存期。目标是鉴定针对 GDF-15 和 Activin-A 的双特异性抗体。成功的结果将是优先考虑 10 个不同的潜在客户。该临床候选药物将癌症患者的血浆 GDF-15 水平抑制至 <1 ng/mL，将 Activin-A 水平抑制至 <0.4 ng/mL。抑制 GDF-15 和激活素 A 将增加食欲、减少分解代谢、逆转肌肉萎缩、增加骨强度并抑制转移性病变。总的来说，这种独特的特征将使患者能够接受最佳的抗癌治疗，以提高生存率和生活质量。