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

厌食症-恶病质是一种虚弱的、危及生命的疾病，与明显的食欲、骨骼肌和脂肪块丧失有关。厌食症-恶病质是一种主要的未得到满足的医疗需求，因为80%的晚期癌症患者表现出恶病质，20%的死亡来自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。没有得到批准的治疗方法代表着高度未得到满足的医疗需求。癌症厌食症-恶病质的病因归因于肿瘤细胞因子诱导的代谢异常。血浆肿瘤衍生的GDF-15和激活素-A水平升高的患者与体重减轻和生存不良有关。GDF-15和激活素-A分别是导致厌食症和肌肉萎缩的原因因素。过度表达GDF-15和激活素-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，逆转恶病质，显著延长生存期。目标是鉴定针对GDF-15和激活素-A的双特异性抗体。一个成功的结果将是对10个不同的线索进行优先排序。这位临床候选人将把癌症患者的血浆GDF-15水平降低到1 ng/mL，将激活素-A水平降低到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，增加骨骼强度和抑制转移灶。总体而言，这一独特的特征将使患者能够接受最佳的抗癌治疗，以提高存活率和生活质量。

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.