Therapeutic antibody for cancer-associated cachexia

用于癌症相关恶病质的治疗性抗体 摘要 恶病质是一种使人衰弱的消耗性疾病，其特征在于食欲、骨骼肌和脂肪量的丧失。 癌症相关恶病质是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，25%的癌症相关死亡率来自恶病质而不是直接肿瘤 负担恶病质患者对放疗、化疗、药物治疗和手术的耐受性较差。为 因此，他们接受的剂量较低，治疗时间缩短，或不符合治疗条件，间接 增加死亡率。目前没有批准的恶病质治疗方法。生长分化因子15 GDF15作为体重减轻的关键介质被充分记录，并且高GDF15水平与体重减轻相关。 许多癌症。GDF15的施用导致小鼠、大鼠和灵长类动物的体重减轻，同时阻断 肿瘤相关恶病质模型中的GDF15快速逆转体重减轻。我们提出了一个高亲和力的嵌合 在肿瘤相关恶病质的动物模型中中和GDF15的单克隆抗体。在此阶段 1项目，我们将人源化该先导抗体并证明其与亲本抗体的等效性。2期 研究将推进临床前试验，包括药代动力学和毒理学，为IND做准备。 该项目开发的治疗性抗体将直接阻断恶病质的一个主要原因， 恶病质患者的最佳癌症治疗。

Therapeutic antibody for cancer-associated cachexia Abstract Cachexia is a debilitating, wasting disease, characterized by loss of appetite, skeletal muscle, and fat mass. Cancer-associated cachexia constitutes a major unmet medical need, as 80% of patients with advanced cancers exhibit cachexia, and 25% of cancer-related mortalities are derived from cachexia rather than direct tumor burden. Cachexic patients are less tolerant to radiotherapy, chemotherapy, pharmacotherapy, and surgery. For this reason, they receive lower doses, reduced duration of treatment, or are not eligible for treatment, indirectly increasing mortality. There is currently no approved treatment for cachexia. Growth differentiation factor 15 (GDF15) is well documented as a critical mediator of body weight loss, and high GDF15 levels are associated with many cancers. Administration of GDF15 causes weight loss in mice, rats, and primates while blocking GDF15 in models of tumor-associated cachexia rapidly reverses weight loss. We present a high-affinity chimeric monoclonal antibody that neutralizes GDF15 in animal models of tumor-associated cachexia. During this Phase 1 project, we will humanize this lead antibody and demonstrate its equivalence to the parent antibody. Phase 2 studies will advance preclinical testing, including pharmacokinetics and toxicology, in preparation for an IND. The therapeutic antibody to be developed in this project will directly block a major cause of cachexia to enable optimal cancer therapy in cachexic patients.