Therapeutic antibody for cancer-associated cachexia

癌症相关恶病质的治疗性抗体

• 批准号: 10244794
• 负责人: JAMES W LARRICK
• 金额: $ 25.23万
• 依托单位: LARIX BIOSCIENCE, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244794
• 关键词: Adipose tissue; Advanced Malignant Neoplasm; Affect; Affinity; Amygdaloid structure; Animal Cancer Model; Animal Model; Animals; Antibodies; Appetite Stimulants; Binding; Body Weight decreased; Brain Stem; Cachexia; Cancer Patient; Cessation of life; Complex; Data; Desire for food; Development; Distress; Dose; Drug Kinetics; Eating; Ensure; Exhibits; Fatty acid glycerol esters; Food Energy; GDF15 gene; Homeostasis; Human; Hypothalamic structure; Immunotherapy; Lateral; Lead; Life; Life Support Care; Malignant Neoplasms; Malignant neoplasm of prostate; Mediator of activation protein; Medical; Modeling; Monoclonal Antibodies; Mus; Muscle Weakness; Neurons; Nucleus solitarius; Operative Surgical Procedures; Palliative Care; Parents; Patients; Pharmacotherapy; Phase; Phosphorylation; Preclinical Testing; Preparation; Primates; Radiation therapy; Rattus; Recombinants; Serum; Signal Transduction; Skeletal Muscle; Structure of area postrema; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Time; Toxic effect; Toxicology; Tumor Burden; Wasting Syndrome; Weight Gain; Work; appetite loss; assay development; base; cancer cachexia; cancer therapy; chemotherapy; effective therapy; energy balance; human monoclonal antibodies; in vitro Assay; in vitro activity; in vivo; mortality; neuronal circuitry; neutralizing monoclonal antibodies; nutrition; parabrachial nucleus; phase 2 study; pre-clinical; prevent; receptor; relating to nervous system; skeletal muscle wasting; targeted treatment; treatment duration; tumor; tumor xenograft

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.

癌症相关恶病质的治疗性抗体 摘要 恶病质是一种衰弱、消瘦的疾病，其特征是食欲不振、骨骼肌和脂肪团。 癌症相关性恶病质是一个主要的未得到满足的医疗需求，因为80%的晚期癌症患者 表现为恶病质，25%的癌症相关死亡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，他们间接地接受较低的剂量、较短的疗程或不符合治疗条件。 死亡率不断上升。目前还没有被批准的治疗恶病质的方法。生长分化因子15 (GDF15)是体重减轻的关键调节因子，与高水平的GDF15相关 罹患多种癌症。给予GDF15可使小鼠、大鼠和灵长类动物在阻断时体重减轻 肿瘤相关恶病质模型中的GDF15可迅速逆转体重下降。我们提出了一种高亲和力嵌合体 在肿瘤相关恶病质动物模型中中和GDF15的单抗。在此阶段中 项目1，我们将人源化这种先导抗体，并证明其与亲本抗体的等效性。第二阶段 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。 将在这个项目中开发的治疗性抗体将直接阻断恶病质的一个主要原因，以使 恶病质患者的最佳癌症治疗。