美国takeda生物制药bernard b allan等研究人员发现，抗体介导的gdf15-gfral活性抑制可逆转小鼠癌症恶病质。这一研究成果于2020年7月13日在线发表在国际学术期刊《自然—医学》上。通过一点一滴的努力，让免疫研究的市场占有率越来越高，得到的投资回报率也稳步攀升。
研究人员表示，癌症恶病质是一种高度普遍的疾病，与生活质量低下和生存率降低相关。肿瘤引起的内分泌、免疫和神经系统紊乱促使脂肪组织和骨骼肌的厌食和分解代谢发生变化，这是癌症恶病质的标志。然而，驱动恶病质的分子机制仍然不清楚，目前还没有批准的药物可以治疗这种病。循环生长分化因子15（gdf15）升高与恶病质以及癌症患者存活率降低相关，而脑干神经元中gdnf家族受体α样（gfral）-ret原癌基因（ret）信号复合物介导gdf15诱导的小鼠体重减轻也已被发现。
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研究人员报告了一种治疗性拮抗性单克隆抗体3p10，该抗体靶向gfral，并通过阻止gdf15驱动的ret与gfral的细胞表面相互作用来抑制ret信号传导。使用3p10进行治疗能够逆转荷瘤小鼠体内过多的脂质氧化，即使在热量受限的情况下也可以防止癌症恶病质。从机制上讲，gfral-ret途径的激活诱导了脂肪组织中参与脂质代谢的基因的表达，而外围化学交感神经切除术和脂肪甘油三脂脂肪酶的丧失均可以保护小鼠免受gdf15诱导的体重减轻。这些数据表明，gdf15在脂肪组织中引起脂解反应且不依赖于厌食症，从而导致荷瘤小鼠的脂肪、肌肉质量和功能降低。
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附：英文原文
title: antibody-mediated inhibition of gdf15–gfral activity reverses cancer cachexia in mice
author: rowena suriben, michael chen, jared higbee, julie oeffinger, richard ventura, betty li, kalyani mondal, zhengyu gao, dina ayupova, pranali taskar, diana li, shelley r starck, hung-i harry chen, michele mcentee, subhash d katewa, van phung, marilyn wang, avantika kekatpure, damodharan lakshminarasimhan, andre white, andrea olland, raj haldankar, mark j solloway, jer-yuan hsu, yan wang, jie tang, darrin a lindhout, bernard b allan
issuevolume: 2020-07-13
abstract: cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival1 tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia2,3,4 however, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition elevation in circulating growth differentiation factor 15 (gdf15) correlates with cachexia and reduced survival in patients with cancer5,6,7,8, and a gdnf family receptor alpha like (gfral)–ret proto-oncogene (ret) signaling complex in brainstem neurons that mediates gdf15-induced weight loss in mice has recently been described9,10,11,12 here we report a therapeutic antagonistic monoclonal antibody, 3p10, that targets gfral and inhibits ret signaling by preventing the gdf15-driven interaction of ret with gfral on the cell surface treatment with 3p10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions mechanistically, activation of the gfral–ret pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from gdf15-induced weight loss these data uncover a peripheral sympathetic axis by which gdf15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice
doi: 101038s41591-020-0945-x