College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China.
KYINNO Biotechnology (Beijing) Co., Ltd., Beijing, China.
PLoS One. 2024 Aug 22;19(8):e0309394. doi: 10.1371/journal.pone.0309394. eCollection 2024.
GDF15 (growth differentiation factor 15), also known as macrophage inhibitory cytokine 1 (MIC-1), is a circulating protein involved in the regulation of energy balance and weight control. Elevated levels of GDF15 have been associated with cachexia and reduced survival rates in cancer patients. Through the activation of the GFRAL (GDNF-family receptor α-like)-RET (Rearranged during Transfection) signaling pathway, GDF15 can induce weight loss, making it a potential target for treating cachexia. Currently, there are no approved antibody drugs specifically targeting GDF15 for cancer cachexia treatment. However, efforts have been made to develop antibody-based therapeutics against this emerging target. In this study, we generated a monoclonal antibody KY-NAb-GDF15 against GDF15 that effectively blocks downstream signaling mediated by GFRAL upon stimulation by GDF15. This antibody demonstrates robust neutralizing activity and exhibits high binding specificity. Importantly, our findings indicate that this antibody holds promise in alleviating cancer-induced cachexia and mitigating chemotherapy-induced weight loss, thereby offering significant therapeutic potential for managing cancer cachexia.
生长分化因子 15（GDF15），也被称为巨噬细胞抑制细胞因子 1（MIC-1），是一种参与调节能量平衡和体重控制的循环蛋白。GDF15 水平的升高与癌症患者的恶病质和生存率降低有关。通过激活 GFRAL（GDNF 家族受体 α 样）-RET（转染期间重排）信号通路，GDF15 可以诱导体重减轻，使其成为治疗恶病质的潜在靶点。目前，尚无专门针对癌症恶病质治疗的针对 GDF15 的批准抗体药物。然而，已经做出努力来开发针对这一新兴靶点的抗体药物。在这项研究中，我们生成了一种针对 GDF15 的单克隆抗体 KY-NAb-GDF15，该抗体可有效阻断 GDF15 刺激 GFRAL 介导的下游信号。该抗体具有强大的中和活性和高度的结合特异性。重要的是，我们的研究结果表明，该抗体有望缓解癌症引起的恶病质和减轻化疗引起的体重减轻，从而为癌症恶病质的治疗提供了重要的治疗潜力。
