Abstract 4258: FL-501 is a potential best in class GDF-15 inhibitor with extended half-life and potent anti-cachexia activity in preclinical models

Cancer cachexia is a devastating syndrome characterized by unintentional weight loss, muscle wasting, fatigue, and severely reduced quality of life. This condition affects up to 80% of cancer patients and represents a major contributor to cancer-related mortality. Despite its significant clinical impact, there are currently no approved therapies for cancer cachexia in most of the world. However, recent pre-clinical and clinical studies have identified Growth Differentiation Factor-15 (GDF-15) as a promising therapeutic target for treating this debilitating condition.FL-501, a novel GDF-15 antibody, was designed to neutralize GDF-15 with high affinity and extended half-life. FL-501 was engineered with specific mutations designed to optimize its pharmacokinetic and safety profiles. In studies using humanized FcRn mice, FL-501 demonstrated a 2-fold increase in half-life and 0.5-fold decrease in clearance compared to both ponsegromab and a wild-type precursor of FL-501.MC38 colorectal cancer (CRC) cells engineered to overexpress human GDF-15 (MC38_hGDF15) were used to assess the role of GDF-15 in driving cancer cachexia. Mice inoculated with these tumor cells exhibited significantly greater body weight loss compared to those bearing wild-type MC38 tumors. The weight loss was attributed to substantial reductions across multiple tissue types, including skeletal muscle mass, fat deposits, and cardiac muscle mass. Importantly, treatment with FL-501 fully restored body composition in mice bearing MC38_hGDF15 tumors to an extent similar or greater than other clinical stage antibodies including visugromab and ponsegromab. To further validate these findings in a clinically relevant setting, non-small cell lung cancer (NSCLC) patient-derived xenografts (Crown Bioscience, Model LU5176) were inoculated in immunocompromised mice. In this therapeutic model, mice were treated with cisplatin (5 mg/kg) alone or in combination with either FL-501 or ponsegromab. While untreated mice and those receiving cisplatin monotherapy experienced significant decreases in weight, the combination with either FL-501 or ponsegromab effectively restored their body weight. Moreover, the addition of anti-GDF-15 therapy significantly improved survival of the mice compared to cisplatin treatment alone. These results support GDF-15 as a key driver of cachexia. Further, the targeted inhibition of GDF-15 with FL-501 was able to effectively reverse characteristics of cancer cachexia in multiple pre-clinical models. Taken together, these findings support the continued evaluation of FL501 and its progression into the clinic. Citation Format: Kelly Foster, Michael S. Haas, Walter Newman, Jason Baum, Roma Kaul. FL-501 is a potential best in class GDF-15 inhibitor with extended half-life and potent anti-cachexia activity in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4258.