KAIST researchers develop GB2Ab antibody to treat cancer cachexia in mice

KAIST researchers have developed the GB2Ab antibody candidate, which targets the GFRAL brain stem receptor to block GDF15 signaling responsibility for cancer cachexia wasting. In colon cancer mouse models, GB2Ab increased food intake, boosted body weight by 20%, and restored grip strength to 90% of normal levels. The treatment aims to preserve physical function alongside standard treatments, with follow-up studies evaluating immunotherapy combinations.

Overview of GB2Ab development

• ▪A KAIST joint research team led by Professor Kim Ho-min and Professor Song Min-ho developed the GB2Ab antibody candidate to reduce weight and muscle loss in cancer cachexia.
• ▪Researchers at KAIST and THOR Therapeutics analyzed the 3D structure of the GB2Ab antibody-GFRAL complex and modified the antibody to enhance production efficiency and stability.

Mechanism of GDF15 and GB2Ab

• ▪GDF15 protein levels increase during cancer or severe stress and bind to GFRAL receptors in the brainstem to suppress appetite and elevate energy expenditure.
• ▪The GB2Ab antibody specifically targets and binds tightly to the GFRAL receptor in the brainstem to block appetite suppression and energy expenditure signals.

Mouse study results for GB2Ab

• ▪Administering a high dose of 100 mg per kilogram of GB2Ab to healthy mice produced no apparent abnormalities in body weight or food intake.
• ▪GB2Ab treatment improved grip strength by about 30% in colon cancer-bearing mice, recovering function to 90% of healthy control mice.
• ▪In mouse experiments with colon cancer cells, GB2Ab administration restored food intake and resulted in body weight approximately 20% higher than in untreated mice.
• ▪GB2Ab administration reduced excessive sympathetic nervous system activity and curtailed excessive energy expenditure in cancer-bearing mice.

Clinical outlook and future applications

• ▪Researchers are conducting follow-up studies to evaluate the therapeutic effects of GB2Ab when combined with cancer immunotherapy.
• ▪GB2Ab is designed to alleviate muscle wasting rather than directly shrink tumors, serving as a supportive therapy alongside standard cancer treatments.
• ▪GB2Ab requires clinical trials in humans to establish safety and efficacy, as animal study results do not yet confirm human therapeutic application.

Impacts of cancer cachexia

• ▪Cancer cachexia limits daily activities and weakens patients, hindering their ability to continue ongoing anticancer treatments.
• ▪Cancer cachexia causes continuous loss of muscle and fat by altering energy usage and nutrient processing, making nutritional support alone insufficient for recovery.