HBM HOLDINGS-B (02142) announced that its board of directors is pleased to present preclinical research data for LET003, the company's first next-generation monoclonal antibody candidate targeting ACVR2A/2B, developed using the Hu-mAtrIx™ AI platform. The results indicate that LET003 exhibits superior pharmacokinetic characteristics compared to several competitor molecules. When used in combination with semaglutide, it significantly enhances fat loss while effectively preserving lean body mass. Furthermore, at lower doses, LET003 achieves lean body mass gains comparable to higher doses of bimagrumab, demonstrating its potential to be a best-in-class therapy for obesity.
In human FcRn transgenic mouse and cynomolgus monkey models, researchers compared the blood clearance rates of LET003 with multiple competitor molecules following subcutaneous administration. The results show that the in vivo clearance rate of LET003 was significantly lower than all tested competitors, suggesting it could achieve efficacy comparable to competitor molecules with longer dosing intervals or lower doses.
In an obesity model using wild-type mice, researchers administered weekly subcutaneous injections of semaglutide (30 nmol/kg) and LET003 (20 mg/kg) as monotherapy and in combination. After three weeks of treatment, results showed that the combination therapy group reduced fat mass by 76.0% compared to the control group (P<0.0001) and by 34.7% compared to the semaglutide monotherapy group (P<0.0001). The combination therapy group's lean body mass decreased by 6.5% compared to the control group (P=0.0001) but increased by 5.7% compared to the semaglutide monotherapy group (P=0.0007). These data indicate that adding LET003 to semaglutide significantly enhances fat reduction and effectively mitigates the potential loss of lean body mass associated with semaglutide monotherapy.
In a high-fat diet-induced obesity model using human FcRn transgenic mice, researchers administered weekly subcutaneous injections of semaglutide (30 nmol/kg) and LET003 (20 mg/kg) as monotherapy and in combination. After three weeks, results showed that the combination therapy group reduced the fat-to-body weight ratio by 17.5% compared to the control group (P<0.0001) and by 6.0% compared to the semaglutide monotherapy group (P=0.0127). The combination therapy group increased the lean body mass-to-body weight ratio by 15.2% compared to the control group (P<0.0001) and by 5.3% compared to the semaglutide monotherapy group (P=0.0194). These data further confirm that LET003 combined with semaglutide not only more effectively reduces body fat percentage but also significantly improves lean body mass percentage, achieving superior body composition regulation.
In an experiment with normally fed human FcRn transgenic mice, the animals received weekly subcutaneous injections of 20 mg/kg LET003 or a competitor molecule. After three weeks of treatment, both molecules induced an increase in lean body mass and a consequent increase in total body weight. Specifically: • The LET003 treatment group increased lean body mass by 18.3% compared to the control group (P<0.0001) and by 13.5% compared to the competitor molecule group (P<0.0001). • The LET003 treatment group increased total body weight by 11.1% compared to the control group (P<0.0001) and by 9.3% compared to the competitor molecule group (P<0.0001). This indicates that LET003 is superior to this competitor molecule in promoting lean body mass.
In another experiment with normally fed human FcRn transgenic mice, the animals received weekly subcutaneous injections of bimagrumab and LET003 at different doses (5 mg/kg, 10 mg/kg, 15 mg/kg). Results showed that both contributed more to lean body mass growth than to fat accumulation. After three weeks of treatment, LET003 at 5 mg/kg achieved effects on promoting lean body mass increase comparable to bimagrumab at 15 mg/kg. This result indicates that LET003 can achieve similar lean body mass promotion at lower doses compared to higher doses of bimagrumab, demonstrating excellent therapeutic potential.
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