Harbour BioMed has announced preclinical data for LET003, its first next-generation ACVR2A/2B-targeting monoclonal antibody developed using the Hu-mAtrIx platform. The results showed that LET003 exhibited superior pharmacokinetic characteristics compared to multiple competitor molecules. When combined with semaglutide, LET003 significantly enhanced fat reduction while effectively preserving lean mass. In addition, LET003 achieved lean mass-promoting effects at lower dose level comparable to bimagrumab at higher dose level, highlighting its potential to become a best-in-class therapy for obesity treatment.

The ACVR2A/2B signaling pathway plays a critical role in regulating the balance between fat and muscle mass in the body. Previously, bimagrumab, the first antibody targeting ACVR2A/2B, demonstrated positive clinical results, showing favorable efficacy and safety in combination with semaglutide for obesity treatment. Building on these findings, Harbour BioMed successfully advanced the molecular optimisation and functional enhancement of LET003 through structure biology and Hu-mAtrIxTM, its AI platform-driven antibody engineering approaches.

In human FcRn transgenic mouse and cynomolgus monkey models, researchers compared the blood clearance rates of LET003 with several competing molecules following subcutaneous administration. Results showed that LET003 exhibited significantly slower clearance than all comparator molecules tested, suggesting that it may achieve comparable efficacy with longer dosing intervals or lower doses relative to competing therapies.

In an obesity model using wild-type mice, semaglutide (30 nmol/kg) and LET003 (20 mg/kg) were administered subcutaneously once weekly as monotherapies or in combination. Results after three weeks of treatment showed that LET003, in combination with semaglutide, decreased fat mass by 76 percent compared with vehicle (P<0.0001), and by 34.7 percent compared with semaglutide monotherapy (P<0.0001).

In the combination group, lean mass decreased by 6.5 percent compared with vehicle (P=0.0001), but increased by 5.7 percent compared with semaglutide monotherapy (P=0.0007).

These data suggest that combining LET003 with semaglutide can significantly enhance fat reduction while effectively mitigating the lean mass loss associated with semaglutide treatment alone.

In a high-fat diet-induced obesity model using human FcRn transgenic mice, semaglutide (30 nmol/kg) and LET003 (20 mg/kg) were administered subcutaneously once weekly as monotherapies or in combination. Results after three weeks of treatment showed that the fat-to-body weight ratio in the combination group was reduced by 17.5 percent compared with vehicle (P<0.0001), and by 6 percent compared with semaglutide monotherapy (P=0.0127).

The lean mass-to-body weight ratio in the combination group was increased by 15.2 percent compared with vehicle (P<0.0001), and by 5.3 percent compared with semaglutide monotherapy (P=0.0194).

These data further confirm that combining LET003 with semaglutide not only more effectively reduces body fat proportion, but also significantly improves lean mass ratio, enabling superior body composition management.

In a separate study using human FcRn transgenic mice maintained on a normal diet, mice received weekly subcutaneous injections of LET003 or a comparator molecule at 20 mg/kg. After three weeks of treatment, both molecules induced an increase in lean mass and a consequent increase in overall body weight. Specifically, the LET003 treatment group showed an 18.3 percent increase in lean mass compared with vehicle (P<0.0001), and a 13.5 percent increase compared with the comparator molecule (P<0.0001).

The LET003 treatment group showed an 11.1 percent increase in overall body weight compared with vehicle (P < 0.0001), and a 9.3 percent increase compared with the competitor molecule (P < 0.0001).

These findings suggest that LET003 is superior to the competitor molecule in promoting lean mass.

In another study using human FcRn transgenic mice maintained on a normal diet, mice received weekly subcutaneous injections of bimagrumab or LET003 at different dose levels (5 mg/kg, 10 mg/kg, and 15 mg/kg). The results showed that both molecules contributed more to the increase in lean mass than to fat accumulation. After 3 weeks of treatment, LET003 at 5 mg/kg achieved lean mass-promoting effects comparable to those observed with 15 mg/kg bimagrumab. These results suggest that LET003 can achieve lean mass-promoting effects at lower dose level comparable to bimagrumab at higher dose level, demonstrating its excellent pharmacological potential.

Dr. Jingsong Wang, Founder, Chairman and Chief Executive Officer (CEO), Harbour BioMed, said, "The rapid advancement of LET003 has been strongly supported by our Hu-mAtrIx AI platform. Built on data generated from our proprietary Harbour Mice platforms, Hu-mAtrIx integrates fine-tuned large language models for sequence generation together with highly accurate AI classification and developability prediction models. We are highly encouraged by the favorable pharmacokinetic profile demonstrated by LET003 in preclinical studies, as well as its potential in fat reduction and lean mass preservation. These findings further validate our technological capabilities in AI-driven antibody engineering and metabolic disease research. We look forward to rapidly advancing LET003 into clinical development and providing obesity patients worldwide with more effective and safer treatment options."