 |
Next-generation ACVR2A/2B-targeting monoclonal antibody, driven by the Hu-mAtrIx™ platform, shows potential as best-in-class in obesity treatment
Shanghai, China; Cambridge, Massachusetts, USA; and Rotterdam, NetherlandsMay 18, 2026 /PRNewswire/ — Harbour BioMed (stock code: 02142.HK), a global biopharmaceutical company focused on the discovery and development of innovative antibody therapies in immunology, oncology, and other areas, today announced preclinical study data for LET003, its first next-generation monoclonal antibody targeting ACVR2A/2B, developed using the Hu-mAtrIx™ artificial intelligence platform. The results show that LET003 exhibits superior pharmacokinetic properties compared to multiple competitor molecules; when combined with semaglutide, it significantly enhances fat reduction effects and effectively preserves lean body mass. Additionally, at lower doses, LET003 achieves comparable effects in promoting lean body mass gain to higher doses of bimagrumab, demonstrating its potential as a best-in-class drug in obesity treatment.
The ACVR2A/2B signaling pathway plays a key role in regulating the balance between body fat and muscle. Previously, bimagrumab, the first antibody targeting ACVR2A/2B, showed positive results in clinical trials, demonstrating good efficacy and safety in treating obesity when combined with semaglutide. Against this backdrop, Harbour BioMed leveraged structural biology and the Hu-mAtrIxTM AI platform for antibody engineering, successfully driving the molecular optimization and functional breakthroughs of LET003.
In human FcRn transgenic mice and cynomolgus monkey models, researchers compared the blood elimination rates of LET003 with several competitor molecules via subcutaneous administration. The results showed that LET003’s in vivo elimination rate was significantly slower than all tested competitors, suggesting it could achieve comparable efficacy to competitor molecules with longer dosing intervals or lower doses.
In a wild-type mouse obesity model, researchers administered semaglutide (30 nmol/kg) and LET003 (20 mg/kg) subcutaneously weekly as monotherapy or in combination. After three weeks of treatment, the results showed:
- 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 showed a 6.5% decrease in lean body mass compared to the control group (P=0.0001) and a 5.7% increase compared to the semaglutide monotherapy group (P=0.0007).
These data indicate that combining LET003 with semaglutide significantly enhances fat reduction and effectively mitigates the lean body mass loss that may occur with semaglutide monotherapy.
In a high-fat diet-induced obesity model in human FcRn transgenic mice, researchers administered semaglutide (30 nmol/kg) and LET003 (20 mg/kg) subcutaneously weekly as monotherapy or in combination. After three weeks of treatment, the results showed:
- The combination therapy group reduced the fat mass/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/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 better body composition regulation.
In an experiment with normally fed human FcRn transgenic mice, mice 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 consequently total body weight. Among them:
- 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 (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 (P<0.0001).
This indicates that LET003 is superior to the competitor molecule in promoting lean body mass.
In another experiment with normally fed human FcRn transgenic mice, mice received weekly subcutaneous injections of bimagrumab and LET003 at different doses (5 mg/kg, 10 mg/kg, 15 mg/kg). The results showed that both molecules contributed more to lean body mass gain than fat accumulation. After three weeks of treatment, 5 mg/kg LET003 achieved effects comparable to 15 mg/kg bimagrumab in promoting lean body mass gain. This result indicates that LET003 can achieve similar lean body mass-promoting effects to higher doses of bimagrumab at lower doses, demonstrating excellent pharmacodynamic potential.
Dr. Wang Jinsong, Founder, Chairman, and CEO of Harbour BioMed, said: “The rapid advancement of LET003 is strongly supported by our Hu-mAtrIx™ AI platform. This platform is based on data from our proprietary Harbour Mice® platform, integrating fine-tuned large language models for sequence generation, supplemented by high-precision AI classification and druggability prediction models. We are excited about the excellent pharmacokinetic properties demonstrated by LET003 in preclinical studies and its potential in fat reduction and muscle preservation. These results fully validate our technical expertise in AI-driven antibody engineering and metabolic disease research. We look forward to advancing LET003 into clinical stages as soon as possible, providing more effective and safer treatment options for global obesity patients.”
About LET003
LET003 is a potential best-in-class next-generation monoclonal antibody targeting the activin receptors ACVR2A/2B. ACVR2A and ACVR2B play key roles in regulating muscle-fat metabolic homeostasis. Extensive preclinical and clinical studies have confirmed that combining blocking antibodies of this receptor with GLP-1 class weight-loss drugs can further reduce body fat and effectively mitigate lean body mass loss. LET003 is the first ACVR2A/2B dual-target blocking antibody developed using the Hu-mAtrIx™ AI platform, with superior pharmacokinetic properties compared to multiple competitors; in preclinical animal models, it also demonstrates excellent synergistic effects in fat reduction and muscle preservation when combined with GLP-1 drugs.
About Harbour BioMed
Harbour BioMed (stock code: 02142.HK) is a global biopharmaceutical company focused on innovative drug research and development in immunology, oncology, and other areas. The company rapidly expands its innovative drug pipeline through independent research and development, joint development, and diversified international collaboration models.
Harbour BioMed’s proprietary antibody technology platform, Harbour Mice®, can generate fully human monoclonal antibodies in dual, double light chain (H2L2) and heavy chain-only (HCAb) formats. The immune cell engagers (HBICE®) developed based on the HCAb antibody platform can achieve anti-tumor efficacy unattainable by traditional drug combination therapies. Meanwhile, the HCAb PLUSTM technology, developed based on the HCAb antibody platform, provides comprehensive new molecular solutions for innovative multispecific drug development in different disease areas. Additionally, leveraging the Harbour Mice® platform, Harbour BioMed has launched the first fully human AI HCAb model driven by its Hu-mAtrIxTM AI platform—a fully human HCAb generation and screening model—to accelerate the development of innovative therapies.
Harbour Mice®, HBICE®, HCAb PLUSTM, the single B cell cloning screening platform, and AI technology together form Harbour BioMed’s next-generation innovative therapeutic antibody research and development engine. For more information, please visit: www.harbourbiomed.com.