In 2023, the global anti-obesity drug market reached $6 billion, and Goldman Sachs forecasts a more than 16-fold increase to reach 100 billion by 2030.

In recent years, glucagon-like peptide-1 receptor (GLP-1R) has become a key target in diabetes and obesity treatment due to its role in regulating blood glucose and weight. Peptide-based GLP-1R agonists have shown significant efficacy in lowering blood glucose and promoting weight loss. Advances in antibody drug technology have led to the emergence of GLP-1R antibody drugs, offering potential for longer-lasting, more effective, and safer treatments.

Structure of GLP-1R

GLP-1R, a key member of the class B G protein-coupled receptor (GPCR) family, features a characteristic seven-transmembrane domain (TMD) and an extracellular domain (ECD) of 120-160 amino acids. Both the ECD and TMD are essential for GLP-1R's interaction with its peptide ligand GLP-1 and subsequent activation. The ECD binds the ligand, anchoring it to the transmembrane region, which induces conformational changes in the TMD and recruits downstream G proteins. In the absence of a ligand, weak ECD-TMD interactions inhibit receptor activation by preventing ligand binding, serving as a negative regulatory mechanism.

https://doi.org/10.1038/s41467-020-14934-5

Activation process of full-length GLP-1R

Biological Functions of GLP-1R

GLP-1R is widely distributed in the body, including in pancreatic beta cells, the stomach, intestines, brain, and heart. It regulates insulin secretion and blood glucose levels through its interaction with GLP-1. Additionally, GLP-1R influences appetite control, weight management, and provides cardiovascular and neuroprotective benefits, making it a key target for treating diabetes, obesity, and related diseases.

https://doi.org/10.3389/fendo.2022.838410

Biological actions of GLP-1 on target tissues

Landscape of GLP-1R-Targeted Drug Development

• Mainstream: Peptide-Based GLP-1R Drugs

Due to GLP-1R's dual role in regulating blood glucose and promoting weight loss, it has become a key target in diabetes treatments and aesthetic medicine. GLP-1R's high affinity for peptide ligands makes peptide-based drugs the primary form of GLP-1R-targeted therapies. However, the native GLP-1 molecule is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) and glomerular filtration, requiring modifications to extend its half-life. To address this, several peptide-based GLP-1R agonists have been developed and approved, enhancing their half-life, efficacy, and bioavailability, effectively mimicking endogenous GLP-1's glucose-lowering and weight loss effects.

https://doi.org/10.3389/fendo.2022.838410

Methods to enhance GLP- 1R action

• Emerging: GLP-1R Antibody Drugs

As macromolecular drugs, antibody therapies offer higher specificity and affinity than peptide-based drugs, allowing precise targeting of antigens like GLP-1R and reducing the risk of nonspecific binding and side effects. Antibodies also benefit from extended circulation through the neonatal Fc receptor (FcRn), prolonging their half-life and reducing dosing frequency. Additionally, their immunomodulatory properties enhance efficacy via interactions with Fc receptors (FcR).

While peptide-based drugs often require weekly or more frequent administration, GLP-1R agonist antibodies offer a promising solution, with several under development to address this limitation.

- Glutazumab by Gmax Biopharm: Glutazumab is the world's first antibody drug directly targeting GLP-1R, developed for treating type 2 diabetes and obesity. It features a fusion of a 23-amino-acid peptide linker and a DPP-4-resistant GLP-1 (7-35) fragment to the light chain of a humanized GLP-1R antibody. The most advanced clinical trial of Glutazumab has entered phase III. Existing clinical data indicate that Glutazumab is superior to similar GLP-1 analogs in terms of safety, tolerability, and glucose-lowering and weight loss effects, making it a potential next-generation ultra-long-acting treatment for diabetes and obesity.

https://doi.org/10.1016/j.bcp.2018.01.029

Schematic diagram of Glutazumab

Source: Gmax Biopharm official website

The pipeline of Gmax Biopharm

- Regeneron's ATDC Technology: In September 2023, Regeneron patented (WO2023173132A1) antibody-tethered drug conjugates (ATDCs). This technology combines an antibody targeting the extracellular domain of GLP-1R with a GLP-1 mimetic, forming ATDCs. The GLP-1R antibody recognizes GLP-1R on the cell surface and inserts the modified GLP-1 peptide into the receptor, enhancing ligand binding. Compared to traditional peptide drugs, ATDCs increase affinity and molecular weight, improving the stability and half-life of GLP-1 peptide analogs.

Source: Patent No. WO2023173132A1

The mechanism of ATDC

- Everestmab: Everestmab is an anti-GLP-1R antibody with agonistic effects achieved through fusion with a GLP-1 peptide segment. It has three domains: a mutated GLP-1 (A8G) fragment with enhanced DPP-4 resistance; a humanized human serum albumin (HSA) nanobody that binds HSA  to extend half-life by preventing rapid clearance; and a humanized GLP-1R nanobody that activates the GLP-1R signaling pathway upon dissociation from HSA.

https://doi.org/10.1080/21691401.2020.1770268

Structure and the prolonged persistence mechanism of everestmab in vivo

- TB59-2 Antibody: Liu et al. used their GPCR synthetic antibody phage display library to identify the anti-GLP-1R antibody TB01-2, which has strong binding but lacks agonistic activity. By fusing the active GLP-1 (7-36) fragment to the N-terminus of TB01-2’s light chain, they created TB59-2. This fusion significantly enhances the antibody’s activity and stability, mimics endogenous GLP-1, and effectively activates GLP-1R, increasing insulin secretion and lowering blood glucose levels.

https://doi.org/10.1080/19420862.2021.1893425

Design of TB59-2

Newly Launched Full-Length GLP-1R Protein

While peptide-based drugs lead in GLP-1R-targeted therapies, antibody-based GLP-1R drugs show significant clinical potential. To overcome challenges in expressing and obtaining the natural conformation of the seven-transmembrane GLP-1R, ACROBiosystems has developed a full-length GLP-1R protein via "FLAG". Expressed in the HEK293 system and validated through binding with GLP-1R agonists, this protein aids in developing GLP-1R-targeting antibody drugs.

Reference:

1. Wu F, Yang L, Hang K, et al. Full-length human GLP-1 receptor structure without orthosteric ligands[J]. Nature communications, 2020, 11(1): 1272. https://doi.org/10.1038/s41467-020-14934-5

2. Tan Q, Akindehin S E, Orsso C E, et al. Recent advances in incretin-based pharmacotherapies for the treatment of obesity and diabetes[J]. Frontiers in Endocrinology, 2022, 13: 838410. https://doi.org/10.3389/fendo.2022.838410

3. Li C, Yang M, Wang X, et al. Glutazumab, a novel long-lasting GLP-1/anti-GLP-1R antibody fusion protein, exerts anti-diabetic effects through targeting dual receptor binding sites[J]. Biochemical Pharmacology, 2018, 150: 46-53. https://doi.org/10.1016/j.bcp.2018.01.029

4. Pan H, Su Y, **e Y, et al. Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects[J]. Artificial cells, nanomedicine, and Biotechnology, 2020, 48(1): 854-866. https://doi.org/10.1080/21691401.2020.1770268

5. Liu Q, Garg P, Hasdemir B, et al. Functional GLP-1R antibodies identified from a synthetic GPCR-focused library demonstrate potent blood glucose control[C]//MAbs. Taylor & Francis, 2021, 13(1): 1893425. https://doi.org/10.1080/19420862.2021.1893425