Week 4, January 2025: Novel Antibodies to Treat Obesity
Biointron2025-02-01Read time: 4 mins
This morning, Helicore Biopharma emerged from stealth with $65M in Series A funding. They are focused on the discovery and development of first-in-class glucose-dependent insulinotropic peptide (GIP) antagonists, with their most advanced asset, HCR-188, being a clinical stage monoclonal antibody (mAb) designed to bind GIP. The company’s portfolio includes GIP antibody conjugates, including GLP-1 and other combinations, designed to address specific obesity subpopulations. Individuals carrying genetic loss-of-function mutations in either GIP or GIPR are protected from obesity and exhibit lean phenotypes thought to arise from diminished GIP/GIPR-mediated triglyceride uptake in adipocytes (fat cells). By antagonizing GIP in the periphery and blocking transit to the central nervous system, Helicore’s compounds may uniquely prevent GIP signaling in the brain, potentially restoring leptin sensitivity that may support increased satiety as well as reduced consumption and fat deposition.
Meanwhile, iBio, Inc., an AI-driven innovator of precision antibody immunotherapies, in collaboration with AstralBio, announced this month the development of an antibody that inhibits the function of Activin E, a promising therapeutic target for cardiometabolic disorders and obesity. Individuals with a protective loss-of-function (pLOF) mutation in the INHBE gene have a healthier cardiometabolic profile, including less abdominal fat, lower triglycerides, and lower risk of type 2 diabetes and cardiovascular disease. While targeting Activin E poses technical challenges for antibody discovery due to its difficulty to produce outside the human body, iBio identified five critical epitope regions on the Activin E protein by developing synthetic epitopes replicating these regions.
Image credit: iBio, Inc.
Another target for obesity is ActRIIA. Laekna has a clinical collaboration with Eli Lilly and Company to accelerate the development of LAE102, a novel ActRIIA mAb as a novel treatment for obesity. ActRIIA is a receptor that has been shown to play a critical role in muscle regeneration and lipid metabolism. LAE102 has been shown to both increase lean mass and decrease fat mass in pre-clinical models. If successful, LAE102 could, in combination with a GLP1R agonist, further reduce fat mass and significantly regain the lean mass loss induced by GLP1R agonist. This positions LAE102 as a promising complementary drug candidate for achieving quality weight control. Blocking the Activin-ActRII pathway could promote muscle regeneration and decrease fat mass.
A few months ago, Confo Therapeutics also raised $60 million in Series B financing to focus on agonistic GPCR antibodies. The proceeds are being used to advance two wholly owned programs through Phase 1 and two additional programs to IND approval, including molecules targeting GPR75 for obesity. G protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in the body. They play a key role in a broad range of biological processes by binding to a wide variety of signaling molecules, yet they share a common architecture. GPCRs are comprised of seven transmembrane (TM) helices that span the cell membrane and intervening loops that are presented towards either the extracellular (EC) or intracellular (IC) environments. Agonists bind to GPCRs at an EC-facing binding pocket and initiate conformational changes that are propagated to the IC loops. This subsequently triggers downstream signaling via G-proteins or G-protein-independent pathways.
Image credit: Confo Therapeutics
These novel antibodies therapeutics are an exciting advancement towards the treatment of obesity. According to the Centers for Disease Control and Prevention, about 2 in 5 adults in the United States have obesity. Overweight and obesity can cause long-lasting inflammation and higher than normal levels of insulin, insulin-like growth factor, and sex hormones. These changes may lead to cancer. The risk of cancer increases with the more excess weight a person gains and the longer a person is overweight.