Creative Biolabs has been entirely devoted to the development of bispecific antibody (BsAb) treatments and has received widespread recognition for its exceptional products and services. We deliver high-grade BsAb for osteology applications based on our well-established BsAb production infrastructure.
Bone is a living, growing tissue that protects soft organs and supports the body. A person may have a condition or disease that affects bone flexibility and strength, such as osteoporosis, osteogenesis imperfecta, osteonecrosis, osteomalacia, etc. Bone remodeling is a continual process in which the skeleton is renewed by highly regulated osteoblast-mediated bone production and osteoclast-mediated bone resorption. Tumors in the bones can affect bone remodeling. Wnt signaling is closely related to bone mass management, playing an important role in driving osteoblastogenesis and bone formation throughout growth, bone homeostasis, and fracture repair.
The tumor necrosis factor superfamily cytokine receptor activator of nuclear factor kappa-B ligand (RANKL), generated by osteoblasts, is an important regulator of bone remodeling. RANKL enhances the production and activity of osteoclasts by binding to its cell surface receptor (RANK) on osteoclasts and their progenitors, resulting in increased bone resorption, all of which stimulate bone tumor development. RANKL is also thought to be a chemotactic factor that influences tumor cell metastatic migration into bones.
Fig.1 RANK signaling pathways.1
In a multitude of domains, including osteology, BsAbs are interesting next-generation therapeutics. Ablynx has developed a creative BsAb comprising of two anti-RANKL single-domain antibodies (sdAbs) and an anti-HAS sdAb. It was indicated to be an effective RANKL inhibitor with extended half-life and favorable tolerance for the treatment of bone-resorptive diseases characterized by low BMD and increased risk of fracture, such as cancer-related bone diseases, osteoporosis, and other disorders². According to studies, bi-specific Wnt mimetics based on Frizzled and low-density lipoprotein receptor-related proteins generate rapid and robust bone building effects and repair BMD deficiency and bone abnormalities in a variety of disease models such as osteoporosis, aging, and long bone fracture³. A first-in-class BsAb with combined inhibition of sclerostin and Wnt antagonist has been shown to lead to synergistic bone growth in mice and nonhuman primates4. Furthermore, by focusing on different aspects of fracture healing, the BsAb outperforms monotherapies in terms of bone repair activity.
| Paper Title | A bispecific antibody binding to RANKL and osteonectin with enhanced localization to the bone |
| Journal | Molecular Pharmaceutics |
| Published | 2017 |
| Abstract | Some anti-RANKL antibodies may be useful in treating patients with bone degeneration. However, certain patients with osteoporosis or confined primary bone malignancies, as well as many patients with bone-metastatic cancer, do not respond well to these antibodies. The anti-RANKL antibody was restructured by fusing it with single-chain variable portions of an antibody to osteonectin (ON), which is abundant in osseous tissues. When given to mice, the BsAb was found to be more concentrated near the endosteum of the bone, where ON is plentiful. By conjugating anti-RANKL with an ON-targeting moiety, researchers observed that a larger proportion of the therapeutic effector can be dispersed in bone. |
| Result |
Researchers constructed a tetravalent BsAb based on ON and an anti-RANKL antibody that had high binding characteristics to RANKL when binding to human and mouse ON. Another study found that the BsAb prevents the production of osteoclasts. Furthermore, the results show that the BsAb is cleared much faster in the circulation than anti-RANKL antibody and is present at much higher levels than anti-RANKL antibody in bone tissues, indicating that ON can serve as a target for increased bone targeting of therapeutic agents.
Fig.2 Inhibition of osteoclastogenesis by Dmab-FvOn in vitro.5 |
Creative Biolabs provides suitable techniques for synthesizing BsAbs for specific scientific and/or clinical research applications based on customer needs. Creative Biolabs, which has extensive experience in BsAb design and production, is available to assist customers in developing BsAbs to inhibit or activate signaling pathways involved in osteoclast differentiation and activity.
References
1. Walsh, Matthew C, and Yongwon Choi. "Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond." Frontiers in immunology vol. 5 511. 20 Oct. 2014.
2. Schoen, Pieter, et al. "Anti-RANKL nanobody ALX-0141 shows sustained biomarker inhibition in a phase I study in healthy postmenopausal women." Bone Abstr 1 (2013).
3. Fowler, Tristan W., et al. "Development of selective bispecific Wnt mimetics for bone loss and repair." Nature Communications12.1 (2021): 3247.
4. Florio, Monica, et al. "A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair." Nature Communications 7.1 (2016): 11505.
5. Chen, Jou-Han et al. "Bispecific Antibody Binding to RANKL and Osteonectin with Enhanced Localization to the Bone." Molecular Pharmaceutics vol. 14,11 (2017): 4113-4120.
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