Activin receptor type-2A

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THP-0319	Sotatercept	10ug	$298.00		Add to Cart Order
		100ug	$1,598.00		Add to Cart Order
		1mg	$3,998.00		Add to Cart Order

Activin receptor type 2A (ACVR2A) is a transmembrane serine/threonine kinase receptor of the transforming growth factor-beta (TGF-β) superfamily that mediates essential biological processes such as cellular proliferation, differentiation and inflammation. Upon ligand binding, ACVR2A forms a complex with type 1 receptors to phosphorylate downstream SMAD proteins, thereby initiating gene transcription. Dysregulated ACVR2A signaling contributes to pathological conditions, including excessive tissue remodeling, inflammation, and abnormal cell proliferation. As a result, ACVR2A has emerged as a promising drug target. Emerging therapeutic strategies focus on modulating ACVR2A activity to treat diseases such as anemia and osteoporosis, with sotatercept showing significant clinical potential.

NCBI Gene ID: 92

UniProtKB ID: P27037

Biological Functions of ACVR2A

ACVR2A serves as a key regulator of cell growth, tissue homeostasis and inflammation by transducing signals from activins and related ligands. It modulates hematopoiesis by influencing erythroid progenitor maturation and plays a critical role in maintaining skeletal integrity by balancing bone formation and resorption. In addition, ACVR2A signaling regulates immune responses and wound healing, underscoring its broad physiological relevance. Dysregulation of ACVR2A signaling is associated with anemia in chronic disease, reduced bone density, fibrosis and tumor progression, highlighting its potential as a therapeutic target.

Figure 1. ACVR1 Signaling. (Valer et al., 2019)

Therapeutic Approaches Targeting ACVR2A

Ligand Traps

Ligand traps are engineered proteins designed to sequester specific ligands, preventing their interaction with ACVR2A. Sotatercept is a fusion protein consisting of the extracellular domain of ACVR2A linked to the Fc portion of human IgG1. Sotatercept acts as a decoy receptor, binding to activins and GDFs, thereby restoring normal signaling in conditions of overactivation. This therapeutic strategy has shown promise in diseases characterized by dysregulated ACVR2A signaling.

Monoclonal Antibodies

Monoclonal antibodies targeting ACVR2A or its ligands represent another therapeutic approach. These antibodies block receptor-ligand interactions or inhibit receptor activation, reducing pathological signaling. While research in this area is ongoing, early studies suggest their potential in addressing fibrotic and inflammatory diseases.

Sotatercept: A Promising Therapeutic Protein

Sotatercept has emerged as a leading candidate for targeting ACVR2A-mediated pathways. By binding to activins and GDFs, sotatercept attenuates excessive activin signaling and restores normal tissue function.

• Applications in Anemia: Sotatercept has shown efficacy in the treatment of anemia in patients with beta-thalassemia and myelodysplastic syndromes by increasing erythropoiesis. It does this by counteracting the suppressive effects of activins on late-stage erythroid maturation, thereby improving hemoglobin levels and reducing the need for transfusions.
• Applications in Pulmonary Arterial Hypertension (PAH): Sotatercept is also being investigated for pulmonary arterial hypertension, a disease characterized by vascular remodeling and elevated pulmonary pressures. By modulating ACVR2A signaling, sotatercept reduces vascular remodeling and inflammation, improving pulmonary hemodynamics and exercise capacity.
• Potential in Bone Disorders: ACVR2A signaling affects the balance between bone formation and resorption. Sotatercept has demonstrated the ability to increase bone density and strength in preclinical studies, offering therapeutic potential for osteoporosis and related bone disorders.

Other Targets of Sotatercept

Sotatercept targets not only activin receptor type 2A (ACVR2A), but also other components of the TGF-β signaling pathway such as activin receptor type 1B (ACVR1B) and growth/differentiation factor 8 (GDF-8).

• Activin receptor type 1B (ACVR1B): ACVR1B is a type 1 receptor in the TGF-β superfamily that partners with type 2 receptors such as ACVR2A to mediate downstream signaling. ACVR1B is involved in various processes such as cell growth, apoptosis and differentiation. Overactivation of ACVR1B-related pathways can lead to pathologies such as fibrosis and cancer. By modulating the ligands that bind to ACVR1B, sotatercept helps restore balance in conditions of dysregulated signaling.
• Growth/Differentiation Factor 8 (GDF-8): Also known as myostatin, GDF-8 is a negative regulator of muscle growth and development. Excessive GDF-8 activity contributes to muscle wasting diseases. Sotatercept acts as a decoy receptor for GDF-8, reducing its bioavailability and promoting muscle growth. This mechanism positions sotatercept as a potential therapeutic for muscle wasting diseases and conditions requiring enhanced muscle regeneration.

Figure 2. Sotatercept's mechanism of action in hematological disorders. This illustration demystifies the molecular actors in sotatercept's mode of action within blood-related diseases. (Lan et al., 2023)

Clinical Implications and Challenges

While targeting ACVR2A with therapies such as sotatercept has shown great promise, challenges remain. The redundancy of ligands and receptors in the TGF-β superfamily complicates efforts to achieve receptor specificity. In addition, long-term modulation of ACVR2A signaling may result in off-target effects or unintended consequences on immune function and tissue homeostasis. Further research is needed to optimize the safety and efficacy of ACVR2A-targeted therapies, particularly in the setting of chronic disease.

Creative BioMart offers sotatercept targeting to ACVR2A, inquiry now or contact us for more details!

References

1. Cascino TM, Sahay S, Moles VM, McLaughlin VV. A new day has come: Sotatercept for the treatment of pulmonary arterial hypertension. The Journal of Heart and Lung Transplantation. 2025;44(1):1-10. doi:10.1056/NEJMoa2024277
2. Goh BC, Singhal V, Herrera AJ, et al. Activin receptor type 2A (Acvr2a) functions directly in osteoblasts as a negative regulator of bone mass. Journal of Biological Chemistry. 2017;292(33):13809-13822. doi:10.1074/jbc.M117.782128
3. Komrokji R, Garcia-Manero G, Ades L, et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018;5(2):e63-e72. doi:10.1016/S2352-3026(18)30002-4
4. Lan Z, Lv Z, Zuo W, Xiao Y. From bench to bedside: The promise of sotatercept in hematologic disorders. Biomedicine & Pharmacotherapy. 2023;165:115239. doi:10.1016/j.biopha.2023.115239
5. Tsuchida K, Nakatani M, Hitachi K, et al. Activin signaling as an emerging target for therapeutic interventions. Cell Communication and Signaling. 2009;7(1):15. doi:10.1186/1478-811X-7-15
6. Valer JA, Sanchez-de-Diego C, Pimenta-Lopes C, Rosa JL, Ventura F. ACVR1 function in health and disease. Cells. 2019;8(11):1366. doi:10.3390/cells8111366