Atrosab and Atrosimab are antibody-based drug candidates that specifically target the pro-inflammatory tumor necrosis factor receptor 1 (TNF-R1), thereby blocking its activation by TNF-alpha without interacting with the TNF receptor 2 (TNF-R2).
TNF-R2 is known to play an important role in the defense of viral and bacterial infections, therefore compounds that do not interfere with its function are expected to have a significantly improved safety profile compared to other TNF antagonists, especially with respect to the occurrence of neurological disorders and opportunistic infections.
With the TNF-alpha pathway being involved in the progression of chronic liver diseases leading to fibrosis, a therapeutic antibody approach could represent a valuable strategy for the prevention or treatment of diseases like non-alcoholic steatohepatitis (NASH).
A full-length humanized antibody, has been shown to be effective in blocking TNF-R1 in a NASH mouse model, leading to a selective reduction in key disease parameters including reduced fibrosis and apoptosis.
Preclinical proof of concept has also been demonstrated in animal models of rheumatoid arthritis¹ and multiple sclerosis². Further possible indications for Atrosab include psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, inflammatory bowel disease, pancreatitis and Alzheimer’s.
Atrosimab is the next generation derivative from Atrosab³. It has been affinity matured and is expressed as a monovalent antibody format lacking the hinge region and the CH1 domain. The optimization process resulted in several favorable characteristics compared to Atrosab including:
- 3.6x stronger inhibition of TNF-R1 activation
- 5x stronger inhibition of TNF-alpha induced cell death
- 6x stronger inhibition of TNF-alpha mediated release of the pro-inflammatory cytokines IL-6 and IL-8.
Additionally, Atrosimab has been designed to feature a longer half-life than standard Fab and scFv fragments.
Atrosimab is currently the subject of early preclinical studies for the treatment of NASH and other immune mediated inflammatory diseases.
- Abe Y et al. Anti-Inflammatory Effects of a Novel TNFR1-Selective Antagonistic TNF Mutant on Established Murine Collagen-Induced Arthritis. Adv Exp Med
- Williams et al. Antibody-Mediated Inhibition of TNFR1 Attenuates Disease in a Mouse Model of Multiple Sclerosis. PLoS One. 2014;9:e90117.
- Richer F et al. Improved Monovalent TNF Receptor 1-Selective Inhibitor with Novel Heterodimerizing Fc. mAbs. 2019;11:653-665.