OBJECTIVE:
Biologic drugs, such as the anti TNF-α antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Despite this, concerns remain over the lack of efficacy in a sizable proportion of patients and the potential for systemic side effects such as infection. The design of improved biologic pro-drugs specifically targeted to the site of inflammation has the potential to alleviate current concerns surrounding biologic anti-cytokine therapies.
METHODS:
Activatable dual variable domain (aDVD) antibodies were designed and constructed to target the intercellular adhesion molecule (ICAM)1, up-regulated at sites of inflammation, and the anti-TNF-&... More
OBJECTIVE:
Biologic drugs, such as the anti TNF-α antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Despite this, concerns remain over the lack of efficacy in a sizable proportion of patients and the potential for systemic side effects such as infection. The design of improved biologic pro-drugs specifically targeted to the site of inflammation has the potential to alleviate current concerns surrounding biologic anti-cytokine therapies.
METHODS:
Activatable dual variable domain (aDVD) antibodies were designed and constructed to target the intercellular adhesion molecule (ICAM)1, up-regulated at sites of inflammation, and the anti-TNF-α antibodies (adalimumab and infliximab). These bispecific molecules include one arm targeting the outer domain of ICAM1 and the other the therapeutic domain of anti-TNF-α, both arms were linked to a Matrix Metalloproteinase cleavable linkers. Constructs were tested both for their ability bind and neutralize targets in vitro and ex-vivo.
RESULTS:
Intact aDVD constructs demonstrated significantly reduced binding and anti TNF-α activity in the pro-drug formulation compared to parent antibodies. Physiological concentrations of MMP enzyme, and human synovial fluid were capable of cleaving the external domain of the antibody revealing a fully active molecule. Activated antibodies retained the same binding and anti-TNF-α inhibitory capacities as parent molecules.
CONCLUSION:
A biological pro-drug with enhanced specificity for inflammatory sites (synovium) and reduced specificity to off-target TNF-α is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of RA and other inflammatory diseases. This article is protected by copyright. All rights reserved.
