New insights into antioxidant effects on monoclonal antibodies

One potential source of modification is the antioxidant enzyme thioredoxin (Trx) which catalyses the reduction of disulphide bonds. Increased Trx levels have been associated with more severe symptoms in many of the diseases that mAbs are used to treat, however, the precise effect of this enzyme on mAb function was poorly understood until now.

Thioredoxin affects structure and function

A team of NIBSC scientists and collaborators from The University of Manchester conducted a series of in vitro experiments to characterise the effect of Trx on 6 clinically important mAbs: infliximab, adalimumab, rituximab, trastuzumab, ofatumumab and cetuximab.  

The results confirmed that Trx is capable of reducing all 6 mAbs tested and in general this enhanced their ability to bind to their target antigen. However, the downstream consequence of this varied depending on their mechanism of action.

For example, Trx reduction increased the neutralisation potency of the anti-TNF mAbs adalimumab and infliximab but decreased the anti-proliferation activity of the cancer drug trastuzumab.

Interestingly, reduction by Trx also inhibited the ability of all 6 mAbs to stimulate the immune system independently of its effect on antigen binding.

It was suggested that these alterations to mAb function occur because the molecules are likely to be more flexible following exposure to Trx, which in turn alters how they interact with their cellular targets.

However, this study reveals that the drugs themselves could become modified in patients potentially making them inactive or appear more foreign, meaning the body will destroy them. If we know how drugs become modified, we can design new versions that are resistant to this meaning more patients will benefit from the effect of these remarkable therapies.”

More information about our research into mAbs can be found on our science and research pages.