Ravulizumab is not quite eculizumab

Ravulizumab is becoming a treatment of choice for aHUS in countries where access is funded. Though eculizumab will still have a part to play in aHUS treatment.

So is Ravulizumab is not just eculizumab with a different name ?
Ravulizumab is essentially eculizumab. It binds to C5 as eculizumab does. It stops the self damaging effects of complement in an aHUS onset.

Yes it has the same biological structure except for some small bits.

Some small bits?

Yes just some small bits. Four amino acids in eculizumab have been altered by Alexion to create Ravulizumab.

Why do four amino acids make a difference?
Well each of them are at a point in the structure where, if altered slightly , FcRN can bind with Ravulizumab.

What is a FcRN and why does it have to bind to Ravulizumab, if it did not attach to eculizumab?

FcRN is a “neonatal fragment crystallizable receptor”. You asked! It is one of a family of proteins in the blood which helps the immune system do its job. Apart from destroying foreign bodies invading the blood, it is also something that helps maternal immunity to be passed to children through the placenta, and in milk after birth. FcRN also helps antibodies to last longer in a recycling process

OK one thing at a time. It helps recycle Ravulizumab because that is an antibody , a monoclonal antibody.

Yes a “mab” is an antibody. I has a Y shaped appearance. A Ravulizumab, like an eculizumab, is designed to stick to a part of the Complement component C5 , which is the starting point of the “membrane attack complex” which causes damage to aHUS patients . In time once those mabs have done their job they begin to degrade and disappear all together from the body.

So how does Ravulizumab take longer to disappear?

Well once Ravulizumab sticks to C5 , the FcRN sticks to C5 and when the conditions are right at endothelial cell level something happens to the antibody. At that point, unlike eculizumab which disappears with C5 , when C5 begins to break up, Ravulizumab is helped by FcRN to recycle itself in something called the endosome , don’t ask, and go back into circulation and attach to another C5. This cycle continues until FcRN can no longer help with the recycling and so new Ravulizumab is needed.

At eight weeks?

Yes , or four weeks for children who have lower doses of Ravulizumab. It is the half life point where a trough is reached to prevent breakthrough thrombotic microangiopathy and when more Ravulizumab is needed.

OK the small differences have made a big difference in the quaity of life for some aHUS patients as infusions are less frequent. But you said that FCRN helps transfer maternal immunity to the child what effect will Ravulizumab have on the unborn or newly born child?

Well this has concerned clinicians as there is little data from the Ravulizumab trial about it. Not getting pregnant was a condition of being included in a trial as it was for eculizumab. Although there were eight patients in the ravulizumab trial whose aHUS was triggered by pregnancy.

So is Ravulizumab indicated or not for aHUS in pregnancy?

Like with eculizumab, evidence will emerge in time from real life experiences. Firstly from PNH patients and then stories will be heard from aHUS patients. Some are now known to have been treated with Ravulizumab during pregnacy. Nothing detrimental has been reported. In a recent webinar about aHUS pregnancy Prof. Fadi Fakhouri said that he would not advise switching back to eculizumab if a Ravulizumab treated patient found she was pregnant.

So it is a case of wait and see?

Guess so. At some point more definite opinion will arise on Ravulizumab and pregnancy.

If any viewer of this article has any experience of Ravulizumab in pregnancy aHUS alliance global action would like to hear from them.

Article No. 465

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