Article No 413
23 January 2021
Very few people have heard of BB5.1 nor even c.3643C>G; p. Arg1215Gly. Yet both are of huge significance to aHUS patients.
BB5.1 was the name given to first ever monoclonal antibody ( mAb) that blocked the fifth protein in complement from doing its job. It was designed by the Frei Group from Basel in Switzerland in 1987 to block C5 and its part in the membrane attack complex in a Complement response to antigens.
It was designed to do it in mice only. An abstract briefly describing the group’s work can read here.
Its significance was that it provided a “proof of concept” that an antibody could be used for immune disease control, even for humans.
And that is what happened. Leonard Bell and a few others worked on designing a human version of it by modifying another mouse mAb, 5G1.1. In 1996 eculizumab was created just four years after Alexion was founded and nine years after the creation of BB5.1.
Recently a complement laboratory in Wales revisited BB5.1 to find out why it had worked and why it may or may not work across species to learn more use of mAbs in developing complement therapies. It’s findings and the way it went about finding them is described in an article by the Zelek Group wich can be read here.
Much of it was about discovering the epitope i.e. the place were something attaches to some part of complement. By its nature as pure biological research into the microscopic world of complement by scientists it is a difficult read for the lay reader.
Dr Paul Warwicker
At the same time as Leonard Bell was working in his laborarory in the USA, a young post graduate student, Paul Warwicker, was setting out under the supervision of Dr Tim Goodship in Newcastle upon Tyne University Hospital to study a family at the opposite end of England. That family had experienced aHUS among its members over several generations .
With the help from clinicians from the family’s local hospital, as well as family members Paul began piecing together family trees and recording who had experienced aHUS. Many had died from it. There were three families sharing this relationship with aHUS but their common ancestor could not be found.
Once the family trees had been mapped, the research group set about screening for a genetic reason in chromosomes that it was suspicious about. Family members were asked to volunteer to have a genetic test. Using the geneticist skills and rearch facilities of Judith Goodship, Tim’s wife, a mutation was found in Complement Factor H which was judged to be the cause of the family’s lack of control of complement during an aHUS onset. It was described as c.3643C>G; p. Arg1215Gly.
It shows the location of the mutation and what had happened. In this case the amino acid Arginine had been replaced by another , glycine.Seemingly small and insignificant but it means the person now becomes susceptible to aHUS.
c.3643C>G; p. Arg1215Gly. The first genetic reason for unregulated Complement had been found, eventually hundreds of such genetic reasons would be discovered.
For those onsetting with aHUS in 1996 because of an uncontrolled membrane attack complex in their complement, there was something in a laboraratory in Connecticet which could have treated them by blocking their C5.. That connection would take a few more years to be made.
In the Cardiff Group’s experiments other anti-C5 mAbs were used. Eculizumab, its own mAb created in house by the laboratory, and Crovalimab which had been provided by Hoffmaan-Roche. Unlike eculizumab, which did not work across species, crovalimab blocked mice C5 as well as humans.
So is this another connection and is crovalimab of interest to those with aHUS. Maybe something to be explored.