Structural epitope mapping for precision medicine

Anna-Luisa Volk, PhD student and first author of the study
To allow for precision medicine the genome of patients is sequenced to identify possible variations of the target gene. These are compared to the known epitopes of the therapeutics in question in order to stratify patients into relevant treatment groups.

The term precision medicine describes the idea of providing effective treatment based on a patient´s molecular make up.

Eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). However, eculizumab is a very expensive drug, and the treatment is not efficient for all patients.

In a recent publication in Nature Scientific Reports researchers from the Human Protein Atlas use a structural epitope mapping strategy based on bacterial surface display, flow cytometric sorting and validation via haemolytic activity testing, to identify six residues essential for binding of the antibody eculizumab to the complement component 5 (C5).

Anna-Luisa Volk is a PhD student in the group of Johan Rockberg and the first author of the paper.

– My undergrad degree is from Bielefeld in Germany and I came to Sweden as an exchange student, and during that time I did a short project in Johan´s group. When it was time to do my undergraduate thesis I wanted to return to the group, so I contacted Johan. So, I came back, and when I was offered a position as a PhD student, I decided to stay, Anna-Luisa Volk says.

This was five years ago, and Anna-Luisa is now almost ready to defend her thesis, in which this study will be a big part.

– This project has been almost like my baby, I have been involved in all the steps. It has been a lot of work, as always much more than can be seen in the publication.

It was previously believed that the eculizumab-epitope on C5 was linear, so when Anna-Luisa and her colleagues found that the critical residues were shattered all over the linear sequence, they were puzzled.

– The residues that we identified as important looked just randomly distributed, but when we looked at the C5 protein in its 3D structure, we saw that they now were situated next to each other, we were so happy, Anna-Luisa explains.

In addition to showing six residues on the complement protein C5 that are essential for the binding and function of the therapeutic antibody eculizumab the group also suggest that other means of treatment should be considered for individuals carrying mutations in these positions.

The researchers show that the C5 complement inhibitor OmCI binds at a site distinct from eculizumab. Considering that OmCI was earlier reported as a possible therapeutic with low immunogenicity and is currently undergoing clinical trial, and given the results presented in this report, OmCI could represent an alternative future treatment strategy for patients responding poorly to eculizumab due to a missense mutation in eculizumab´s epitope on C5.

– The methods we have developed for epitope mapping and precision medicine should be applicable to several other diseases and therapeutics, Anna-Luisa Volk concludes.

Read the whole paper here >>

Frida Henningson Johnson