TopSpec – Next generation precision antibody profiling – from science fiction to reality

A major and growing challenge in the EU health system is the cost of drugs and targeted therapies. Reducing time taken to develop novel therapies will reduce costs to the health system. To address this grand challenge, it is imperative to better understand how the human organism defends itself against diseases. The biggest mystery is the human immune system; and, understanding this ultimately requires knowledge of the sequence repertoire of human antibodies and their respective antigens.

The purpose of the TopSpec project is to be the first in the world aiming to solve this challenge, opening up opportunities in medical research and drug development that are today only dreamt about. We will create a breakthrough technology that will revolutionize academic, clinical and industrial proteomics and dramatically advance the development of new generation antibody- and protein-based therapeutics.

Antibodies are the most sophisticated line of natural defence against disease. Knowing which antibodies are produced in response to a given disease enables us not only to better understand the disease cause but also to provide next-generation cures in form of personalized therapeutic antibodies. The limiting factor for this to truly be achieved is to find a way to sequence large molecules in the gas phase, and this represents a formidable challenge.

The TopSpec project will develop a ground-breaking TOP-down tandem mass SPECtrometry (MS/MS) platform. One major innovation is the novel radical gas-phase ion-electron and ion-atom reactions. Another “killer innovation” is the method to greatly simplify MS/MS spectra of large molecules by adding another dimension of separation – collisional cross-sections of fragment ions, using two parallel innovative approaches. TopSpec will pioneer the deconvolution of massively overlapping isotopic clusters, solving one of the greatest challenges in top-down MS/MS of large molecules, the analysis of protein variants (proteoforms ).

In this project, key experts in radical-assisted sequencing of proteins team up with the best developers in ultrahigh-resolution MS and MS/MS, as well as top European scientists in online protein separation and MS data processing. Achieving the seemingly impossible, we plan to create, test and validate a seamless platform capitalizing on our ground-breaking innovations, enable scientists from academia and industry to explore the antibody repertoire, enhancing our ability to explore new effective cures for major global diseases.

The first TopSpec progress meeting was hosted by Thermo Fisher during two intense meeting days in September 2019 at the Thermo Fisher Site for Advanced Mass Spectrometry Product Development & Manufacturing in Bremen, Germany.

This project receives funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 829157