The release of the HELM Editor by the Pistoia Alliance in 2013 inspired a team at Roche and quattro research to use this technology for the registration of antibodies engineered at Roche’s research sites. The first version was released to the open source community in 2015, but work continued, and a comprehensive set of enhancements has been included in this new release.
In former years, antibodies have followed nature’s standard format: A set of 2 identical light and heavy chains forms an antibody. In current research projects increasingly complex formats are designed by the scientists. These formats pose a challenge to fully describe their chemical structure.
While the HELM Editor provides the power to efficiently build and describe all kind of biologicals, its canvas doesn’t really scale with large molecules like antibodies. Especially if novel antibodies do not follow nature’s standard and the localization of the Cys-Cys bonds within and between domains and chains isn’t straightforward.
To tackle this challenge, the team led by Stefan Klostermann (Roche Innovation Center Munich) developed the HELM Antibody Editor (HAbE). Like the HELM Editor, that is essentially based on a monomer library, HAbE employs a domain library to describe the functional building blocks of antibodies and other conjugated proteins. Based on this library, HAbE decomposes raw protein sequences of even complex antibody formats into their domains and fully analyzes and annotates them. This process is supported by a mutation library that enables the identification of known mutations in standard domains.
Using an integrated auto-connector algorithm, HAbE also aims to automatically assemble the complete drug molecule into its complete final structure by finding the correct Cys-Cys bonds. The underlying rules are laid down in a flexible, user customizable syntax describing advanced formats and functional modules like scFV/ scFab. The GUI enables further editing of the molecule to close Cys-Cys bonds not yet covered by the rule set.
The HAbE2 release adds major new functionality to multiple enhancements under the surface. Now, automated reactions can be carried out, including: Domain Protease Reactions, Sortase Coupling and Biotinylation. There is also an Antibody Drug Conjugate Designer which allows the scientist to define statistical binding ratios defined for the attachment of chemical molecules to the antibody and a Monomer Designer, so new monomers can be designed, used and stored.
These enhancements to one of the most sophisticated applications in the HELM family further cements HELM as the industry standard for the description of biological macromolecules.