Computer aided de novo design of nanobodies

Introduction

Antibodies have become major players in the pharmaceutical industry and were valued at 0.16 billion US dollars in 2023. Traditionally, antibodies are obtained after immunization of different animals and then produced in relevant cells for use in research, diagnostics, and therapy.

Background

In recent years, there has been a growing public opinion in Europe to ban the use of animals for biomedical research. Therefore, there is increasing pressure to move from animal-produced antibodies to designing and producing them in vitro.

Advantages of Antibody Engineering

Antibody engineering has another important advantage: the possibility of targeting a precise epitope rather than relying on serendipity, as is the case when injecting an animal with an antigen.

Recent Advances

In recent years, there have been significant advances in protein design based on the use of artificial intelligence and precise force fields. Despite this progress, the majority of companies that work on antibody design combine rational engineering with massive proprietary screening methods. So far, there are no reported cases of fully de novo design of an antibody with nanomolar (nM) affinity against a defined epitope.

Case Study

Using an interleukin receptor as a case study, we have shown that we can indeed fully design de novo a nanobody that recognizes the target with nM affinity, using our proprietary protein design software FoldX and ModelX. Experts consulted to date indicate that the results obtained so far are “truly impressive,” prompting us to continue validating and optimizing our process.

Objectives

Our proposal has two main objectives:

1. To fully automate our pipeline that involves:

   • Epitope selection
   • Antibody framework selection
   • Docking
   • Backbone move
   • Side chain search

2. To demonstrate that our optimized pipeline can design fully de novo nanobodies against a defined target in a fast and cost-effective way.

Conclusion

Success in both objectives will open the way to fully de novo antibodies with desired properties and position ourselves in the search for funding and spin-off incorporation.