IDERT: Intelligent Deimmunization for Enzyme Replacement Therapies

Lysosomal storage diseases (LSDs) are rare inherited diseases caused by the deficiency of lysosomal enzymes, which cause the accumulation of substrates in the lysosome and ultimately lead to organ damage and premature death.

Since LSDs are caused by inherited mutations, they cannot be cured but can be treated using Enzyme Replacement Therapies (ERTs), which consist in restoring physiological enzymatic levels through the intravenous infusion of a recombinant version of the defective enzyme. Response to ERT is variable, because recombinant enzymes are less active than the human wildtype, are unstable in blood and are not properly absorbed by the cells. Moreover, repeated infusions usually trigger an immune response and the formation of anti-drug antibodies (ADAs), which limit the efficacy of ERTs and preclude long-term treatment for many patients.

Fabry Disease (FD) is the most common LSD. It is characterised by X-linked mutations in the gene encoding the alpha galactosidase (AGAL) enzyme, which cause irreversible damage to heart, vasculature, and kidney. Immune response is common, especially in males, who usually experience the most severe form since they have no enzyme activity. With the increasing number of FD patients due to better diagnosis, there is the pressing clinical need to improve ERT efficacy and reduce their immunogenicity.

Since the formation of anti-drug antibodies is initiated by T-cell recognition of peptides of antigen presenting cells, we propose to lower the immunogenicity of a recombinant enzyme by "recoding" known epitopes in the enzyme sequence, while preserving its catalytic function.

Here we will use Artificial Intelligence (AI) to design enzymes with a desired function but lacking known epitopes, a process called deimmunization, to deliver better therapies for FD patients. We will manufacture these enzymes (up to 200) using a mammalian cell line expression system, to ensure our ERTs have human-like biochemical properties, and then we will measure their catalytic activity in vitro and the immune reaction using patients' sera. Importantly, since AI has the potential to impact the life of millions of patients and their families, we will engage with patients through open meetings to show and explain the potential of this new technology in addressing an unmet clinical need.

Our project builds on the team's unique expertise in AI, biologics production and medicine and represents one of the largest ERT deimmunization study to date, with the potential to provide effective treatment options for FD and other LSD patients in the future.