PORTEFEUILLE

Rare diseases that arise from mutations or partial deletion of key metabolic enzymes often require life-long enzyme replacement therapy (ERT) to regain physiological function. As patients with such diseases have failed to undergo immunological tolerance towards the key enzyme during development, administration of the enzyme primes the immune system to mount humoral immune responses towards the therapeutic, thus rendering treatment inefficacious and potentially dangerous. Although our approach will apply to many ERTs and thus many rare diseases, we have selected antigen-specific tolerance towards the enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase, galsulfase), a deficiency in which causes mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome), as a starting point. Arylsulfatase is a highly glycosylated protein, and to consider an example of a nonglycosylated protein, we also considered L-asparaginase, which is used to treat acute lymphoblastic leukemia, also a rare disease occurring mostly in children, and also highly immunogenic. The goal of the project is to produce a variant of Arylsulfatase B and asparaginase, which induces tolerance towards the recombinant, produced Arylsulfatse B and asparaginase. The approach chosen to achieve tolerance is to create an erythrocyte-binding variant of Arylsulfatase B and asparaginase. Erythrocyte binding technology has been developed in the lab and was shown do induce tolerance towards foreign antigen by deleting CD4+ and CD8+ T-cells in an antigen specific fashion. In work recently published, this was shown to induce immunological tolerance to the enzyme asparaginase, used as the non-glycosylated model.

Although working in the specific example of MPS VI, the technology being developed applies to many rare diseases treated protein replacement therapy, including all lysosomal storage diseases, hemophilia A and B, and other examples as well.

The project proceeded much faster with the non-glycosylated example, asparaginase, which was technically easier to functionalized with erythrocyte-binding domains. We demonstrated that it was possible to provide a single tolerogenic dose of the erythrocyte-binding enzyme and then cross to treatment with the wild-type enzyme with reduced immunogenicity compared to treatment only with wild-type of 1000- to 10000-fold. This immunological tolerance was long-lived, allowing repeated dosing without re-tolerization.

Prof. Hubbell’s laboratory, the Laboratory for Regenerative Medicine and Pharmacobiology at EPFL, has spun out a company in the field of immunological tolerance, Anokion SA, located in EPFL’s Science Park. The Anokion team collaborates closely with the team carrying out the project funded by Geber Rüf Stiftung, providing a pathway toward clinical development of the technology. Anokion has closed a CHF 33 million Series A financing to develop technology to prevent immunity to protein drugs, such as those used in enzyme replacement therapies as being explored by Prof. Hubbell’s laboratory with the funding of Gebert Rüf Stiftung.

Lorentz, K.M., Kontos, S., Diaceri, G., Henry, H. & Hubbell, J.A. Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase. Science Advances 1 (2015);
Kontos, S., Grimm, A.J. & Hubbell, J.A. Engineering antigen-specific immunological tolerance. Curr Opin Immunol 35, 80-88 (2015);
Kontos, S., Kourtis, I.C., Dane, K.Y. & Hubbell, J.A. Engineering antigens for in situ erythrocyte binding induces T-cell deletion. Proc Natl Acad Sci U S A 110, E60-68 (2013).

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