A CD25-biased Interleukin-2 for Autoimmune Therapy Engineered Via a Semi-synthetic Organism

Overview

Journal Commun Med (Lond)

Publisher Nature Portfolio

Specialty General Medicine

Date 2024 Mar 27

PMID 38532017

Authors

Jerod L Ptacin

Lina Ma

Carolina E Caffaro

Nicole V Acuff

Kristine Germar

Peter Severy

Yanyan Qu

Jose-Luis Vela

Xinming Cai

Kristine M San Jose

Hans R Aerni

David B Chen

Ean Esche

Taylor K Ismaili

Rob Herman

Yelena Pavlova

Michael J Pena

Jasmine Nguyen

Lilia K Koriazova

Laura K Shawver

Ingrid B Joseph

Jill Mooney

Mark Peakman

Marcos E Milla

Affiliations

Soon will be listed here.

Abstract

Background: Natural cytokines are poorly suited as therapeutics for systemic administration due to suboptimal pharmacological and pharmacokinetic (PK) properties. Recombinant human interleukin-2 (rhIL-2) has shown promise for treatment of autoimmune (AI) disorders yet exhibits short systemic half-life and opposing immune responses that negate an appropriate therapeutic index.

Methods: A semi-synthetic microbial technology platform was used to engineer a site-specifically pegylated form of rhIL-2 with enhanced PK, specificity for induction of immune-suppressive regulatory CD4 + T cells (Tregs), and reduced stimulation of off-target effector T and NK cells. A library of rhIL-2 molecules was constructed with single site-specific, biorthogonal chemistry-compatible non-canonical amino acids installed near the interface where IL-2 engages its cognate receptor βγ (IL-2Rβγ) signaling complex. Biorthogonal site-specific pegylation and functional screening identified variants that retained engagement of the IL-2Rα chain with attenuated potency at the IL-2Rβγ complex.

Results: Phenotypic screening in mouse identifies SAR444336 (SAR'336; formerly known as THOR-809), rhIL-2 pegylated at H16, as a potential development candidate that specifically expands peripheral CD4+ Tregs with upregulation of markers that correlate with their suppressive function including FoxP3, ICOS and Helios, yet minimally expands CD8 + T or NK cells. In non-human primate, administration of SAR'336 also induces dose-dependent expansion of Tregs and upregulated suppressive markers without significant expansion of CD8 + T or NK cells. SAR'336 administration reduces inflammation in a delayed-type hypersensitivity mouse model, potently suppressing CD4+ and CD8 + T cell proliferation.

Conclusion: SAR'336 is a specific Treg activator, supporting its further development for the treatment of AI diseases.

Citing Articles

The IL-2 SYNTHORIN molecule promotes functionally adapted Tregs in a preclinical model of type 1 diabetes.

Alvarez F, Acuff N, La Muraglia 2nd G, Sabri N, Milla M, Mooney J JCI Insight. 2024; 9(24).

PMID: 39704171 PMC: 11665582. DOI: 10.1172/jci.insight.182064.

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