학술논문
A CD25-biased interleukin-2 for autoimmune therapy engineered via a semi-synthetic organism
Document Type
article
Author
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
Source
Communications Medicine, Vol 4, Iss 1, Pp 1-16 (2024)
Subject
Language
English
ISSN
2730-664X
Abstract
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.