A Split, Conditionally Active Mimetic of IL-2 Reduces the Toxicity of Systemic Cytokine Therapy

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2022 Nov 1

PMID 36316485

Authors

Alfredo Quijano-Rubio

Aladdin M Bhuiyan

Huilin Yang

Isabel Leung

Elisa Bello

Lestat R Ali

Kevin Zhangxu

Jilliane Perkins

Jung-Ho Chun

WenTao Wang

Marc J Lajoie

Rashmi Ravichandran

Yun-Huai Kuo

Stephanie K Dougan

Stanley R Riddell

Jamie B Spangler

Michael Dougan

Daniel-Adriano Silva

David Baker

Affiliations

Soon will be listed here.

Abstract

The therapeutic potential of recombinant cytokines has been limited by the severe side effects of systemic administration. We describe a strategy to reduce the dose-limiting toxicities of monomeric cytokines by designing two components that require colocalization for activity and that can be independently targeted to restrict activity to cells expressing two surface markers. We demonstrate the approach with a previously designed mimetic of cytokines interleukin-2 and interleukin-15-Neoleukin-2/15 (Neo-2/15)-both for trans-activating immune cells surrounding targeted tumor cells and for cis-activating directly targeted immune cells. In trans-activation mode, tumor antigen targeting of the two components enhanced antitumor activity and attenuated toxicity compared with systemic treatment in syngeneic mouse melanoma models. In cis-activation mode, immune cell targeting of the two components selectively expanded CD8 T cells in a syngeneic mouse melanoma model and promoted chimeric antigen receptor T cell activation in a lymphoma xenograft model, enhancing antitumor efficacy in both cases.

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