Targeting highly attenuated IL-18 to PD-1 for enhanced anti-tumor activity

Sep 28, 2026

Uploaded by Rowan

Checkpoint inhibitors targeting the PD-1/PD-L1 axis have transformed cancer immunotherapy, but many patients show limited or no durable response. To improve efficacy, the study explores cytokine potentiation delivered to PD-1 as a way to combine checkpoint blockade with controlled activation. The work hypothesizes that a highly attenuated IL-18 variant targeted to PD-1 can activate PD-1+ T cells, counter exhaustion, and antagonize PD-1 while reducing toxicity.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Results

Attenuated IL-18 design and IL-18BP resistance

Tumor model efficacy and receptor/immune readouts

Effects on TIL composition after remission

Discussion

TYPE Original Research PUBLISHED 18 December 2025 DOI 10.3389/fimmu.2025.1718321 OPEN ACCESS EDITED BY Amorette Barber, Longwood University, United States REVIEWED BY Sudhir Kumar, Emory University, United States Claudia Cerella, Department of Cancer Research, Luxembourg *CORRESPONDENCE Brian Rabinovich [brabinovich@fusebiotx.com](brabinovich@fusebiotx.com)[ ](brabinovich@fusebiotx.com)Harald Kolmar [Harald.Kolmar@TU-Darmstadt.de](Harald.Kolmar@TU-Darmstadt.de) †These authors have contributed equally to this work and share ﬁrst authorship RECEIVED 03 October 2025 REVISED 28 November 2025 ACCEPTED 01 December 2025 PUBLISHED 18 December 2025 CITATION Zhou X, Geyer FK, Takimoto J, Kolmar H and Rabinovich B (2025) Targeting highly attenuated IL-18 to PD-1 for enhanced antitumor activity. Front. Immunol. 16:1718321 . doi: 10.3389/fimmu.2025.1718321 COPYRIGHT © 2025 Zhou, Geyer, Takimoto, Kolmar and Rabinovich. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Targeting highly attenuated IL-18 to PD-1 for enhanced anti-tumor activity Xueyuan Zhou 1†, Felix Klaus Geyer 2†, Jeffrey Takimoto 1, Harald Kolmar 2,3* and Brian Rabinovich 1* 1 Drug Discovery and Development, Fuse Biotherapeutics, Woburn, MA, United States, 2 Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Darmstadt, Germany, 3Centre for Synthetic Biology, Technical University of Darmstadt, Darmstadt, Germany Checkpoint inhibitors targeting the PD-1/PD-L1 axis have revolutionized cancer immunotherapy, yet response rates remain limited. To enhance efﬁcacy, nextgeneration approaches target T cell-activating cytokines to PD-1 via antibodies. The goal is simultaneous checkpoint blockade and cytokine potentiation but ﬁne-tuning cytokine activity such that checkpoint inhibition can be preserved with manageable toxicity has been a difﬁcult challenge. We hypothesized that targeting a highly attenuated interleukin (IL)-18 to PD-1 can activate PD-1+ T cells and oppose exhaustion while antagonizing PD-1 . We generated a highly attenuated IL-18 variant, which is resistant to IL-18BP binding and assessed its receptor binding ability. Tumor growth inhibition was evaluated across multiple models. Additionally, we examined post-remission tumor resistance and lymphocyte inﬁltration into the tumor ex vivo using ﬂow cytometry. The IL-18 fusion resisted interleukin-18 binding protein (IL-18BP) inhibition and exhibited a 10,000-fold reduction in activity while preserving cis-signaling and demonstrated strong efﬁcacy across tumor models. It increased CD8+ progenitor-exhausted tumor-inﬁltrating lymphocytes (TILs) while reducing myeloid TILs. Attaching a highly attenuated IL-18 to an anti-PD-1 antibody goes beyond simply targeting a cytokine to PD-1, representing a novel cytokine-enhanced checkpoint inhibitor that activates PD-1+ T cells via the cytokine receptor while simultaneously antagonizing PD-1 . KEYWORDS checkpoint inhibitor, cytokine, IL-18, immunocytokine, PD-1 1 Introduction PD-1 is an inhibitory receptor expressed on activated/exhausted T cells, B cells, NK cells and myeloid cells (1) . Its ligand, PD-L1, is found on various cell types, including lymphocytes, epithelial cells, and tumor cells (2) . The PD-1/PD-L1 interaction plays a crucial role in maintaining immune balance and preventing autoimmunity by acting as a checkpoint to prevent uncontrolled T cell activity (3) . This regulatory axis is often active in tumors, where PD-L1 promotes an immunosuppressive environment (2) . Activated or

FAQs

What problem limits PD-1/PD-L1 checkpoint therapy?

Response rates are limited because many patients are intrinsically resistant or develop a refractory phenotype during treatment, producing durable responses in only a subset of eligible patients.

How does the study aim to improve checkpoint inhibitor efficacy?

By attaching a highly attenuated IL-18 to an anti-PD-1 antibody to enable simultaneous checkpoint inhibition and cytokine potentiation, targeting PD-1+ T cells while keeping toxicity manageable.

What are the key experimental outcomes reported for the IL-18 variant fusion?

The attenuated IL-18 fusion resists IL-18BP binding with a large reduction in activity while preserving signaling and shows strong tumor growth inhibition across models; it increases CD8+ progenitor-exhausted TILs and reduces myeloid TILs.

Sep 28, 2026

Uploaded by Rowan