EGFR-selective activation of CD27 co-stimulatory signaling by a bispecific antibody enhances anti-tumor activity of T cells

Sep 24, 2026

A higher density of tumor-infiltrating lymphocytes (TILs), especially cytotoxic CD8+ T cells, predicts improved clinical outcomes, yet local inhibitory factors can suppress anti-tumor immunity. Many TIL subsets express the co-stimulatory receptor CD27, enabling potential T-cell re-activation, but CD27 agonist antibodies have limited clinical responses because they require higher-order receptor cross-linking. This study reports CD27xEGFR, a bispecific Fc-silent antibody that targets CD27 and EGFR to drive EGFR-restricted CD27 co-stimulation and potent T-cell responses, including proliferation, activation markers, cytokine release, and effector-to-target–dependent tumor cell killing.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

1 Introduction

Tumor-reactive T cells and immune checkpoint inhibitors

Need for additional co-stimulatory signals in the tumor microenvironment

CD27 as a co-stimulatory receptor target

Rationale for CD27 activation

TYPE Original Research PUBLISHED 20 July 2023 DOI 10.3389/fimmu.2023.1191866 OPEN ACCESS EDITED BY Adam Zwolak, Janssen Research and Development, United States REVIEWED BY Inger Øynebråten, Oslo University Hospital, Norway Shahram Salek-Ardakani, Pﬁzer, United States *CORRESPONDENCE Edwin Bremer [e.bremer@umcg.nl](e.bremer@umcg.nl) RECEIVED 22 March 2023 ACCEPTED 03 July 2023 PUBLISHED 20 July 2023 CITATION Melo V, Nelemans LC, Vlaming M, Lourens HJ, Wiersma VR, Bilemjian V, Huls G, de Bruyn M and Bremer E (2023) EGFR-selective activation of CD27 co-stimulatory signaling by a bispeciﬁc antibody enhances anti-tumor activity of T cells. Front. Immunol. 14:1191866 . doi: 10.3389/fimmu.2023.1191866 COPYRIGHT © 2023 Melo, Nelemans, Vlaming, Lourens, Wiersma, Bilemjian, Huls, de Bruyn and Bremer. 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. EGFR-selective activation of CD27 co-stimulatory signaling by a bispeciﬁc antibody enhances anti-tumor activity of T cells Vinicio Melo 1, Levi Collin Nelemans 1, Martijn Vlaming 1, Harm Jan Lourens 1, Valerie R. Wiersma 1, Vrouyr Bilemjian 1, Gerwin Huls 1, Marco de Bruyn 2 and Edwin Bremer 1* 1 Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands, 2 Department of Obstetrics & Gynecology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands A higher density of tumor inﬁlt rating lymphocytes (TILs) in the tumor microenvironment, particularly cytotoxic CD8+ T cells, is associated with improved clinical outcome in various cancers. However, local inhibitory factors can suppress T cell activity and hinder anti-tumor immunity. Notably, TILs from various cancer types express the co-stimulatory Tumor Necrosis Factor receptor CD27, making it a potential target for co-stimulation and re-activation of tumorinﬁltrated and tumor-reactive T cells. Anti-cancer therapeutics based on exploiting CD27-mediated T cell co-stimulation have proven safe, but clinical responses remain limited. This is likely because current monoclonal antibodies fail to effectively activate CD27 signaling, as this receptor requires higher-order receptor cross-linking. Here, we report on a bispeciﬁc antibody, CD27xEGFR, that targets both CD27 and the tumor antigen, epidermal growth factor receptor (EGFR) . By targeting EGFR, which is commonly expressed on carcinomas, CD27xEGFR induced cancer cell-localized crosslinking and activation of CD27 . The design of CD27xEGFR includes an Fc-silent domain, which is designed to minimize potential toxicity by reducing Fc gamma receptor-mediated binding and activation of immune cells. CD27xEGFR bound to both of its targets simultaneously and triggered EGFR-restricted co-stimulation of T cells as measured by T cell proliferation, T cell activation markers, cytotoxicity and IFN-g release. Further, CD27xEGFR augmented T cell cytotoxicity in a panel of artiﬁcial antigen-presenting carcinoma cell line models, leading to Effector-toTarget ratio-dependent elimination of cancer cells. Taken together, we present the in vitro characterization of a novel bispeciﬁc antibody that re-activates T cell immunity in EGFR-expressing cancers through targeted co-stimulation of CD27 . KEYWORDS immunotherapy, bispeciﬁc antibody, CD27, EGFR, T cell, co-stimulation Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) 1 Introduction The re-activation of tumor-reactive T cells with so-called immune checkpoint inhibitors (ICIs) has translated into remarkable clinical breakthr

FAQs

What problem does CD27xEGFR aim to solve in T-cell anti-tumor immunity?

It addresses limited responses from current immune checkpoint inhibitors by providing additional co-stimulatory activation through CD27, overcoming suppression within the tumor microenvironment.

How is CD27xEGFR designed to activate CD27 signaling?

CD27xEGFR is a bispecific, Fc-silent antibody that binds both CD27 and EGFR, enabling EGFR-restricted localization that promotes cancer cell-localized CD27 cross-linking and activation.

What immune and functional readouts were used to evaluate CD27xEGFR activity?

The study assesses T-cell proliferation, activation markers, cytotoxicity, IFN-γ release, and effector-to-target ratio–dependent elimination of cancer cells in model systems.

Sep 24, 2026

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