CAR-Ts redirected against the Thomsen-Friedenreich antigen CD176 mediate specific elimination of malignant cells from leukemia and solid tumors

Sep 24, 2026

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Chimeric antigen receptor-engineered T cells (CAR-Ts) are assessed for cancer treatment by redirecting specificity toward the Thomsen-Friedenreich carbohydrate antigen CD176. CD176 is broadly associated with carcinoma and leukemia progression, metastasis, and therapy resistance, while being masked on most healthy cells, reducing on-target/off-tumor toxicity risk. Using the anti-CD176 monoclonal antibody Nemod-TF2 and two CD176-CAR constructs with different spacer lengths, the study evaluates specificity, signaling, cytokine release, and cytotoxicity after recognition of CD176-positive tumor cells and unmasking in healthy contexts.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Methods

Results

Discussion

TYPE Original Research PUBLISHED 17 October 2023 DOI 10.3389/fimmu.2023.1219165 OPEN ACCESS EDITED BY Robin Parihar, Baylor College of Medicine, United States REVIEWED BY Maria Themeli, Amsterdam University Medical Center, Netherlands Mohamad Hamieh, Memorial Sloan Kettering Cancer Center, United States *CORRESPONDENCE Britta Eiz-Vesper [eiz-vesper.britta@mh-hannover.de](eiz-vesper.britta@mh-hannover.de) †These authors have contributed equally to this work and share ﬁrst authorship RECEIVED 08 May 2023 ACCEPTED 28 September 2023 PUBLISHED 17 October 2023 CITATION Dragon AC, Beermann LM, Umland M, Bonifacius A, Malinconico C, Ruhl L, Kehler P, Gellert J, Weiß L, Mayer-Hain S, Zimmermann K, Riese S, Thol F, Beutel G, Maecker-Kolhoff B, Yamamoto F, Blasczyk R, Schambach A, Hust M, Hudecek M and Eiz-Vesper B (2023) CAR-Ts redirected against the Thomsen-Friedenreich antigen CD176 mediate speciﬁc elimination of malignant cells from leukemia and solid tumors. Front. Immunol. 14:1219165 . doi: 10.3389/fimmu.2023.1219165 COPYRIGHT © 2023 Dragon, Beermann, Umland, Bonifacius, Malinconico, Ruhl, Kehler, Gellert, Weiß, Mayer-Hain, Zimmermann, Riese, Thol, Beutel, Maecker-Kolhoff, Yamamoto, Blasczyk, Schambach, Hust, Hudecek and Eiz-Vesper. 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. CAR-Ts redirected against the Thomsen-Friedenreich antigen CD176 mediate speciﬁc elimination of malignant cells from leukemia and solid tumors Anna Christina Dragon 1†, Luca Marie Beermann 1†, Melina Umland 1, Agnes Bonifacius 1, Chiara Malinconico 1, Louisa Ruhl 1, Patrik Kehler 2, Johanna Gellert 2, Lisa Weiß 2, Sarah Mayer-Hain 2, Katharina Zimmermann 3, Sebastian Riese 1, Felicitas Thol4, Gernot Beutel 4, Britta Maecker-Kolhoff 5, Fumiichiro Yamamoto 6, Rainer Blasczyk 1, Axel Schambach 3, Michael Hust 7, Michael Hudecek 8 and Britta Eiz-Vesper 1* 1 Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany, 2Glycotope GmbH, Berlin, Germany, 3 Institute of Experimental Hematology, Hannover Medical School (MHH), Hannover, Germany, 4 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany, 5 Department of Pediatric Hematology and Oncology, Hannover Medical School (MHH), Hannover, Germany, 6Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain, 7 Department of Medical Biotechnology, Technical University of Braunschweig, Braunschweig, Germany, 8 Department of Internal Medicine II, University Hospital of Würzburg, Wuerzburg, Germany Introduction: Chimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identiﬁcation of a target antigen with high expression on the tumor but no expression on healthy cells, since “ontarget/off-tumor” cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no “on-target/off-tumor” cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts. Methods: Using the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancer

FAQs

Why is CD176 considered a suitable CAR-T target for cancer therapy?

CD176 is highly expressed in many carcinomas and leukemias and is linked to tumor progression, metastasis, and therapy resistance. It is masked on healthy cells, which helps avoid intolerable “on-target/off-tumor” cytotoxicity and lowers the probability of antigen escape.

How did the researchers evaluate CD176 presence and CAR-T targeting specificity?

They used the anti-CD176 monoclonal antibody Nemod-TF2 to evaluate CD176 on multiple healthy and cancer tissues and cells. CD176 targeting was tested with two CD176-CAR constructs in reporter cells and primary CD8+ T cells against CD176+ tumor cell models, including after unmasking CD176 on healthy cells using vibrio cholerae neuraminidase (VCN).

What did the results show about signaling, cytokine release, and cytotoxicity?

CD176-specific recognition was observed on primary tumor tissues and corresponding cell lines. CD176-CARs induced T-cell signaling (NF-kB activation) and activation markers (CD69, CD137), released effector molecules such as interferon-g, granzyme B, and perforin, and mediated cytotoxicity against CD176+ cancer cells without reacting to CD176- controls. A shorter spacer improved target recognition, and CD176L-CAR-Ts showed slightly higher proliferation and mediator-release capacities.

Sep 24, 2026

Uploaded by Elsa