Reviving low-affinity glycan-targeting CAR with combinatorial design
10 affiliations
- 1Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, 0379 Oslo, Norway
- 2Faculty of Medicine, University of Oslo, 0316 Oslo, Norway
- 3Faculty of Mathematics and Natural Sciences, University of Oslo, 0315 Oslo, Norway
- 4i3S, Institute for Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal
- 5IPATIMUP – Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
- 6Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway
- 7Department of Clinical Science, Precision Oncology Research Group, University of Bergen, 5020 Bergen, Vestland, Norway
- 8Centre for Cancer Biomarkers (CCBIO), University of Bergen, 5020 Bergen, Vestland, Norway
- 9Centre for Pharmacy, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
- 10Department of Haematology, Haukeland University Hospital, 5020 Bergen, Vestland, Norway
Abstract
CD19CAR T cells demonstrate remarkable therapeutic efficacy in the treatment of B cell malignancies. A global limitation of conventional CD19CAR therapy is its mono-specificity. Thus, defining complementary targets to CD19 is critical to avoid target-dependent limitations. Alternatives to protein antigens include secondary modifications, such as glycosylation. One example of aberrant glycosylation in lymphoma is the increase in N-glycans capped with α2,6-linked sialic acid, named CD75s. Here, we generate a CAR that recognizes CD75s based on an IgM monoclonal antibody called HH2. HH2CAR shows cytotoxic activity against B cell lymphoma cell lines, although it induces little to no cytokine release. However, while HH2CAR alone cannot control tumor progression in vivo, its combination with CD19CAR results in a functional molecule. Beyond overcoming the limited efficiency of HH2CAR T cells, this combination also prevents potential off-tumor/on-target toxicity associated with CD19 single targeting. Thus, inefficient mono-specific CAR molecules can be effectively leveraged in combinatorial formats.
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BibTeX
@article{forcados2026reviving,
title = {{Reviving low-affinity glycan-targeting CAR with combinatorial design}},
author = {Christopher Forcados and Hakan Köksal and Eveline Scherer and Rafaela Abrantes and Pierre Dillard and Henrique O. Duarte and Sarah Josefsson and Catarina Gomes and Constance de Montlaur and Henrik T.Z. Hellesøy and Ryan Dunkel and Erlend.B. Smeland and June H. Myklebust and Celso A. Reis and Emmet McCormack and Pascal Gelebart and Else Marit Inderberg and Sébastien Wälchli},
journal = {Cell Reports Medicine},
year = {2026},
month = oct,
doi = {10.1016/j.xcrm.2026.103108},
url = {https://doi.org/10.1016/j.xcrm.2026.103108},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Reviving low-affinity glycan-targeting CAR with combinatorial design
AU - Christopher Forcados
AU - Hakan Köksal
AU - Eveline Scherer
AU - Rafaela Abrantes
AU - Pierre Dillard
AU - Henrique O. Duarte
AU - Sarah Josefsson
AU - Catarina Gomes
AU - Constance de Montlaur
AU - Henrik T.Z. Hellesøy
AU - Ryan Dunkel
AU - Erlend.B. Smeland
AU - June H. Myklebust
AU - Celso A. Reis
AU - Emmet McCormack
AU - Pascal Gelebart
AU - Else Marit Inderberg
AU - Sébastien Wälchli
PY - 2026
DA - 2026/10/08
JO - Cell Reports Medicine
DO - 10.1016/j.xcrm.2026.103108
UR - https://doi.org/10.1016/j.xcrm.2026.103108
AB - CD19CAR T cells demonstrate remarkable therapeutic efficacy in the treatment of B cell malignancies. A global limitation of conventional CD19CAR therapy is its mono-specificity. Thus, defining complementary targets to CD19 is critical to avoid target-dependent limitations. Alternatives to protein antigens include secondary modifications, such as glycosylation. One example of aberrant glycosylation in lymphoma is the increase in N-glycans capped with α2,6-linked sialic acid, named CD75s. Here, we generate a CAR that recognizes CD75s based on an IgM monoclonal antibody called HH2. HH2CAR shows cytotoxic activity against B cell lymphoma cell lines, although it induces little to no cytokine release. However, while HH2CAR alone cannot control tumor progression in vivo, its combination with CD19CAR results in a functional molecule. Beyond overcoming the limited efficiency of HH2CAR T cells, this combination also prevents potential off-tumor/on-target toxicity associated with CD19 single targeting. Thus, inefficient mono-specific CAR molecules can be effectively leveraged in combinatorial formats.
SN - 2666-3791
ER -