Journal Article

DKFZ-2026-02252

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cancer-driver-agnostic targeting of amplified surface proteins identifies MPZL1 for selective CAR-T cell therapy.

Jiménez-Vázquez, S. (First author)DKFZ* ; Berthel, A. ; Patsis, C.DKFZ* ; Mitstorfer, M. ; Grimm, M. ; Butthof, L.DKFZ* ; Wendler-Link, L.DKFZ* ; Böse, L.DKFZ* ; Wiethoff, H. ; Hofmann, I.DKFZ* ; Breuhahn, K. ; Longerich, T. ; Gaida, M. M. ; Schirmacher, P. ; Feucht, J. ; Suarez-Carmona, M. ; Schmidt, P.DKFZ* ; Klupp, F. ; Schneider, M. ; Wallwiener, M. ; Jäger, D.DKFZ* ; Halama, N. ; Breinig, M.DKFZ* ; Tschaharganeh, D. F. (Last author)DKFZ*

2026
Springer Nature [London]

Abstract: Most cancer therapies target genetic alterations driving tumor growth, but many drivers are undruggable or rare, limiting their therapeutic reach. Here, we demonstrate that amplified genes encoding cell surface proteins provide a rich, cancer-driver-agnostic source of targets. We identify MPZL1 (myelin protein zero-like 1), amplified in up to 75% of patients with certain solid tumor types, as abundantly expressed on the surface tumor cells across diverse cancer types while being largely absent from healthy tissues, offering a favorable therapeutic window. We develop a monoclonal antibody targeting MPZL1's extracellular domain and engineer chimeric antigen receptor (CAR)-T cells that selectively eliminate MPZL1-positive cancer cells in vitro. These CAR-T cells exhibit antitumor activity in human xenograft, autochthonous mouse, and patient-derived tissue explant preclinical models. This work establishes MPZL1 as a viable CAR-T cell target and provides a generalizable framework for exploiting amplified cell surface receptors as broadly applicable therapeutic targets.

Keyword(s): Humans (MeSH) ; Animals (MeSH) ; Receptors, Chimeric Antigen: immunology (MeSH) ; Receptors, Chimeric Antigen: metabolism (MeSH) ; Receptors, Chimeric Antigen: genetics (MeSH) ; Mice (MeSH) ; Membrane Proteins: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Membrane Proteins: immunology (MeSH) ; Membrane Proteins: antagonists & inhibitors (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; Neoplasms: therapy (MeSH) ; Neoplasms: genetics (MeSH) ; Neoplasms: immunology (MeSH) ; Neoplasms: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Antibodies, Monoclonal: immunology (MeSH) ; Female (MeSH) ; Receptors, Chimeric Antigen ; Membrane Proteins ; Antibodies, Monoclonal

Note: #EA:F190#LA:F190# / #NCTZFB26#

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Contributing Institute(s):

1. NWG Cell Plasticity and Epigenetic Remodeling (F190)
2. Monoklonale Antikörper (W170)
3. GMP-Einheit Zelluläre Therapie (D210)
4. Koordinierungsstelle NCT Heidelberg (HD02)

Research Program(s):

1. 319H - Addenda (POF4-319H) (POF4-319H)

Appears in the scientific report 2026

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