Preclinical in vitro and in vivo evidence for CD74-targeting as effective treatment strategy for cutaneous T cell lymphomas

Mariantonia Costanza Mariantonia Costanza Catello Giordano Catello Giordano Ann-Christin von Brünneck Ann-Christin von Brünneck Jing Zhao Jing Zhao Ahmad Makky Ahmad Makky Katharina Vinh Katharina Vinh Ivonne Aidee Montes-Mojarro Ivonne Aidee Montes-Mojarro Florian Reisinger Florian Reisinger Stephan Forchhammer Stephan Forchhammer Agnieszka Witalisz-Siepracka Agnieszka Witalisz-Siepracka Sophie Edtmayer Sophie Edtmayer Dagmar Stoiber Dagmar Stoiber Gang Yin Gang Yin David Horst David Horst Anja Fischer Anja Fischer Reiner Siebert Reiner Siebert Jan P. Nicolay Jan P. Nicolay Menghong Yin Menghong Yin Martin Janz Martin Janz Falko Fend Falko Fend Jürgen C. Becker Jürgen C. Becker Christian M. Schürch Christian M. Schürch Lukas Kenner Lukas Kenner Chalid Assaf Chalid Assaf Olaf Merkel Olaf Merkel Stephan Mathas Stephan Mathas Preclinical in vitro and in vivo evidence for CD74-targeting as effective treatment strategy for cutaneous T cell lymphomas Oxford University Press 2025 Prognosis and quality of life in patients with advanced cutaneous T-cell lymphoma (CTCL), particularly in those with Sézary syndrome (SS) or advanced-stage mycosis fungoides (MF), are poor. Monoclonal antibodies or antibody-drug conjugates (ADCs) have been added into CTCL treatment algorithms, but the spectrum of antibody-targetable cell surface antigens in T-cell non-Hodgkin lymphomas (T-NHLs) is limited.To evaluate the expression of the major histocompatibility complex class II chaperone CD74 in common subtypes of CTCL by various methods, and to explore the efficacy of targeting CD74 in CTCL cells with an anti-CD74 ADC in vitro and in vivo.We comprehensively investigated the expression of CD74 in well-defined CTCL cell lines by polymerase chain reaction, immunoblotting and flow cytometry. More than 140 primary CTCL samples of all common subtypes were analysed by immunohistochemistry, flow cytometry, immunofluorescence and 'co-detection by indexing' (CODEX) multiplexed tissue imaging, as well as by single-cell RNA sequencing (scRNAseq) analyses. DNA methylation of CTCL cell lines was interrogated by the generation of genome-wide methylation profiling. The effect of a maytansinoid-conjugated humanized ADC against CD74 was investigated in CTCL cell lines in vitro, alone or in combination with gemcitabine, and in vivo after xenotransplantation of CTCL cell lines in NOD-scid Il2rgnull mice.We demonstrated that CD74 is widely and robustly expressed in CTCL cells. In addition, CD74 expression in SS and MF was confirmed by scRNAseq data analysis and was correlated in CTCL cell lines with CD74 DNA hypomethylation. CD74 was rapidly internalized in CTCL cells and CD74 targeting by the ADC STRO-001 efficiently killed CTCL-derived cell lines. Finally, targeting of CD74 synergized with conventional chemotherapy in vitro and eradicated murine xenotransplants of CTCL cell lines in vivo.CD74 is expressed in common CTCL subtypes. Targeting CD74 efficiently killed CTCL cells in vitro and in vivo. We therefore suggest the targeting of CD74 to be a highly promising treatment strategy for CTCL. PDFDocument eng 2025-05-09T08:50:04.992939Z 2025 Monoclonal-Antibody Milatuzumab Invariant Chain Mycosis-Fungoides Sezary-Syndrome Anti-Cd74 Antibody Mif Receptor Brefeldin-A Phase-I Pralatrexate Organization 3522053 b application/pdf http://creativecommons.org/licenses/by/4.0/