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@ARTICLE{Costanza:299525,
author = {M. Costanza and C. Giordano and A.-C. von Brünneck and J.
Zhao and A. Makky and K. Vinh and I. A. Montes-Mojarro and
F. Reisinger and S. Forchhammer$^*$ and A.
Witalisz-Siepracka and S. Edtmayer and D. Stoiber and G. Yin
and D. Horst$^*$ and A. Fischer and R. Siebert and J. P.
Nicolay$^*$ and M. Yin$^*$ and M. Janz and F. Fend$^*$ and
J. C. Becker$^*$ and C. M. Schürch$^*$ and L. Kenner and C.
Assaf and O. Merkel and S. Mathas$^*$},
title = {{P}reclinical in vitro and in vivo evidence for
{CD}74-targeting as effective treatment strategy for
cutaneous {T} cell lymphomas.},
journal = {British journal of dermatology},
volume = {192},
number = {5},
issn = {0366-2845},
address = {Oxford},
publisher = {Oxford University Press},
reportid = {DKFZ-2025-00483},
pages = {883-895},
year = {2025},
note = {2025 Apr 28;192(5):883-895},
abstract = {Prognosis and quality of life of advanced cutaneous T cell
lymphoma (CTCL) patients, in particular those with Sézary
syndrome (SS) and advanced-stage mycosis fungoides (MF), are
poor. Monoclonal antibodies or antibody-drug conjugates
(ADCs) have been implemented into CTCL therapy algorithms,
but the spectrum of antibody-targetable cell-surface
antigens on T cell non-Hodgkin lymphomas (T-NHL) is
limited.To evaluate expression of the MHC-II chaperone CD74
across common subtypes of CTCL by various methods, and to
explore the efficacy of CD74-targeting of CTCL cells by
anti-CD74 antibody-drug conjugate (ADC) in vitro and in
vivo.We comprehensively investigate expression of CD74 in
well-defined CTCL cell lines by PCR analyses, immunoblotting
and flow cytometry. More than 140 primary CTCL samples of
all common entities are analyzed by immunohistochemistry,
flow cytometry, immunofluorescence and 'co-detection by
indexing' (CODEX) multiplexed tissue imaging as well as
single-cell RNAseq analyses. DNA methylation of CTCL cell
lines is interrogated by generation of genome-wide
methylation profiling. The effect of a
maytansinoid-conjugated humanized ADC against CD74 is
investigated on CTCL cell lines in vitro, alone or in
combination with gemcitabine, and in vivo after
xenotransplantation of CTCL cell lines in NOD-scid Il2rgnull
(NSG) mice.We demonstrate by different experimental
approaches in CTCL cell lines and a broad collection of
primary CTCL samples that CD74 is widely and robustly
expressed in CTCL cells. Additionally, CD74 expression in SS
and MF is confirmed by analyses of single cell (sc)RNA-seq
data, and correlates in CTCL cell lines with CD74 gene DNA
hypomethylation. CD74 is rapidly internalized in CTCL cells,
and CD74 targeting by the ADC STRO-001 efficiently kills
CTCL-derived cell lines. Finally, CD74 targeting synergizes
with conventional chemotherapy in vitro, and eradicates
murine xenotransplants of CTCL cell lines in vivo.CD74 is
expressed across common CTCL subtypes, and CD74-targeting
efficiently kills CTCL cells in vitro and in vivo. Our data
thus identify CD74-targeting as highly promising treatment
strategy for CTCL.},
cin = {TU01 / BE01 / A370 / HD01 / ED01},
ddc = {610},
cid = {I:(DE-He78)TU01-20160331 / I:(DE-He78)BE01-20160331 /
I:(DE-He78)A370-20160331 / I:(DE-He78)HD01-20160331 /
I:(DE-He78)ED01-20160331},
pnm = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
pid = {G:(DE-HGF)POF4-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40036608},
doi = {10.1093/bjd/ljaf001},
url = {https://inrepo02.dkfz.de/record/299525},
}