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@PHDTHESIS{Altunay:1020750,
author = {Altunay, Betül},
othercontributors = {Panstruga, Ralph and Jahnen-Dechent, Wilhelm},
title = {{E}insatz von radioaktiv markierten
{S}ingle-{D}omain-{A}ntikörpern bei {HER}2-positivem
{B}rustkrebs},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2025-09214},
pages = {1 Online-Ressource : Illustrationen},
year = {2025},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University 2026; Dissertation, RWTH Aachen University, 2025},
abstract = {The human epidermal growth factor receptor 2 (HER2) is
overexpressed in various types of cancer, particularly
breast and ovarian cancer. Accurate imaging and targeted
therapy of HER2-positive tumors are therefore central goals
in oncological research. Several single-domain antibodies
(sdAbs), also known as nanobodies, have been investigated as
specific carriers for non-invasive molecular imaging
techniques and represent a promising platform for
theranostic applications. The aim of this work was the
development and preclinical characterization of a
HER2-targeted, sdAb-based theranostic pair, consisting of a
diagnostic tracer and a therapeutic counterpart.
Additionally, the impact of the hexahistidine-tag (HIS-tag)
was investigated by comparing sdAbs with (NM-02) and without
(NM-02.1) the HIS-tag in terms of pharmacokinetics, tumor
uptake, and renal clearance. The Technetium-99m (99mTc)
labeled sdAb NM-02, termed RAD201, demonstrated high
radiochemical purity as well as specific and significant
accumulation in HER2-positive BT474 xenografted mice four
hours post-injection. Tumor uptake was com-petitively
inhibited by approximately $50\%$ by co-injection of
non-radiolabeled (“cold”) sdAbs, confirming target
specificity. In a clinical feasibility study, RAD201 showed
a favorable pharmacokinetic profile, high
tumor-to-background ratio, and rapid blood clearance,
enabling imaging within a few hours post-injection. The use
of the plasma expander Gelofusine® further reduced renal
radiation dose by nearly $50\%$ without compromising tumor
uptake. In contrast, the therapeutic counterpart RAD202
(Rhenium-188 (188Re) labeled NM-02) faced several technical
challenges, including low yields, high osmolarity, and
limited serum stability. Due to these limitations, in vivo
therapeutic studies could not be pursued further. The
Gallium-68 (68Ga) labeled sdAb variants GLNM-02 (with
HIS-tag) and GLNM-02.1 (without HIS-tag) enabled PET imaging
with rapid tumor accumulation and high tumor-to-background
ratio in HER2-positive SKOV-3 xenografted mice. The
HIS-tag-free variant showed markedly reduced renal retention
and was there-fore selected for subsequent therapeutic
studies. In therapy studies using the Lutetium-177 (177Lu)
labeled sdAb, termed LLNM-02.1, both single-dose and
fractionated administration significantly inhibited tumor
growth and prolonged survival compared to the control
groups. However, the fractionated therapy showed superior
efficacy in inhibiting tumor growth compared to the single
dose. The HER2-specific sdAb-based tracers presented here
combine high target affinity with favorable safety profiles,
enabling both non-invasive imaging and therapeutic
intervention. In particular, the reduction of renal uptake
through HIS-tag removal and Gelofusine® administration
offers clinically relevant advantages. These findings form a
solid foundation for further clinical validation and dose
optimization in future studies.},
cin = {161920 / 160000},
ddc = {570},
cid = {$I:(DE-82)161920_20140620$ / $I:(DE-82)160000_20140620$},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2025-09214},
url = {https://publications.rwth-aachen.de/record/1020750},
}
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