Comparative Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Radionuclide Molecular Imaging of HER2 Expression in Malignant Tumors

Abstract

High expression of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal carcinomas is a predictive biomarker for treatment using HER2-targeted therapeutics (antibodies trastuzumab and pertuzumab, antibody-drug conjugate trastuzumab DM1, and tyrosine kinase inhibitor lapatinib). Radionuclide molecular imaging of HER2 expression might permit stratification of patients for HER2-targeting therapies. In this study, we evaluated a new HER2-imaging probe based on the designed ankyrin repeat protein (DARPin) 9_29. DARPin 9_29 was labeled with iodine-125 by direct radioiodination and with [99mTc]Tc(CO)3 using the C-terminal hexahistidine tag. DARPin 9_29 preserved high specificity and affinity of binding to HER2-expressing cells after labeling. Uptake of [125I]I-DARPin 9_29 and [99mTc]Tc(CO)3-DARPin 9_29 in HER2-positive SKOV-3 xenografts in mice at 6 h after injection was 3.4 ± 0.7 %ID/g and 2.9 ± 0.7 %ID/g, respectively. This was significantly (p < 0.00005) higher than the uptake of the same probes in HER2-negative Ramos lymphoma xenografts, 0.22 ± 0.09 %ID/g and 0.30 ± 0.05 %ID/g, respectively. Retention of [125I]I-DARPin 9_29 in the lung, liver, spleen, and kidneys was appreciably lower compared with [99mTc]Tc(CO)3-DARPin 9_29, which resulted in significantly (p < 0.05) higher tumor-to-organ ratios. The biodistribution data were confirmed by SPECT/CT imaging. In conclusion, radioiodine is a preferable label for DARPin 9_29.

The Role of Interleukin-37 in the Pathogenesis of Allergic Diseases

“…This assumption is supported by the fact that DC isolated from IL-37tg mice had a reduced level of CD40 and MHC class II molecules [59]. In addition, IL-37 increases the level of T regulatory cells, which suppress inflammation via secretion of the anti-inflammatory factor TGF-β [49,60].…”

“…Adoptive transfer of bone marrow cells from IL-37tg mice to wildtype mice led to a significant reduction in signs of experimental colitis. This indicates the anti-inflammatory effect of myeloid cells expressing IL-37 [49] (see review [27]).…”

“…It is believed that the C-terminal domain of IL-37 binds to Smad3, undergoes phosphorylation and then enters the nucleus, where it inhibits the expression of pro-inflammatory genes (Fig. 2) [49]. Thus, IL-37 exhibits anti-inflammatory properties in extracellular and intracellular conditions.…”

“…The biological role of IL-37 was studied in vivo in so-called IL-37tg mice with IL-37b gene insertion [49]. LPS was administered to these mice, after which the production of a number of pro-inflammatory and anti-inflammatory factors was evaluated.…”

Breast Cancer Typing Using Rt-PCR Assay

“…Однако, несмотря на широкое клиническое распространение, данное распределение характеризуется рядом ограничений и высокой вероятностью неточностей в постановке правильного диагноза, что в большей степени обусловлено возможными нарушениями методологии выполнения и интерпретации исследования, а также неточностью полученных результатов [7][8][9]. Этот факт подтверждают результаты ряда исследований, по данным которых только 73 % злокачественных опухолей молочной железы с наличием экспрессии рецептора эстрогена относятся к люминальным А и В подтипам [10].…”