Synergistic Cytotoxic Effect on Gastric Cancer Cells of an Immunotoxin Cocktail in Which Antibodies Recognize Different Epitopes on CDH17

Kusano-Arai, Osamu; Iwanari, Hiroko; Kudo, Shota; Kikuchi, Chika; Yui, Anna; Akiba, Hiroki; Matsusaka, Keisuke; Kaneda, Atsushi; Fukayama, Masashi; Tsumoto, Kouhei; Hamakubo, Takao

doi:10.1089/mab.2017.0043

Cited by 8 publications

(14 citation statements)

References 37 publications

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“…AGS cells (CRL-1739) and MKN74 cells (JCRB0255) were obtained from ATCC (Manassas, VA, USA) and the Japanese Collection of Research Bioresources Cell Bank (Osaka, Japan), respectively. In a previous study, we isolated an AGS cell clone with high CDH17 expression levels from the parental AGS cell line [13]. The isolated AGS cells have high CDH17 expression (200,000 molecules per cell) [13].…”

Section: Cell Culture and Animal Modelsmentioning

confidence: 99%

“…In a previous study, we isolated an AGS cell clone with high CDH17 expression levels from the parental AGS cell line [13]. The isolated AGS cells have high CDH17 expression (200,000 molecules per cell) [13]. MKN74 cells do not express CDH17 and were used as a negative control [13].…”

Section: Cell Culture and Animal Modelsmentioning

confidence: 99%

“…The isolated AGS cells have high CDH17 expression (200,000 molecules per cell) [13]. MKN74 cells do not express CDH17 and were used as a negative control [13]. AGS cells were cultured in RPMI-1640 medium (Wako Pure Chemical Industries, Osaka, Japan) supplemented with 15% fetal bovine serum (Gibco, Tokyo, Japan), 1% penicillin-streptomycin mixed solution (Nacalai Tesque, Tokyo, Japan), 1.25 mM sodium pyruvate (Sigma-Aldrich, Tokyo, Japan), and 60 mg/L gentamicin reagent solution (GIBCO, Tokyo, Japan) at 37 °C in a humidified atmosphere with 5% CO 2 .…”

Section: Cell Culture and Animal Modelsmentioning

confidence: 99%

“…Monoclonal antibodies against human CDH17 (D2101 and D2111) were generated as previously described [13]. D2101 was radiolabeled with 111 In and used for biodistribution and SPECT/CT studies.…”

Section: Antibodiesmentioning

confidence: 99%

“…We previously generated monoclonal antibodies (Mab) recognizing the extracellular domain of CDH17 [13]. In vitro assays using a gastric cancer cell line AGS revealed a Mab D2101 binds to the antigen on the membrane of living cells with high affinity [13]. D2101, therefore, has the potential of an agent for CDH17-targeted noninvasive imaging.…”

Section: Introductionmentioning

confidence: 99%

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111In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis

et al. 2019

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Objective Cadherin-17 (CDH17) is a transmembrane protein that mediates cell-cell adhesion and is frequently expressed in adenocarcinomas, including gastric cancer. CDH17 may be an effective diagnostic marker for the staging of gastric cancer. Here, we developed an 111 In-labeled anti-CDH17 monoclonal antibody (Mab) as an imaging tracer and performed biodistribution and single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging studies using mice with CDH17-positive gastric cancer xenografts. CDH17 expression in gastric cancer specimens was also analyzed. Methods The cross-reactivity and affinity of our anti-CDH17 Mab D2101 was evaluated by surface plasmon resonance analysis and cell enzyme-linked immunosorbent assay, respectively. Biodistribution and SPECT/CT studies of 111 In-labeled D2101 ( 111 In-D2101) were performed. CDH17 expression in gastric cancer specimens was evaluated by immunohistochemistry. Results Surface plasmon resonance analysis revealed that D2101 specifically recognizes human CDH17, but not murine CDH17. The affinity of D2101 slightly decreased as a result of the radiolabeling procedures. The biodistribution study revealed high uptake of 111 In-D2101 in tumors (maximum, 39.2 ± 9.5% ID/g at 96 h postinjection), but low uptake in normal organs, including the stomach. Temporal SPECT/CT imaging with 111 In-D2101 visualized tumors with a high degree of tumor-to-nontumor contrast. Immunohistochemical analysis revealed that, compared with HER2, which is a potential marker of N-stage, CDH17 had a higher frequency of positivity in specimens of primary and metastatic gastric cancer. Conclusion Our 111 In-anti-CDH17 Mab D2101 depicted CDH17-positive gastric cancer xenografts in vivo and has the potential to be an imaging probe for the diagnosis of primary lesions and lymph-node metastasis in gastric cancer.

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Section: Cell Culture and Animal Modelsmentioning

confidence: 99%

Section: Cell Culture and Animal Modelsmentioning

confidence: 99%

Section: Cell Culture and Animal Modelsmentioning

confidence: 99%

Section: Antibodiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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111In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis

et al. 2019

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Nanobody‐Engineered Biohybrid Bacteria Targeting Gastrointestinal Cancers Induce Robust STING‐Mediated Anti‐Tumor Immunity

Xu,

Ding,

Dong

et al. 2024

Advanced Science

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Bacteria can be utilized for cancer therapy owing to their preferential colonization at tumor sites. However, unmodified non‐pathogenic bacteria carry potential risks due to their non‐specific targeting effects, and their anti‐tumor activity is limited when used as monotherapy. In this study, a biohybrid‐engineered bacterial system comprising non‐pathogenic MG1655 bacteria modified with CDH17 nanobodies on their surface and conjugated with photosensitizer croconium (CR) molecules is developed. The resultant biohybrid bacteria can efficiently home to CDH17‐positive tumors, including gastric, pancreatic, and colorectal cancers, and significantly suppress tumor growth upon irradiation. More importantly, biohybrid bacteria‐mediated photothermal therapy (PTT) induced abundant macrophage infiltration in a syngeneic murine colorectal model. Further, that the STING pathway is activated in tumor macrophages by the released bacterial nucleic acid after PTT is revealed, leading to the production of type I interferons. The addition of CD47 nanobody but not PD‐1 antibody to the PTT regimen can eradicate the tumors and extend survival. This results indicate that bacteria endowed with tumor‐specific selectivity and coupled with photothermal payloads can serve as an innovative strategy for low‐immunogenicity cancers. This strategy can potentially reprogram the tumor microenvironment by inducing macrophage infiltration and enhancing the efficacy of immunotherapy targeting macrophages.

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Cadherin-17 as a target for the immunoPET of adenocarcinoma

Delaney,

Keinänen,

Lam

et al. 2024

Eur J Nucl Med Mol Imaging

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Purpose Cadherin-17 (CDH17) is a calcium-dependent cell adhesion protein that is overexpressed in several adenocarcinomas, including gastric, colorectal, and pancreatic adenocarcinoma. High levels of CDH17 have been linked to metastatic disease and poor prognoses in patients with these malignancies, fueling interest in the protein as a target for diagnostics and therapeutics. Herein, we report the synthesis, in vitro validation, and in vivo evaluation of a CDH17-targeted 89Zr-labeled immunoPET probe. Methods The CDH17-targeting mAb D2101 was modified with an isothiocyanate-bearing derivative of desferrioxamine (DFO) to produce a chelator-bearing immunoconjugate — DFO-D2101 — and flow cytometry and surface plasmon resonance (SPR) were used to interrogate its antigen-binding properties. The immunoconjugate was then radiolabeled with zirconium-89 (t1/2 ~ 3.3 days), and the serum stability and immunoreactive fraction of [89Zr]Zr-DFO-D2101 were determined. Finally, [89Zr]Zr-DFO-D2101’s performance was evaluated in a trio of murine models of pancreatic ductal adenocarcinoma (PDAC): subcutaneous, orthotopic, and patient-derived xenografts (PDX). PET images were acquired over the course of 5 days, and terminal biodistribution data were collected after the final imaging time point. Results DFO-D2101 was produced with a degree of labeling of ~ 1.1 DFO/mAb. Flow cytometry with CDH17-expressing AsPC-1 cells demonstrated that the immunoconjugate binds to its target in a manner similar to its parent mAb, while SPR with recombinant CDH17 revealed that D2101 and DFO-D2101 exhibit nearly identical KD values: 8.2 × 10−9 and 6.7 × 10−9 M, respectively. [89Zr]Zr-DFO-D2101 was produced with a specific activity of 185 MBq/mg (5.0 mCi/mg), remained >80% stable in human serum over the course of 5 days, and boasted an immunoreactive fraction of >0.85. In all three murine models of PDAC, the radioimmunoconjugate yielded high contrast images, with high activity concentrations in tumor tissue and low uptake in non-target organs. Tumoral activity concentrations reached as high as >60 %ID/g in two of the cohorts bearing PDXs. Conclusion Taken together, these data underscore that [89Zr]Zr-DFO-D2101 is a highly promising probe for the non-invasive visualization of CDH17 expression in PDAC. We contend that this radioimmunoconjugate could have a significant impact on the clinical management of patients with both PDAC and gastrointestinal adenocarcinoma, most likely as a theranostic imaging tool in support of CDH17-targeted therapies.

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Synergistic Cytotoxic Effect on Gastric Cancer Cells of an Immunotoxin Cocktail in Which Antibodies Recognize Different Epitopes on CDH17

Cited by 8 publications

References 37 publications

111In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis

111In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis

Nanobody‐Engineered Biohybrid Bacteria Targeting Gastrointestinal Cancers Induce Robust STING‐Mediated Anti‐Tumor Immunity

Cadherin-17 as a target for the immunoPET of adenocarcinoma

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