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Early administration of amatuximab, a chimeric high-affinity anti-mesothelin monoclonal antibody, suppresses liver metastasis of mesothelin-expressing pancreatic cancer cells and enhances gemcitabine sensitivity in a xenograft mouse model

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Summary

Amatuximab is a promising therapeutic antibody targeting mesothelin, a 40-kDa glycoprotein that is highly expressed in pancreatic cancer. We investigated the effectiveness of early amatuximab treatment, imitating an adjuvant chemotherapy setting, and combination therapy with amatuximab and gemcitabine in liver metastasis of pancreatic cancer. Liver metastasis mouse models were established in 8-week-old male BALB/c nu/nu mice using the hemisplenic injection method. Tridaily amatuximab monotherapy or combination with gemcitabine was administered to the liver metastasis mouse model before metastatic lesions had formed huge masses. Gaussia luciferase-transfected AsPC-1 was used as a mesothelin-overexpressing pancreatic cancer cell line. The amount of liver metastases and the serum luciferase activity were significantly lower in the treatment groups than those in the control IgG group. Notably, the anti-tumor activity of gemcitabine was synergically enhanced by combination therapy with amatuximab. Furthermore, western blotting revealed that the high expression of phosphorylated c-Met and AKT in liver metastatic lesions treated with gemcitabine monotherapy was canceled by its combination with amatuximab. This result indicated that the observed synergic therapeutic effect may have occurred as a result of the inhibitory effect of amatuximab on the phosphorylation of c-Met and AKT, which were promoted by exposure to GEM. In conclusion, our study revealed that early administration of amatuximab alone or in combination with GEM significantly suppressed the liver metastases of mesothelin-expressing pancreatic cancer cells. A phase II clinical trial of amatuximab as part of an adjuvant chemotherapy regimen for resected pancreatic cancer is expected.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Abbreviations

ADCC:

antibody-dependent cellular cytotoxicity

FACS:

fluorescence-activated cell sorting

GEM:

gemcitabine

Gluc:

Gaussia luciferase

H&E:

hematoxylin and eosin

IHC:

immunohistochemistry

MSLN:

mesothelin

OS:

overall survival

PBS:

phosphate-buffered saline

PDAC:

pancreatic ductal adenocarcinoma

RLU:

relative light unit

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Acknowledgements

We are grateful to Dr. Keiji Furuuchi (Morphotek Inc.) for providing amatuximab from Morphotek Inc. We would like to thank Dr. Hidemitsu Kitamura (Institute for Genetic Medicine, Research Section of Disease Control, Hokkaido University) and Dr. Yutaka Hatanaka (Research Division of Companion Diagnostics, Hokkaido University Hospital) for their constructive advice. Finally, we would also like to thank H. Nikki March, PhD, Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

Funding

This study was supported by Japan Society for the Promotion of Science under Grant-in-Aid for Scientific Research C-20 K09024.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan

    Yuki Fujii, Hirofumi Kamachi, Fumihiko Matsuzawa, Tatsuzo Mizukami, Nozomi Kobayashi, Moto Fukai & Akinobu Taketomi

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  1. Yuki Fujii
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  2. Hirofumi Kamachi
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  3. Fumihiko Matsuzawa
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Contributions

Yuki Fujii: Writing - Original Draft, Data Curation, Investigation, Formal Analysis, Visualization. Hirofumi Kamachi: Conceptualization, Methodology, Funding acquisition, Writing - Review & Editing. Fumihiko Matsuzawa: Investigation, Writing - Review & Editing. Tatsuzo Mizukami: Investigation, Writing - Review & Editing. Nozomi Kobayashi: Methodology, Investigation, Resources. Moto Fukai: Resources, Writing - Review & Editing. Akinobu Taketomi: Supervision, Project administration, Writing - Review & Editing.

Corresponding author

Correspondence to Hirofumi Kamachi.

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This article does not contain any studies with human participants. For this type of study, formal consent is not required. All procedures involving animals and their care were approved by the ethics committee of Hokkaido University and were conducted under institutional and Japanese governmental guidelines for animal experiments.

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This article does not contain any studies with human participants. All procedures involving animals and their care were approved by the ethics committee of Hokkaido University and were conducted under institutional and Japanese governmental guidelines for animal experiments.

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Supplementary Information

Supplemental Table 1

(PDF 164 kb)

Supplemental Figure 1

AsPC-1 and Capan-2 expressed robust levels of MSLN whereas Panc-1 and MIA PaCa-2 did not. All cell lines showed robust comparable levels of MUC16 expression. (PDF 81 kb)

Supplemental Figure 2

Comparison of the total tumor weight of liver metastases in the four cell lines (n = 5). Mean total weights of liver metastases in mice with AsPC-1, Capan-2, MIA PaCa-2, and Panc-1 were 665.1 ± 249.2 mg, 6.8 ± 2.1 mg, 4.0 ± 3.9 mg, and 9.3 ± 3.4 mg, respectively. (PDF 81 kb)

Supplemental Figure 3

Comparison of the expression of mesothelin and MUC16 between AsPC-1 and As-PC1-Gluc. (A) Western blotting revealed that AsPC-1-Gluc cells expressed equivalent levels of MSLN and MUC16 to wild-type AsPC-1 cells. (B) FACS analysis revealed strong MSLN expression on the cell surface of both AsPC-1 and AsPC-1-Gluc cells using amatuximab (MORAb-009). (C) A strong correlation was recognized between the number of AsPC-1-Gluc cells and Gluc activity in the medium (R2 = 0.981, P < 0.001). (D) A strong correlation between the total tumor weight of liver metastases and serum Gluc activity was also observed (n = 25; R2 = 0.972, P < 0.001). (PDF 91 kb)

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Fujii, Y., Kamachi, H., Matsuzawa, F. et al. Early administration of amatuximab, a chimeric high-affinity anti-mesothelin monoclonal antibody, suppresses liver metastasis of mesothelin-expressing pancreatic cancer cells and enhances gemcitabine sensitivity in a xenograft mouse model. Invest New Drugs 39, 1256–1266 (2021). https://doi.org/10.1007/s10637-021-01118-1

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