TY - JOUR
T1 - Anti-metastatic activity of an anti-egfr monoclonal antibody against metastatic colorectal cancer with kras p.G13d mutation
AU - Ohishi, Tomokazu
AU - Kato, Yukinari
AU - Kaneko, Mika K.
AU - Ohba, Shun Ichi
AU - Inoue, Hiroyuki
AU - Harakawa, Akiko
AU - Kawada, Manabu
N1 - Funding Information:
Funding: This research was supported in part by the Japan Agency for Medical Research and Development: Grant Numbers 19cm0106213h0004 (M.K.), JP19am0401013 (Y.K.), JP19am0101078 (Y.K.), and JP19ae0101028 (Y.K.), and by the Japan Society for the Promotion of Science, JSPS KAKENHI: Grant numbers 18K08693 (T.O.), 17K07299 (M.K.K.) and 19K07705 (Y.K.).
Publisher Copyright:
© 2020 by the authors.Licensee MDPI, Basel, Switzerland.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - The now clinically-used anti-epidermal growth factor receptor (EGFR) monoclonal antibodies have demonstrated significant efficacy only in patients with metastatic colorectal cancer (mCRC), with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS). However, no effective treatments for patients with mCRC with KRAS mutated tumors have been approved yet. Therefore, a new strategy for targeting mCRC with KRAS mutated tumors is desired. In the present study, we examined the anti-tumor activities of a novel anti-EGFR monoclonal antibody, EMab-17 (mouse IgG2a, kappa), in colorectal cancer (CRC) cells with the KRAS p.G13D mutation. This antibody recognized endogenous EGRF in CRC cells with or without KRAS mutations, and showed a high sensitivity for CRC cells in flow cytometry, indicating that EMab-17 possesses a high binding affinity to the endogenous EGFR. In vitro experiments showed that EMab-17 exhibited antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity activities against CRC cells. In vivo analysis revealed that EMab-17 inhibited the metastases of HCT-15 and HCT-116 cells in the livers of nude mouse metastatic models, unlike the anti-EGFR monoclonal antibody EMab-51 of subtype mouse IgG1. In conclusion, EMab-17 may be useful in an antibody-based therapy against mCRC with the KRAS p.G13D mutation.
AB - The now clinically-used anti-epidermal growth factor receptor (EGFR) monoclonal antibodies have demonstrated significant efficacy only in patients with metastatic colorectal cancer (mCRC), with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS). However, no effective treatments for patients with mCRC with KRAS mutated tumors have been approved yet. Therefore, a new strategy for targeting mCRC with KRAS mutated tumors is desired. In the present study, we examined the anti-tumor activities of a novel anti-EGFR monoclonal antibody, EMab-17 (mouse IgG2a, kappa), in colorectal cancer (CRC) cells with the KRAS p.G13D mutation. This antibody recognized endogenous EGRF in CRC cells with or without KRAS mutations, and showed a high sensitivity for CRC cells in flow cytometry, indicating that EMab-17 possesses a high binding affinity to the endogenous EGFR. In vitro experiments showed that EMab-17 exhibited antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity activities against CRC cells. In vivo analysis revealed that EMab-17 inhibited the metastases of HCT-15 and HCT-116 cells in the livers of nude mouse metastatic models, unlike the anti-EGFR monoclonal antibody EMab-51 of subtype mouse IgG1. In conclusion, EMab-17 may be useful in an antibody-based therapy against mCRC with the KRAS p.G13D mutation.
KW - Antibody-dependent cell cytotoxicity
KW - Colorectal cancer
KW - Complement-dependent cytotoxicity
KW - Epidermal growth factor receptor
KW - Metastasis
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U2 - 10.3390/ijms21176037
DO - 10.3390/ijms21176037
M3 - Article
C2 - 32839411
AN - SCOPUS:85089660871
VL - 21
SP - 1
EP - 16
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1422-0067
IS - 17
M1 - 6037
ER -
