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29.04.2019 | Original Article | Ausgabe 1/2019

Cancer Chemotherapy and Pharmacology 1/2019

Monomethyl auristatin E-conjugated anti-EGFR antibody inhibits the growth of human EGFR-positive non-small cell lung cancer

Zeitschrift:
Cancer Chemotherapy and Pharmacology > Ausgabe 1/2019
Autoren:
Zhuanglin Li, Mingxue Wang, Deling Yu, Wenting Luo, Jianmin Fang, Changjiang Huang, Xuejing Yao
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00280-019-03848-9) contains supplementary material, which is available to authorized users.

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Abstract

Purpose

Epidermal growth factor receptor (EGFR) is highly expressed on non-small cell lung cancers (NSCLC) and a valuable therapeutic target. This study aimed at producing and characterizing monomethyl auristatin E (MMAE)-conjugated anti-EGFR antibody as a novel EGFR-targeting therapy for NSCLC.

Methods

A humanized anti-EGFR monoclonal antibody (named RC68) was purified and conjugated with MMAE using a MC-VC-PAB or PY-VC-PAB linker. The in vitro and in vivo antitumor activity of RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE were characterized.

Results

The RC68 was generated from RC68-expressing cells and had a purity of > 99.0%. The RC68 recognized EGFR on tumor cells, particularly for higher EGFR expressing H125, A431, HCC827 and H1975 cells. The RC68 was conjugated with an average of 4 MMAE molecules to generate RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE, respectively. The RC68-MC-VC-PAB-MMAE, RC68-PY-VC-PAB-MMAE and RC68 displayed similar binding affinity to EGFR on tumor cells, and RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE were effectively internalized by H125 cells. The RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE inhibited the growth of H125 cells in vitro with an IC50 7.37–8.04 ng/mL and implanted H125 tumors in vivo, but did not affect body weights of mice. The antitumor effect of RC68-MC-VC-PAB-MMAE was stronger than RC68-PY-VC-PAB-MMAE, which was also stronger than docetaxel in vivo.

Conclusions

These novel antibody–drug conjugates, particularly for RC68-MC-VC-PAB-MMAE, may be a potential candidate for treatment of EGFR + NSCLC.

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Zusatzmaterial
Supplementary file1 (DOCX 24 kb)
280_2019_3848_MOESM1_ESM.docx
Literatur
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