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Eur J Pharm Sci. 2016 Oct 10;93:274-86. doi: 10.1016/j.ejps.2016.08.015. Epub 2016 Aug 7.

HER2-targeted antibody drug conjugates for ovarian cancer therapy.

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Department of Pharmacology, Binzhou Medical University, Yantai 256603, Shandong, China.
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
RemeGen, Ltd, Yantai 264000, Shandong, China.
School of Life Science and Technology, Tongji University, Shanghai 200092, China. Electronic address:
Department of Pharmacology, Binzhou Medical University, Yantai 256603, Shandong, China. Electronic address:


HER2 targeted delivery of ovarian cancer therapy has been beneficial for some patients, although, its efficacy is yet to be confirmed in large populations. We generated a novel anti-HER2 humanized antibody (Hertuzumab) and conjugated it to a microtubule-disrupting drug monomethyl auristatin E conjugate (MMAE) with a lysosomal protease-cleavable valine-citrulline linker. The average drug to antibody ratio (DAR) of Hertuzumab-vc-MMAE was varied by conjugating Hertuzumab antibodies with increasing linker-drugs (LDs) from D0-D8. The resulting conjugates were tested for kinetic affinity for soluble HER2-ECD, cytotoxicity, and in vivo pharmacokinetics. The kinetic binding constant values (KD) were obtained by the bio-layer interference (BLI) method. The half time (t1/2) and clearance (Cl) results of the pharmacokinetic profile in rats were DAR-dependent. Hertuzumab-vc-MMAE with DAR4 was selected for further evaluation. Both Hertuzumab and Hertuzumab conjugates could bind to HER2 antigen, and exhibited significant cytotoxicity on HER2 positive tumor cells after internalization by receptor-mediated endocytosis. Hence, Hertuzumab-vc-MMAE conjugates were significantly selective both in vitro and in vivo as compared to other ovarian cancer clinical therapies that are currently used. Cell signal transduction and cell cycle were also affected, as shown by down regulation of PI3K/AKT pathway and arrested mitosis in the G2/M phase. The pharmacokinetics and pharmacodynamics (PK-PD) of the conjugates in nude mouse xenograft model demonstrated a correlation between efficacy and drug concentration. These results show that Hertuzumab-vc-MMAE is a potential therapeutic agent for HER2 positive ovarian cancer.


Antibody drug conjugates (ADCs); Cisplatine (PubChem CID:441,203), Paclitaxel (PubChem CID: 91,885,464), Tris (2-carboxyethyl) phosphine, TCEP (PubChem CID:119,411); DM1 (PubChem CID:11,343,137); HER2/ErbB2; MC-VC-PAB-MMAE (PubChem CID: 71,586,737); MMAE (PubChem CID: 53,297,465); Monomethyl auristatin E (MMAE); Ovarian cancer

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