Reference Detail

Ref Type

PMID

(27509865)

Authors

Jiang J, Dong L, Wang L, Zhang J, Chen F, Zhang X, Huang M, Li S, Ma W, Xu Q, Huang C, Fang J, Wang C

Title

HER2-targeted antibody drug conjugates for ovarian cancer therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
European journal of pharmaceutical sciences : official journal of the European			2016 Aug 7	274-86	Eur J Pharm Sci

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Disitamab vedotin	Disitamab vedotin	0	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Disitamab vedotin		RC48\|Hertuzumab-vc-MMAE\|RC-48	HER2 (ERBB2) Antibody 72	Disitamab vedotin (RC48) is an antibody-drug conjugate comprising a monoclonal antibody that targets HER2 (Hertuzumab) linked to the cytotoxic drug MMAE, which delivers the cytotoxic agent to HER2-expressing tumor cells, potentially resulting in increased cell death (PMID: 27509865, PMID: 31877330).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References