HER2-targeted antibody drug conjugates for ovarian cancer therapy.

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.

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

A novel humanized anti-HER2 antibody conjugated with MMAE exerts potent anti-tumor activity.

Yao X ，Jiang J ，Wang X ，Huang C ，Li D ，Xie K ，Xu Q ，Li H ，Li Z ，Lou L ，Fang J ... -  《-》

An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer.

Li H ，Yu C ，Jiang J ，Huang C ，Yao X ，Xu Q ，Yu F ，Lou L ，Fang J ... -  《-》

An EGFR-targeting antibody-drug conjugate LR004-VC-MMAE: potential in esophageal squamous cell carcinoma and other malignancies.

Epidermal growth factor receptor (EGFR) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however, EGFR-targeted antibody-drug conjugate (ADC) therapy for esophageal squamous cell carcinoma (ESCC) is exceedingly rare. LR004 is a novel anti-EGFR antibody with the advantages of improved safety and fewer hypersensitivity reactions. It may be of great value as a carrier in ADCs with high binding affinity and internalization ability. Here, we prepared an EGFR-targeting ADC, LR004-VC-MMAE, and evaluated its antitumor activities against ESCC and EGFR-positive cells. LR004 was covalently conjugated with monomethyl auristatin E (MMAE) via a VC linker by antibody interchain disulfide bond reduction. VC-MMAE was conjugated with LR004 with approximately 4.0 MMAE molecules per ADC. LR004-VC-MMAE showed a potent antitumor effect against ESCC and other EGFR-positive cells with IC50 values of nM concentrations in vitro. The in vivo antitumor effects of LR004-VC-MMAE were investigated in ESCC KYSE520 and A431 xenograft nude mice models. Significant activity was seen at 5 mg·kg-1 , and complete tumor regression was observed at 15 mg·kg-1 in the KYSE520 xenograft nude mice after four injections, while the naked antibody LR004 had little effect on inhibiting tumor growth. Similar promising results were obtained in the A431 models. In addition, the tumors also remained responsive to LR004-VC-MMAE for large tumor experiments (tumor volume 400-500 mm3 ). The study results demonstrated that LR004-VC-MMAE could be a potential therapeutic agent for ESCC and other EGFR-expressing malignancies. We also evaluated PK profile of LR004-VC-MMAE ADC in the mice model, which would provide qualitative guiding significance for the further research.

Hu XY ，Wang R ，Jin J ，Liu XJ ，Cui AL ，Sun LQ ，Li YP ，Li Y ，Wang YC ，Zhen YS ，Miao QF ，Li ZR ... -  《-》

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

Li Z ，Wang M ，Yu D ，Luo W ，Fang J ，Huang C ，Yao X ... -  《-》