Abstract P6-15-16: LIV-1 Antibody-Drug Conjugate: A Novel Therapeutic Agent for Breast Cancer

Abstract

Abstract LIV-1, also known as SLC39A6 or ZIP6, is a member of the zinc transporter family and was first identified as an estrogen-inducible gene in breast cancer. LIV-1, as a downstream target of STAT3, promotes the epithelial to mesenchymal transition that is important in the malignant progression to metastasis. Consistent with its role in cancer, we determined by immunohistochemical (IHC) analysis that LIV-1 is expressed in 86% (n=22) of estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites), and in 65% (n=20) of ER-/PR-/Her2- (triple-negative) breast cancers. In healthy human tissues, LIV-1 expression is limited to hormonally-regulated organs (prostate, uterus, and breast). We generated an antibody-drug conjugate (ADC) consisting of a humanized anti-LIV-1 mAb conjugated to the antitubulin agent monomethyl auristatin E (MMAE), via a plasma stable, enzyme-cleavable linker (vc). The humanized LIV-1 mAb bound with high affinity to both human and cynomolgous LIV-1 (2-4 nM). In vitro, anti-LIV-1-vcMMAE showed specific cytotoxic activity against a MCF-7 cell line with an IC50= 78 ng/ml. In vivo studies also demonstrated antitumor activity of anti-LIV-1-vcMMAE in preclinical xenograft models, including MCF-7 breast cancer cell line, with significant delay of tumor growth compared to control groups. The broad expression of LIV-1 in both hormonally-treated and triple-negative tumors and the limited expression in vital organs make LIV-1 an excellent target for an ADC. These findings support the further development of anti-LIV-1-vcMMAE as a promising therapeutic agent for the treatment of ER+ and triple-negative breast cancers. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-16.