P3-17-09: Neutralizing the Prolactin Receptor with Therapeutic Antibody LFA102: A Novel Approach for the Treatment of Breast Cancer.

Abstract The prolactin receptor (PRLR) is a class I cytokine receptor required for the normal development of the mammary gland and is frequently found to be overexpressed in breast tumors. The polypeptide hormone prolactin (PRL) has been demonstrated to induce PRLR signaling through the Jak/Stat, PI3-kinase/AKT and MAPK pathways, leading to cell proliferation and survival. Mammary gland-specific overexpression of PRL in transgenic mice leads to a higher incidence of ER+ and ER- mammary tumors. In addition, the PRLR locus is the site of frequent viral integrations in MMTV-induced mammary tumors. Elevated serum PRL levels in humans have been correlated with an increased risk for breast cancer, especially for ER+ cases, implicating a role for this hormone in the development of human breast tumors. An analysis of more than 3000 breast tumor specimens indicates that PRLR is expressed with high prevalence (60-70% of tumors) across all breast cancer subtypes, with a trend towards higher expression in ER+ tumors. All of these lines of evidence support the hypothesis that targeting the PRL/PRLR axis may be a new approach for addressing unmet medical need in breast cancer. LFA102 is a Human Engineered™ anti-PRLR antibody of the IgG1 isotype that neutralizes the function of PRLR through a non-ligand competitive binding interaction. LFA102 blocks PRL-induced signaling and proliferation in T47D and MCF7 ER+ human breast cancer cells in vitro, and abolishes PRL-induced phosphorylation of Stat5 in T47D xenograft tumors in vivo. An examination of disaggregated primary human breast tumors ex vivo has indicated that PRL frequently induces signaling through Stat5 in the cells and that LFA102 is capable of completely antagonizing this signaling. LFA102 also neutralizes rat PRLR and the antibody potently regresses PRL-dependent Nb2-C11 pre-T cell lymphoma tumors in vivo. Preliminary data suggests that LFA102 is also capable of inhibiting the growth of carcinogen-induced rat mammary tumors. In vitro studies have shown that LFA102 can also mediate antibody-dependent cellular cytotoxicity (ADCC) and inhibit the PRL-dependent release of the pro-angiogenic factor VEGF from breast cancer cells. Thus, there are multiple potential mechanisms through which LFA102 could show anti-tumor activity in vivo. Preclinical toxicological studies of LFA102 indicate that this therapeutic is well tolerated and exhibits a normal pharmacokinetic profile in relevant animal species. The safety and pharmacokinetics of LFA102 in humans are currently being evaluated in a phase I healthy volunteer trial. At the three dose levels explored so far, no infusion reactions or severe adverse events related to the drug have been reported. Preliminary results suggest that LFA102 has an adequate pharmacokinetic profile for further clinical development. An assessment of LFA102 in a population of metastatic breast cancer patients predicted to have the highest probability of benefit is imminent. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-09.