Numerous lines of evidence suggest that the polypeptide hormone prolactin (PRL) may contribute to breast and prostate tumorigenesis through its interactions with the prolactin receptor (PRLR). Here, we describe the biologic properties of LFA102, a humanized neutralizing monoclonal antibody directed against the extracellular domain of PRLR. This antibody was found to effectively antagonize PRL-induced signaling in breast cancer cells in vitro and in vivo and to block PRL-induced proliferation in numerous cell line models, including examples of autocrine/paracrine PRL activity. A single administration of LFA102 resulted in regression of PRL-dependent Nb2-11 tumor xenografts and significantly prolonged time to progression. Finally, LFA102 treatment significantly inhibited PRLR signaling as well as tumor growth in a carcinogen-induced, estrogen receptor-positive rat mammary cancer model as a monotherapy and enhanced the efficacy of the aromatase inhibitor letrozole when administered in combination. The biologic properties of LFA102, elucidated by the preclinical studies presented here, suggest that this antibody has the potential to be a first-in-class, effective therapeutic for the treatment of PRL-dependent cancers. Mol Cancer Ther; 12(3); 295-305. Ó2012 AACR.

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The cell surface glycoprotein P-cadherin is an attractive target for an antibody-drug conjugate (ADC) therapy as it is known to be highly expressed in a number of malignancies, including those arising in the epithelium of the breast, lung, bladder, esophagus, stomach, endometrium and colon, among others. In breast cancer, P-cadherin is frequently overexpressed in high grade invasive tumors and is a reliable marker of the basal-like breast cancer molecular subtype, a disease with no effective therapeutic treatment options. Based on the expression profile of P-cadherin in human cancer, a highly selective and potent ADC was developed to target cancer types overexpressing this glycoprotein. This ADC consists of a fully human anti-P-cadherin-specific antibody conjugated to the potent maytansine-derived microtubule-disruptor, DM1, via an SMCC non-cleavable thioether linkage (technology licensed from ImmunoGen, Inc.). In vitro, the ADC was demonstrated to selectively bind P-cadherin expressing cell lines, to rapidly internalize and traffic to lysosomes, and to release a sufficient amount of activated payload to potently induce a cytotoxic response in cell viability assays. Profiling of activity in a cell line panel indicated that this ADC can effectively target and kill P-cadherin-positive cancer cells representing breast, head and neck, and bladder carcinomas. In vivo, the ADC was highly efficacious in numerous relevant xenograft models of P-cadherin expressing cancers, including breast, head and neck, bladder and lung. From this promising cellular and in vivo activity, this ADC may be an effective treatment for patients with P-cadherin positive cancers of high unmet medical need. Citation Format: Daniel Menezes, Tinya J. Abrams, Christopher Karim, Yan Tang, Chi Ying, Kathy Miller, Christie Fanton, Majid Ghoddusi, Zhen Wang, Montesa Patawaran, Nancy Pryer, Emma Lees, Jason Damiano. Development and activity of a novel antibody-drug conjugate for the treatment of P-cadherin expressing cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1682. doi:10.1158/1538-7445.AM2015-1682

The prolactin receptor (PRLR) is a class I cytokine receptor frequently expressed in breast and prostate cancer. 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. Breast- and prostate-specific overexpression of PRL in transgenic mice leads to a higher incidence of mammary and prostate tumors, respectively. In addition, the PRLR locus is the site of frequent viral integrations in MMTV-derived mammary tumors. Elevated serum PRL levels in humans have been correlated with an increased risk for breast cancer, and 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. In prostate cancer specimens, the presence of prolactin and phosphorylated Stat5 have been reported to be associated with high-grade tumors and poor clinical outcomes, suggesting a role of the PRL/PRLR signaling pathway in the pathology of this disease as well. 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 these tumor types. LFA102 is a Human Engineered™ anti-PRLR antibody of the IgG1 isotype that neutralizes the function of PRLR through a nonligand competitive binding interaction. LFA102 blocks PRL-induced signaling and proliferation in T47D and MCF7 human breast cancer cells in vitro, and abolishes PRL-induced phospho-Stat5 signaling in T47D xenograft tumors in vivo. This antibody also cross-reacts with and neutralizes rat PRLR and is capable of potently regressing PRL-dependent Nb2-C11 pre-T cell lymphoma tumors in vivo. In vitro studies have shown that LFA102 can mediate antibody-dependent cellular cytotoxicity (ADCC) and inhibit the PRL-dependent release of the proangiogenic factor VEGF from breast cancer cells. Thus, there are multiple potential mechanisms through which LFA102 could show antitumor 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. A phase 1b trial in breast and prostate cancer is planned to evaluate the efficacy of this antibody in patient populations predicted to have the highest probability of benefiting from an anti-PRLR therapeutic. This presentation will provide a summary of the preclinical data supporting the clinical development of LFA102. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2011-DDT02-02

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