Abstract
The Prolactin Receptor (PRLR) is a type 1 cytokine receptor that is expressed in a subset of breast cancers and may contribute to its pathogenesis. It is relatively overexpressed in approximately 25% of human breast tumors while expressed at low levels in some normal human tissues including the mammary gland. We developed an anti-PRLR antibody-drug conjugate (ADC), to target PRLR-positive breast cancer. REGN2878-DM1 is comprised of a fully human high-affinity function-blocking anti-PRLR IgG1 antibody (REGN2878) conjugated via a noncleavable SMCC linker to the cytotoxic maytansine derivative DM1. Both unconjugated REGN2878 and conjugated REGN2878-DM1 block PRL-mediated activation in vitro and are rapidly internalized into lysosomes. REGN2878-DM1 induces potent cell-cycle arrest and cytotoxicity in PRLR-expressing tumor cell lines. In vivo, REGN2878-DM1 demonstrated significant antigen-specific antitumor activity against breast cancer xenograft models. In addition, REGN2878-DM1 showed additive activity when combined with the antiestrogen agent fulvestrant. These results illustrate promising antitumor activity against PRLR-positive breast cancer xenografts and support the evaluation of anti-PRLR ADCs as potential therapeutic agents in breast cancer. Mol Cancer Ther; 16(7); 1299-311. ©2017 AACR.
Highlights
Increased understanding of breast cancer has revealed that it is a heterogeneous disease comprised of various subtypes based on pathology and different molecular profiles [1]
Prolactin Receptor (PRLR) is expressed in human breast cancers To examine the extent of PRLR expression in breast cancers, RNAscope, a form of ISH, was performed on a panel of commercially obtained Formalin-Fixed Paraffin Embedded (FFPE)-embedded breast tumor samples
The expression patterns of PRLR assessed by RNAscope and Western blotting are consistent with analysis of PRLR mRNA expression levels in human breast cancer from The Cancer Genome Atlas gene expression database
Summary
Increased understanding of breast cancer has revealed that it is a heterogeneous disease comprised of various subtypes based on pathology and different molecular profiles [1]. A clear example of this is the classification of tumors based on expression of receptor tyrosine kinase HER2 and hormone receptors for estrogen (ER) and progesterone (PR). ER/PR-positive tumors are treated with hormonal therapy comprised of agents such as tamoxifen, aromatase inhibitors, and selective estrogen receptor downregulators (SERD) such as fulvestrant [2]. 15% to 20% of breast cancers do not express significant levels of these receptors [4]. These tumors, classified as triple-negative cancers, as well as patients that progress following hormonal or HER2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
