title: Preclinical Activity of the Novel Anti-Prolactin Receptor (PRLR) Antibody-Drug Conjugate REGN2878-DM1 in PRLR-Positive Breast Cancers.
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 activationin vitroand 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.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York. marcus.kelly@regeneron.com.
authors.forename: Marcus P
authors.initials: MP
authors.lastname: Kelly
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Carlos
authors.initials: C
authors.lastname: Hickey
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Sosina
authors.initials: S
authors.lastname: Makonnen
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Sandra
authors.initials: S
authors.lastname: Coetzee
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Sumreen
authors.initials: S
authors.lastname: Jalal
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Frank
authors.initials: F
authors.lastname: Delfino
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Jing
authors.initials: J
authors.lastname: Shan
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Terra B
authors.initials: TB
authors.lastname: Potocky
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Ishita
authors.initials: I
authors.lastname: Chatterjee
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Julian
authors.initials: J
authors.lastname: Andreev
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kunz
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Christopher
authors.initials: C
authors.lastname: D'Souza
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Giurleo
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nittoli
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Trail
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Kirshner
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000276:immunology; D051379:Mice; D011981:Receptors, Prolactin / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D011981:Receptors, Prolactin