Preclinical Activity of the Novel Anti-Prolactin Receptor (PRLR) Antibody-Drug Conjugate REGN2878-DM1 in PRLR-Positive Breast Cancers

  • Mol Cancer Ther. 2017 Jul;16(7):1299-1311. doi: 10.1158/1535-7163.MCT-16-0839.
Marcus P Kelly  1 ,  Carlos Hickey  2 ,  Sosina Makonnen  2 ,  Sandra Coetzee  2 ,  Sumreen Jalal  2 ,  Yu Wang  2 ,  Frank Delfino  2 ,  Jing Shan  2 ,  Terra B Potocky  2 ,  Ishita Chatterjee  2 ,  Julian Andreev  2 ,  Arthur Kunz  2 ,  Christopher D'Souza  2 ,  Jason T Giurleo  2 ,  Thomas Nittoli  2 ,  Pamela A Trail  2 ,  Gavin Thurston  2 ,  Jessica R Kirshner  2
Affiliations
  • 1. Regeneron Pharmaceuticals, Inc., Tarrytown, New York. [email protected].
  • 2. Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
PMID: 28377489 DOI: 10.1158/1535-7163.MCT-16-0839
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.

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