Preclinical Activity of the Novel Anti-Prolactin Receptor (PRLR) Antibody–Drug Conjugate REGN2878-DM1 in PRLR-Positive Breast Cancers
| Autor: | Sandra Coetzee, Jing Shan, Sosina Makonnen, Thomas Nittoli, Christopher A. D’Souza, Ishita Chatterjee, Yu Wang, Marcus Kelly, Arthur Kunz, Carlos Hickey, Julian Andreev, Jason T. Giurleo, Jessica R. Kirshner, Pamela Trail, Frank Delfino, Sumreen Jalal, Terra Potocky, Gavin Thurston |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_specialty Antibody-drug conjugate Immunoconjugates Receptors Prolactin Mammary gland Breast Neoplasms Antibodies Monoclonal Humanized Mice 03 medical and health sciences 0302 clinical medicine Breast cancer In vivo Internal medicine medicine Animals Humans Cell Proliferation Fulvestrant Chemistry Prolactin receptor Cancer medicine.disease Antiestrogen Xenograft Model Antitumor Assays Antibodies Anti-Idiotypic 030104 developmental biology Endocrinology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research Female medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 16:1299-1311 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-16-0839 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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