Abstract
BackgroundProlactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations.MethodsWe derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models.ResultsIn both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage.ConclusionsCollectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.
Highlights
Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers
Generation of a PRLR antibody-drug conjugate (ADC) Candidate antibodies were initially conjugated to Monomethyl auristatin (MMAE) payloads and evaluated for their ability to inhibit the growth of the BT-474, an Estrogen receptor (ER)+, progesterone receptor (PR), Human epidermal growth factor receptor 2 (HER2)+ breast cancer cell line
BT-474 has ~ 10, 000 PRLR receptors per cell, which is lower than the number typically necessary to mediate effective ADC killing, suggesting that efficient internalization may be a critical component for activity of a PRLR ADC (Table 1)
Summary
Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. Development of targeted agents has led to improved outcomes in patients with breast cancer, 50% of patients with advanced disease treated with current standard of care will suffer from disease progression [3]. This observation highlights the need for additional treatment options for patients with advanced breast cancer including Her2+, TDM-1 refractory breast cancer and triple negative breast cancer (TNBC). PRLR has been shown to confer resistance against chemotherapeutic agents including docetaxel, doxorubicin and cisplatin [17]
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