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ABBV-176, a PRLR antibody drug conjugate with a potent DNA-damaging PBD cytotoxin and enhanced activity with PARP inhibition.
- Source :
-
BMC cancer [BMC Cancer] 2021 Jun 09; Vol. 21 (1), pp. 681. Date of Electronic Publication: 2021 Jun 09. - Publication Year :
- 2021
-
Abstract
- Background: Prolactin 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.<br />Methods: We 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.<br />Results: In 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.<br />Conclusions: Collectively 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.
- Subjects :
- Animals
Cell Line, Tumor
Disease Models, Animal
Female
Humans
Immunoconjugates pharmacology
Mice
Mice, SCID
Poly(ADP-ribose) Polymerase Inhibitors pharmacology
Cytotoxins metabolism
Immunoconjugates therapeutic use
Poly(ADP-ribose) Polymerase Inhibitors therapeutic use
Receptors, Prolactin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2407
- Volume :
- 21
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- BMC cancer
- Publication Type :
- Academic Journal
- Accession number :
- 34107902
- Full Text :
- https://doi.org/10.1186/s12885-021-08403-5