A Neutralizing Prolactin Receptor Antibody Whose In Vivo Application Mimics the Phenotype of Female Prolactin Receptor-Deficient Mice.
The prolactin receptor (PRLR) has been implicated in a variety of physiological processes (lactation, reproduction) and diseases (breast cancer, autoimmune diseases). Prolactin synthesis in the pituitary and extrapituitary sites is regulated by different promoters. Dopamine receptor agonists such as bromocriptine can only interfere with pituitary prolactin synthesis and thus do not induce a complete blockade of PRLR signaling. Here we describe the identification of a human monoclonal antibody 005-C04 that blocks PRLR-mediated signaling at nanomolar concentrations in vitro. In contrast to a negative control antibody, the neutralizing PRLR antibody 005-C04 inhibits signal transducer and activator of transcription 5 phosphorylation in T47D cells and proliferation of BaF3 cells stably expressing murine or human PRLRs in a dose-dependent manner. In vivo application of this new function-blocking PRLR antibody reflects the phenotype of PRLR-deficient mice. After antibody administration female mice become infertile in a reversible manner. In lactating dams, the antibody induces mammary gland involution and negatively interferes with lactation capacity as evidenced by reduced milk protein expression in mammary glands and impaired litter weight gain. Antibody-mediated blockade of the PRLR in vivo stimulates hair regrowth in female mice. Compared with peptide-derived PRLR antagonists, the PRLR antibody 005-C04 exhibits several advantages such as higher potency, noncompetitive inhibition of PRLR signaling, and a longer half-life, which allows its use as a tool compound also in long-term in vivo studies. Therefore, we suggest that this antibody will help to further our understanding of the role of auto- and paracrine PRLR signaling in health and disease.
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Christiane
C
Otto
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Anna
A
Särnefält
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Anne
A
Ljungars
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Siegmund
S
Wolf
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Beate
B
Rohde-Schulz
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Iris
I
Fuchs
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Jenny
J
Schkoldow
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Mikael
M
Mattsson
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Richardus
R
Vonk
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Axel
A
Harrenga
TRG Oncology and Gynaecological Therapy (C.O., S.W., B.R.-S., I.F., J.S.), and Department of Research and Clinical Sciences Statistics (R.V.), Bayer Pharma AG, 13342 Berlin, Germany; Department of Protein Engineering (A.S., A.L., M.M.), BioInvent International AB, Soelvegatan 41, SE-223 70 Lund, Sweden; and Department of Global Biologics (A.H., C.F.), Bayer Pharma AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
Christoph
C
Freiberg
D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011981:Receptors, Prolactin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D057134:Antibodies, Neutralizing; D011981:Receptors, Prolactin