Monoclonal Antibody Against Prolactin Receptor: A Randomized Placebo-Controlled Study Evaluating Safety, Tolerability, and Pharmacokinetics of Repeated Subcutaneous Administrations in Postmenopausal Women

Abstract

BAY 1158061 is a potent monoclonal prolactin (PRL) receptor antibody, blocking PRL receptor (PRLR)-mediated signaling in a noncompetitive manner, which was tested in a randomized, placebo-controlled multiple dose study in postmenopausal women. The objective was to investigate safety, tolerability, pharmacokinetic characteristics, and effects of BAY 1158061 on serum PRL level. The study consisted of 4 parallel groups receiving up to 3 subcutaneous (sc) administrations of BAY 1158061 or placebo in 2 different dosing regimens. Twenty-nine healthy postmenopausal women were randomized and treated with BAY 1158061 or placebo: 30 mg at 14-day interval (7 participants), 60 mg at 28-day interval (8 participants), 90 mg at 14-day interval (7 participants), and placebo (7 participants). To keep the blinding, all randomized participants received sc injections biweekly (14-day interval) on 3 occasions in the lower abdomen. The PRLR antibody showed a favorable safety and tolerability profile in postmenopausal women with no distinct differences in occurrence of adverse events in BAY 1158061 or placebo-treated participants. BAY 1158061 displayed low immunogenicity with low titers of antidrug antibodies and absence of neutralizing antidrug antibodies. Pharmacokinetics were characterized by slow absorption after sc administration with median peak plasma concentrations 7 to 11 days after first dose and about 2-fold accumulation after repeated dosing every 2 weeks. The apparent mean elimination half-life was 9 to 16 days. The PRL concentration-time profiles over 24 hours showed no differences between verum- and placebo-treated participants. Based on the data obtained, BAY 1158061 is considered a good candidate for further development in endometriosis or other PRL-mediated disease conditions.

The effects of prolactin receptor blockade in a murine endometriosis interna model

“…The antibody 005‐C04 and its derivative Mat3 have been characterized previously 10,13–15 . Both behave as noncompetitive, selective PRLR antagonists in vitro and in vivo.…”

“…The antibody 005-C04 and its derivative Mat3 have been characterized previously. 10,[13][14][15] Both behave as noncompetitive, selective PRLR antagonists in vitro and in vivo. As antibody 005-C04 displayed no cross-reactivity to the rhesus monkey PRLR and toxicity studies were required in this species for subsequent clinical development, Mat3 was derived from 005-C04 by a two-staged mutagenesis approach.…”

“…Mat3 proved to be safe and well tolerated in a multiple dose phase I study conducted in postmenopausal women and there were no differences in treatment emergent adverse events between placebo and Mat3-treated women. 14 Taken together, in contrast to D2R agonists, PRLR blocking antibodies offer for the first time the opportunity to completely block…”

“…We previously identified and characterized the PRLR antibodies 005‐C04 13 and Mat3 which is closely related to its precursor antibody 005‐C04 14,15 . Both antibodies act as PRLR antagonists in vitro and in vivo 10,13–15 …”

“…To achieve complete blockade of PRLR‐mediated signaling activated by prolactin from pituitary as well as extra‐pituitary origin PRLR antagonists are required. We previously identified and characterized the PRLR antibodies 005‐C04 13 and Mat3 which is closely related to its precursor antibody 005‐C04 14,15 . Both antibodies act as PRLR antagonists in vitro and in vivo 10,13–15 …”