Peptide Logic LLC

Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons).

We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood–brain barrier) and impedes their downstream effects.

Case/control.

Academic medical center.

Mice.

Administration of peripherally restricted kappa receptor agonists and frequent blood sampling to determine hormone release and body temperature.

LH pulse parameters and body temperature.

First, chronic administration of a PRKA to bilaterally ovariectomized mice with experimentally induced hyperactivity of KNDy neurons reduces the animals’ elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity.

The inhibition of kisspeptin neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.

Prolactin (PRL) has recently been demonstrated to elicit female-selective nociceptor sensitization and increase pain-like behaviors in female animals.Here we report the discovery and characterization of first-in-class, humanized PRL neutralizing monoclonal antibodies (PRL mAbs).We obtained two potent and selective PRL mAbs, PL 200,031 and PL 200,039.PL 200,031 was engineered as human IgG1 whereas PL 200,039 was reformatted as human IgG4.Both mAbs have sub-nanomolar affinity for human PRL (hPRL) and produce concentration-dependent and complete inhibition of hPRL signaling at the hPRL receptor (hPRLR).These two PRL mAbs are selective for hPRL as they do not inhibit other hPRLR agonists such as human growth hormone or placental lactogen.They also cross-react with non-human primate PRL but not with rodent PRL.Further, both mAbs show long clearance half-lives after i.v. administration in FcRn-humanized mice.Consistent with their isotypes, these mAbs only differ in binding affinities to Fcγ receptors, as expected by design.Finally, PL 200,019, the murine parental mAb of PL 200,031 and PL 200,039, fully blocked stress-induced and PRL-dependent pain behaviors in female PRL-humanized mice, thereby providing in vivo preclin. proof-of-efficacy for PRL mAbs in mechanisms relevant to pain in females.