A long-lasting prolactin to combat lactation insufficiency

Human infants are born to breastfeed. While 50% of lactating persons report struggling to make enough milk, there are no governmentally-approved drugs to enhance lactation1. Here, we engineer a variant of the naturally-occurring driver of lactation, the hormone Prolactin, to increase its serum half-life and produce a viable drug candidate. Our engineered variant,Prolactin-eXtra Long-acting(Prolactin-XL), is comprised of endogenously active human prolactin fused to an engineered human IgG1 Fc domain designed to overcome the unique drug development challenges specific to the lactating person-infant dyad. Our Prolactin-XL has a serum half-life of 70.9h in mice, 2,625-fold longer than endogenously active prolactin alone (70.9h v. 0.027h). We demonstrate that Prolactin-XL increases milk production and restores growth of pups fed by dams with pharmacologically-ablated lactation. We show that Prolactin-XL-enhanced lactation is accompanied by reversible, alveolar cell-driven changes in mammary gland morphology. Prolactin-XL treatment was associated with no identifiable pathology or adverse side effect in the lactating mice or nursing pups. This work establishes long-acting prolactins as a potentially powerful pharmacologic means to combat insufficient lactation. Implications for future research in lactating mammary gland biology and a potential preclinical path for developing Prolactin-XL for use in lactating persons are discussed. Overall design: All animal work was approved by the Harvard Medical School IACUC under protocol IS00003310. C57bl/6j mice (Jackson; 000664) were mated at 8 weeks of age. On day 7 postpartum, litters were normalized to 5 pups per dam. Pups were weighed daily until they were weaned at day 21 postpartum or they reached endpoint (20% weight loss compared to positive controls). Beginning on day 7 postpartum, and every other day thereafter, dams were administered 5mg/kg dose of Fc-PRL-13 or a PBS control by subcutaneous. Dams were dosed until their pups were weaned at day 21 postpartum. Abdominal mammary glands were harvested and stored in RNAlater (Thermo Fisher Scientific, AM7020) overnight at 4C. Samples were then stored at -80C until submitted to Azenta/Genewiz for standard RNA sequencing.