Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative

Abstract

Somapacitan is a long-acting, once-weekly, albumin-binding growth hormone (GH) derivative. The reversible albumin-binding properties leads to prolonged circulation half-life. Here, we investigated and compared somapacitan with human GH on downstream receptor signaling in primary hepatocytes and hepatocellular models and using isothermal titration calorimetry to characterize receptor binding of somapacitan in the presence or absence of human serum albumin (HSA). With non-invasive fluorescence imaging we quantitatively visualize and compare the temporal distribution and examine the tissue-specific growth hormone receptor (GHR) activation at distribution sites. We found that signaling kinetics were slightly more rapid and intense for GH compared with somapacitan. Receptor binding isotherms were characterized by a high and a low affinity interaction site with or without HSA. Using in vivo optical imaging we found prolonged systemically biodistribution of somapacitan compared with GH, which correlated with plasma pharmacokinetics. Ex vivo mouse organ analysis revealed that the temporal fluorescent intensity in livers dosed with somapacitan was significantly increased compared with GH-dosed livers and correlated with the degree of downstream GHR activation. Finally, we show that fluorescent-labeled analogs distributed to the hypertrophic zone in the epiphysis of proximal tibia of hypophysectomized rats and that somapacitan and GH activate the GHR signaling in epiphyseal tissues.

Discovery of a Long-Acting Parathyroid Hormone 1–34 Analogue to Treat Hypoparathyroidism

“…Other methods based on thermodynamic techniques ( e.g. , isothermal titration calorimetry) or NMR were also reported to predict fatty acid–HSA binding capacity. , Recently, direct HSA binding tests of fatty acids based on ELISA or surface plasmon resonance have also been attempted. , The unspecific adhesion and non-specific adsorption of fatty acids is the main obstacle to the establishment of an in vitro method . In this study, we developed a method based on molecular interaction equipment (Blitz) using the principle of BLI.…”

Developments in the Management of Growth Hormone Deficiency: Clinical Utility of Somapacitan

“… 21 Somapacitan is cleared in the kidneys by glomerular filtration and subsequently degraded in the tubular cells or during the receptor-mediated internalization by the GH receptor in target tissues. 29 …”

“… 29 The level of activation was measured based on downstream tyrosine P-STAT5, as it is the primary mediator of insulin-like growth factor-I (IGF-I) transcription. 29 In addition, fluorescently tagged somapacitan administered to hypophysectomized rats with GHD was shown to distribute to the growth plate in living rats to bind specifically to the hypertrophic zone and primary spongiosa. These data demonstrate the ability of somapacitan to distribute to relevant tissues to promote growth and metabolic activities.…”

“…[26][27][28] Somapacitan binds reversibly, but extensively (>90% of somapacitan molecules are bound in the circulation and tissues), to a specific site on endogenous circulating human serum albumin domain II. 25,29 In a Phase 1 dose-escalation trial, the ratio of the highest somapacitan dose of 0.12 mg/kg/week administered in the presence of the lowest normal albumin concentration was 88,000. 21 This suggests that albumin occupancy was around 0.001%; hence, displacement of circulating albumin that is bound to somapacitan is unlikely to be of clinical significance.…”

“…21 Somapacitan is cleared in the kidneys by glomerular filtration and subsequently degraded in the tubular cells or during the receptor-mediated internalization by the GH receptor in target tissues. 29 In a study that investigated the tissue distribution and receptor activation of somapacitan in hypophysectomized rats with GHD, a dose-and time-dependent activation of phosphorylated STAT5 (P-STAT5) was observed for somapacitan in multiple tissues including the epiphyseal growth plates. 29 The level of activation was measured based on downstream tyrosine P-STAT5, as it is the primary mediator of insulin-like growth factor-I (IGF-I) transcription.…”