Anti-hGH monoclonal antibody, clone A091-11213

Background: Growth hormone (GH) deficiency is common in patients with Prader-Willi syndrome (PWS) and leads to short adult stature. The current study assessed clinical outcomes based on real-world observational data in pediatric patients with PWS who were treated with GH. Methods: Data from patients previously naive to treatment with GH who began therapy with somatropin were collected from 2006 to 2016 in the observational American Norditropin (R) Studies: Web-Enabled Research (ANSWER) Program (R) and NordiNet (R) International Outcome Study. Variables affecting change from baseline in height standard deviation scores (HSDS; n = 129) and body mass index standard deviation scores (BMI SDS; n = 98) were determined. Results: Patients included in both HSDS and BMI SDS analyses were treated with a mean GH dose of 0.03 mg/kg/d (SD, 0.01 mg/kg/d). Results from the HSDS analysis revealed that baseline age and years on treatment had a significant impact on the change in HSDS. In the BMI SDS analysis, longer GH treatment time led to a greater change in BMI SDS from baseline, and patients with a higher BMI at the start of treatment had a greater decrease in BMI over time. Conclusions: GH is effective in the management of children with PWS. Earlier treatment resulted in a greater gain in height, and a longer treatment period resulted in better outcomes for both height and BMI.

Carbohydrate side chain conformation confers a significant influence on reactivity during glycosylation and anomeric bond hydrolysis due to stabilization of the oxocarbenium-like transition state. By analysis of 513 pyranoside-bound glycoside hydrolase (GH) crystal structures, we determine that most glucosidases and beta-mannosidases preferentially bind their substrates in the most reactive gauche,gauche (gg) conformation, thereby maximizing stabilization of the corresponding oxocarbenium ion-like transition state during hydrolysis. alpha-Galactoside hydrolases mostly show a preference for the second most activating gauche,trans (gt) conformation to avoid the energy penalty that would arise from imposing the gg conformation on galacto-configured ligands. These preferences stand in stark contrast to the side chain populations observed for these sugars both in free solution and bound to nonhydrolytic proteins, where for the most part a much greater diversity of side chain conformations is observed. Analysis of sequences of GH-ligand complexes reveals that side chain restriction begins with the enzyme-substrate complex and persists through the transition state until release of the hydrolysis product, despite changes in ring conformation along the reaction coordinate. This work will inform the design of new generations of glycosidase inhibitors with restricted side chains that confer higher selectivity and/or affinity.