Extended Data Fig. 1: In vivo pharmacokinetic profile and in vitro activity of mGIPR-Ab.
To determine dose level and dose frequency of central administration of mGIPR-Ab, pharmacokinetic profile of (a) brain and (b) plasma exposure was assessed at 4, 24, 72, 120, and 168 h following a single ICV injection of 15 µg/µL/mouse dose of mGIPR-Ab. To evaluate and compare weight loss from ICV vs. IP mGIPR-Ab treatment, (c) change in body weight was normalized to change in body weight in IgG1 control antibody treatment group with corresponding route of administration. To define meaningful levels of exposure in vivo, (d) mGIPR-Ab antagonist inhibition of GIP-induced cAMP production was measured in neuro2A cells (mGIPR-Ab run in technical quadruplicates and GIP run in technical duplicates). In vitro IC50 value of mGIPR-Ab could then be used to compare with exposure levels in brain, plasma, and peripheral tissues following central or systemic administration of mGIPR-Ab in diet-induced obese male mice. (A-B) 4 h (n=3), 24 h (n=3), 72 h (n=3), 120 h (n=3), 168 h (n=2). (A-B) Data represent mean ± SEM. (c) Data represent mean normalized to Control-Ab for the corresponding route of administration. (d) Assay was run in technical quadruplicate (mGIPR-Ab) and triplicate (GIP). cAMP = cyclic AMP; EC50 = half-maximal effective concentration; IC50 = half-maximal inhibitory concentration; ICV = intracerebroventricular.
