👤 Chawita Netirojjanakul

Multispecific therapeutics represent an increasingly important approach for enhancing the efficacy in complex diseases. Here, we report the design and optimization of novel antibody-peptide conjugates that combine glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonism with glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism for the treatment of obesity. A series of hybrid molecules was generated by conjugating synthetic GLP-1 peptides to IgG-based anti-GIPR antibodies, yielding markedly prolonged systemic exposure of the structurally intact GLP-1 peptide. In diet-induced obese mice and obese monkeys, once weekly administration of anti-GIPR-Ab/GLP-1 conjugates produced sustained body weight loss and improvements in metabolic parameters. This optimization effort culminated in the discovery of AMG 133, currently in phase III clinical trials with a profile that may support monthly dosing. Show less

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 bispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters. BW loss is greater with GIPR-Ab/GLP-1 than with GIPR-Ab or a control antibody conjugate, suggesting synergistic effects. GIPR-Ab/GLP-1 also reduces the respiratory exchange ratio in DIO mice. Simultaneous receptor binding and rapid receptor internalization by GIPR-Ab/GLP-1 amplify endosomal cAMP production in recombinant cells expressing both receptors. This may explain the efficacy of the bispecific molecules. Overall, our GIPR-Ab/GLP-1 molecules promote BW loss, and they may be used for treating obesity. Show less