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 Show more
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