Bin Wu, James R. Falsey, Chawita Netirojjanakul, Brad Herberich, Jerry Ryan Holder, Kelvin Sham, Jennifer Aral, Neil Forsythe, Kenneth W. Walker, Shu-Chen Lu, Todd Hager, Shanaka Stanislaus, Renée Komorowski, Larissa Atangan, Michał Achmatowicz, Dante W. Romanini, Dohan Weeraratne, Les P. Miranda, Murielle M. Véniant, Yuan Cheng
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.