Author: Ahern, Elizabeth ; Hoofring, Sarah ; Wang, Jin ; Cook, Kevin D ; Zhang, Xinwen ; Aeffner, Famke ; Zuch de Zafra, Christina L ; Hui, Mun ; Mytych, Daniel T ; Lolkema, Martijn P ; Cabanas, Elena Garralda ; Starcevic Manning, Marta ; Saini, Gurleen ; Gupta, Shalini ; Kroenke, Mark A ; Govindan, Ramaswamy ; Archer, Michael
AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.