2026-04-14T03:04:22Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/110942025-10-24T10:25:25Zcom_2072_378070com_2072_378040col_2072_378092

Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein Kroenke, Mark Starcevic Manning, Marta de Zafra, Christina Zhang, Xinwen Cook, Kevin Archer, Michael GARRALDA, Elena Institut Català de la Salut [Kroenke MA] Clinical Immunology, Amgen, Thousand Oaks, CA, United States. [Starcevic Manning M] Translational Safety & Bioanalytical Sciences, Amgen, Thousand Oaks, CA, United States. [Zuch de Zafra CL] Translational Safety & Bioanalytical Sciences, Amgen, South San Francisco, CA, United States. [Zhang X] Clinical Pharmacology, Modeling, and Simulation, Amgen, South San Francisco, CA, United States. [Cook KD] Pharmacokinetics and Drug Metabolism, Amgen, South San Francisco, CA, United States. [Archer M] Global Safety, Amgen, Thousand Oaks, CA, United States. [Garralda Cabanas E] Vall d’Hebron Hospital Universitari, Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus Càncer - Immunoteràpia Macacos Anticossos monoclonals CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, Monoclonal ORGANISMS::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Primates::Haplorhini::Catarrhini::Cercopithecidae::Cercopithecinae::Macaca::Macaca fascicularis DISEASES::Neoplasms ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales ORGANISMOS::Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::primates::Haplorhini::Catarrhini::Cercopithecidae::Cercopithecinae::Macaca::Macaca fascicularis ENFERMEDADES::neoplasias TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapia biológica::inmunomodulación::inmunoterapia Anti-drug antibodies; Immunogenicity; Mutein Anticossos antidroga; Immunogenicitat; Muteïna Anticuerpos antidroga; Inmunogenicidad; Muteína 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. This research was funded by Amgen. 2024-02-21T08:04:36Z 2024-02-21T08:04:36Z 2024-01-26 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Kroenke MA, Starcevic Manning M, Zuch de Zafra CL, Zhang X, Cook KD, Archer M, et al. Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein. Front Immunol. 2024 Jan 26;15:1345473. 1664-3224 https://hdl.handle.net/11351/11094 10.3389/fimmu.2024.1345473 38343535 001159630800001 http://hdl.handle.net/11351/11094 eng Frontiers in Immunology;15 https://doi.org/10.3389/fimmu.2024.1345473 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf Frontiers Media Scientia