2. Academic Validation
  3. 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

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. doi: 10.3389/fimmu.2024.1345473.
Mark A Kroenke 1,  Marta Starcevic Manning 2,  Christina L Zuch de Zafra 3,  Xinwen Zhang 4,  Kevin D Cook 5,  Michael Archer 6,  Martijn P Lolkema 7,  Jin Wang 2,  Sarah Hoofring 2,  Gurleen Saini 2,  Famke Aeffner 3,  Elizabeth Ahern 8,  Elena Garralda Cabanas 9,  Ramaswamy Govindan 10,  Mun Hui 11,  Shalini Gupta 2,  Daniel T Mytych 1
Affiliations

Affiliations

  • 1 Clinical Immunology, Amgen, Thousand Oaks, CA, United States.
  • 2 Translational Safety & Bioanalytical Sciences, Amgen, Thousand Oaks, CA, United States.
  • 3 Translational Safety & Bioanalytical Sciences, Amgen, South San Francisco, CA, United States.
  • 4 Clinical Pharmacology, Modeling, and Simulation, Amgen, South San Francisco, CA, United States.
  • 5 Pharmacokinetics and Drug Metabolism, Amgen, South San Francisco, CA, United States.
  • 6 Global Safety, Amgen, Thousand Oaks, CA, United States.
  • 7 Early Development, Amgen, Thousand Oaks, CA, United States.
  • 8 Medical Oncology, Monash Health, Clayton, VIC, Australia.
  • 9 Research Unit, Hospital Universitario Vall d'Hebron, Barcelona, Spain.
  • 10 Division of Hematology and Oncology, Washington University Medical School, St. Louis, MO, United States.
  • 11 Chris O'Brien Lifehouse, Camperdown, NSW, Australia.
PMID: 38343535 DOI: 10.3389/fimmu.2024.1345473
Abstract

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.

Keywords

IL-21; IgE; PD-1; anti-drug antibodies; immunogenicity; mutein.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P99687
    99.00%, Anti-PD-1 Antibody/IL-21 Mutein