Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody

  • PLoS One. 2018 Apr 4;13(4):e0191926. doi: 10.1371/journal.pone.0191926.
Randi B Gombos  1 ,  Ana Gonzalez  1 ,  Mariana Manrique  1 ,  Dhan Chand  1 ,  David Savitsky  1 ,  Benjamin Morin  2 ,  Ekaterina Breous-Nystrom  3 ,  Christopher Dupont  4 ,  Rebecca A Ward  1 ,  Cornelia Mundt  3 ,  Benjamin Duckless  4 ,  Hao Tang  4 ,  Mark A Findeis  2 ,  Andrea Schuster  3 ,  Jeremy D Waight  1 ,  Dennis Underwood  2 ,  Christopher Clarke  5 ,  Gerd Ritter  6 ,  Taha Merghoub  7 ,  David Schaer  7 ,  Jedd D Wolchok  7 ,  Marc van Dijk  8 ,  Jennifer S Buell  9 ,  Jean-Marie Cuillerot  9 ,  Robert Stein  10 ,  Elise E Drouin  4 ,  Nicholas S Wilson  1
Affiliations
  • 1. Immuno-modulatory Drug Discovery, Agenus Incorporated, Lexington, Massachusetts, United States of America.
  • 2. Research Biochemistry, Agenus Incorporated, Lexington, Massachusetts, United States of America.
  • 3. Agenus Switzerland Incorporated, Basel, Switzerland.
  • 4. Translational Biomarkers, Agenus Incorporated, Lexington, Massachusetts, United States of America.
  • 5. Safety, Pharmacology and Toxicology, Agenus Incorporated, Lexington, Massachusetts, United States of America.
  • 6. The Ludwig Institute for Cancer Research, New York, New York, United States of America.
  • 7. Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
  • 8. Agenus United Kingdom Limited, Cambridge, United Kingdom.
  • 9. Research and Development Management, Agenus Incorporated, Lexington, Massachusetts, United States of America.
  • 10. Research and Development Consultant, Agenus Incorporated, Lexington, Massachusetts, United States of America.
PMID: 29617360 DOI: 10.1371/journal.pone.0191926
Abstract

CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with Other immunomodulatory antibodies. AGEN1884 was well-tolerated in non-human primates and enhanced vaccine-mediated antigen-specific immunity. AGEN1884 combined effectively with PD-1 blockade to elicit a T cell proliferative response in the periphery. Interestingly, an IgG2 variant of AGEN1884 revealed distinct functional differences that may have implications for optimal dosing regimens in patients. Taken together, the pharmacological properties of AGEN1884 support its clinical investigation as a single therapeutic and combination agent.

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