Carcinoembryonic Antigen (CEA)-Specific 4-1BB-Costimulation Induced by CEA-Targeted 4-1BB-Agonistic Trimerbodies

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  • Kasper Mikkelsen
  • ,
  • Seandean Lykke Harwood
  • Marta Compte, Leadartis SL, Dept Antibody Engn
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  • Nekane Merino, CIC bioGUNE, CIC bioGUNE, Struct Biol Unit
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  • Kasper Molgaard
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  • Simon Lykkemark
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  • Ana Alvarez-Mendez, Univ Complutense Madrid, Complutense University of Madrid, Dept Nursing
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  • Francisco J. Blanco, IKERBASQUE Basque Fdn Sci, Basque Foundation for Science, CIC BioGUNE, Struct Biol Unit
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  • Luis Alvarez-Vallina, Hosp Univ 12 Octubre, Hospital Universitario 12 de Octubre, Dept Immunol, Canc Immunotherapy Unit UNICA, Inst Invest Sanitaria 12 Octubre I 12, Hospital Universitario 12 de Octubre, Immunooncol & Immunotherapy Grp

4-1BB (CD137) is an inducible costimulatory receptor that promotes expansion and survival of activated T cells; and IgG-based 4-1BB-agonistic monoclonal antibodies exhibited potent antitumor activity in clinical trials. However, the clinical development of those antibodies is restricted by major off-tumor toxicities associated with Fc gamma R interactions. We have recently generated an EGFR-targeted 4-1BB-agonistic trimerbody that demonstrated strong antitumor activity and did not induce systemic inflammatory cytokine secretion and hepatotoxicity associated with first-generation 4-1BB agonists. Here, we generate a bispecific 4-1BB-agonistic trimerbody targeting the carcinoembryonic antigen (CEA) that is highly expressed in cancers of diverse origins. The CEA-targeted anti-4-1BB-agonistic trimerbody consists of three 4-1BB-specific single-chain fragment variable antibodies and three anti-CEA single-domain antibodies positioned around a murine collagen XVIII-derived homotrimerization domain. The trimerbody was produced as a homogenous, non-aggregating, soluble protein purifiable by standard affinity chromatographic methods. The purified trimerbody was found to be trimeric in solution, very efficient at recognizing 4-1BB and CEA, and potently costimulating T cells in vitro in the presence of CEA. Therefore, trimerbody-based tumor-targeted 4-1BB costimulation is a broadly applicable and clinically feasible approach to enhance the costimulatory environment of disseminated tumor lesions.

TidsskriftFrontiers in Immunology
Antal sider10
StatusUdgivet - jul. 2019

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