RT Journal Article
T1 Carcinoembryonic Antigen (CEA)-Specific 4-1BB-Costimulation Induced by CEA-Targeted 4-1BB-Agonistic Trimerbodies
A1 Mikkelsen, Kasper
A1 Harwood, Seandean Lykke
A1 Compte, Marta
A1 Merino, Nekane
A1 Mølgaard, Kasper
A1 Lykkemark, Simon
A1 Álvarez Méndez, Ana María
A1 Blanco, Francisco J.
A1 Álvarez Vallina, Luis
AB 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 FcgR interactions. We have recently generated an EGFR-targeted 4-1BB-agonistictrimerbody 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.
PB Frontiers Media
YR 2019
FD 2019-07-31
LK https://hdl.handle.net/20.500.14352/108540
UL https://hdl.handle.net/20.500.14352/108540
LA eng
NO Mikkelsen K, Harwood SL, Compte M, Merino N, Mølgaard K, Lykkemark S, Alvarez-Mendez A, Blanco FJ and Álvarez-Vallina L (2019) Carcinoembryonic Antigen (CEA)-Specific 4-1BB-Costimulation Induced by CEA-Targeted 4-1BB-Agonistic Trimerbodies. Front. Immunol. 10:1791. doi: 10.3389/fimmu.2019.01791
NO grants from the Danish Council for Independent Research (DFF-6110-0053), the Spanish Ministry of Economy and Competitiveness (SAF2017-89437-P), and the CRIS Cancer Foundation.
DS Docta Complutense
RD 10 abr 2025