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Kemper, Kristel; Gielen, Ellis; Boross, Peter; Houtkamp, Mischa; Plantinga, Theo S; de Poot, Stefanie AH; Burm, Saskia M; Janmaat, Maarten L; Koopman, Louise A; van den Brink, Edward N; Rademaker, Rik; Verzijl, Dennis; Engelberts, Patrick J; Satijn, David; Sasser, A Kate; Breij, Esther CW

Mechanistic and pharmacodynamic studies of DuoBody-CD3x5T4 in preclinical tumor models

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  • Media type: E-Article
  • Title: Mechanistic and pharmacodynamic studies of DuoBody-CD3x5T4 in preclinical tumor models
  • Contributor: Kemper, Kristel; Gielen, Ellis; Boross, Peter; Houtkamp, Mischa; Plantinga, Theo S; de Poot, Stefanie AH; Burm, Saskia M; Janmaat, Maarten L; Koopman, Louise A; van den Brink, Edward N; Rademaker, Rik; Verzijl, Dennis; Engelberts, Patrick J; Satijn, David; Sasser, A Kate; Breij, Esther CW
  • Published: Life Science Alliance, LLC, 2022
  • Published in: Life Science Alliance, 5 (2022) 11, Seite e202201481
  • Language: English
  • DOI: 10.26508/lsa.202201481
  • ISSN: 2575-1077
  • Keywords: Health, Toxicology and Mutagenesis ; Plant Science ; Biochemistry, Genetics and Molecular Biology (miscellaneous) ; Ecology
  • Origination:
  • Footnote:
  • Description: CD3 bispecific antibodies (bsAbs) show great promise as anticancer therapeutics. Here, we show in-depth mechanistic studies of a CD3 bsAb in solid cancer, using DuoBody-CD3x5T4. Cross-linking T cells with tumor cells expressing the oncofetal antigen 5T4 was required to induce cytotoxicity. Naive and memory CD4+and CD8+T cells were equally effective at mediating cytotoxicity, and DuoBody-CD3x5T4 induced partial differentiation of naive T-cell subsets into memory-like cells. Tumor cell kill was associated with T-cell activation, proliferation, and production of cytokines, granzyme B, and perforin. Genetic knockout ofFASorIFNGR1in 5T4+tumor cells abrogated tumor cell kill. In the presence of 5T4+tumor cells, bystander kill of 5T4−but not of 5T4−IFNGR1−tumor cells was observed. In humanized xenograft models, DuoBody-CD3x5T4 antitumor activity was associated with intratumoral and peripheral blood T-cell activation. Lastly, in dissociated patient-derived tumor samples, DuoBody-CD3x5T4 activated tumor-infiltrating lymphocytes and induced tumor-cell cytotoxicity, even when most tumor-infiltrating lymphocytes expressed PD-1. These data provide an in-depth view on the mechanism of action of a CD3 bsAb in preclinical models of solid cancer.
  • Access State: Open Access