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

ABSTRACT: 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 of FAS or IFNGR1 in 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.

SUBMITTER: Kemper K

PROVIDER: S-EPMC9458754 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Kemper Kristel K Gielen Ellis E Boross Peter P Houtkamp Mischa M Plantinga Theo S TS de Poot Stefanie Ah SA Burm Saskia M SM Janmaat Maarten L ML Koopman Louise A LA van den Brink Edward N EN Rademaker Rik R Verzijl Dennis D Engelberts Patrick J PJ Satijn David D Sasser A Kate AK Breij Esther Cw EC

Life science alliance 20220908 11

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<sup>+</sup> and CD8<sup>+</sup> T cells were equally effective at mediating cytotoxicity, and DuoBody-CD3x5T4 induced partial differentiation of naive T-cell subsets into memory-like cells ...[more]

PMID: 36271507

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

Publications

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

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