Mechanistic and pharmacodynamic studies of DuoBody-CD3x5T4 in preclinical tumor models
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...
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Published in | Life science alliance Vol. 5; no. 11; p. e202201481 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Life Science Alliance LLC
01.11.2022
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Subjects | |
Online Access | Get full text |
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Summary: | 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
or
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. |
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ISSN: | 2575-1077 2575-1077 |
DOI: | 10.26508/lsa.202201481 |