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Mechanistic and pharmacodynamic studies of DuoBody-CD3x5T4 in preclinical tumor models
Kristel Kemper1, Ellis Gielen1, Peter Boross1
1Genmab, Utrecht, The Netherlands.
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.
Insights
CD3 bispecific antibodies (bsAbs) effectively target solid tumors by linking T cells to 5T4-expressing cancer cells. This bispecific antibody therapy activates T cells, leading to tumor cell destruction and T-cell differentiation.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- CD3 bispecific antibodies (bsAbs) are a promising class of anticancer therapeutics.
- Understanding the precise mechanisms of CD3 bsAbs in solid tumors is crucial for optimizing their efficacy.
Purpose of the Study:
- To conduct in-depth mechanistic studies of a CD3 bsAb, DuoBody-CD3x5T4, in solid cancer models.
- To elucidate the role of T-cell subsets, tumor cell targets, and host factors in CD3 bsAb-mediated cytotoxicity.
Main Methods:
- Utilized DuoBody-CD3x5T4 in preclinical solid cancer models.
- Investigated T-cell activation, proliferation, cytokine production, and cytotoxicity.
- Employed genetic knockout models (FAS, IFNGR1) and humanized xenograft models.
- Analyzed patient-derived tumor samples.
Main Results:
- Cytotoxicity required cross-linking of T cells with 5T4-expressing tumor cells.
- Both naive and memory CD4+ and CD8+ T cells mediated tumor kill, with partial differentiation of naive cells.
- Tumor cell kill involved T-cell activation, proliferation, cytokine release, and was dependent on FAS and IFNGR1 expression.
- Observed bystander killing of tumor cells lacking 5T4 but expressing IFNGR1.
- DuoBody-CD3x5T4 demonstrated antitumor activity in vivo, correlating with T-cell activation.
- Activated tumor-infiltrating lymphocytes and induced cytotoxicity in patient samples, even in PD-1-expressing settings.
Conclusions:
- DuoBody-CD3x5T4 mediates solid tumor cell killing through T-cell engagement and activation.
- The mechanism involves T-cell differentiation, cytokine production, and is dependent on specific tumor cell factors (FAS, IFNGR1).
- This CD3 bsAb shows potential in diverse solid tumor contexts, including those with PD-1 expression.
