Unknown

Dataset Information

0

Silencing Fc Domains in T cell-Engaging Bispecific Antibodies Improves T-cell Trafficking and Antitumor Potency.


ABSTRACT: Bispecific antibodies (BsAb) that engage T cells bind to tumor cells via a tumor-associated antigen and to T cells through surface CD3. BsAbs have promising antitumor properties in vivo Here, we describe the effects of Fc silencing on BsAb-driven T-cell trafficking to solid tumors. We used BsAbs specific for disialoganglioside GD2 or oncoprotein ErbB2 (HER2) and built on the IgG(L)-scFv platform with or without Fc silencing. We studied the kinetics of T-cell infiltration from blood into solid tumor masses when driven by these BsAbs. We also investigated the therapeutic efficacy of these BsAbs in two mouse models: immunodeficient mice xenografted with patient-derived GD2+ neuroblastoma or HER2+ breast cancer, and human CD3? transgenic mice implanted with a GD2+ murine tumor. BsAbs built with intact Fc domain were unable to drive T cells to tumor, thereby failing to achieve an antitumor effect in mice. T cells became sequestered in lungs by myeloid cells or depleted in circulation. In contrast, when Fc function was silenced by N297A ± K322A mutations, T cells were able to infiltrate into subcutaneous solid tumors, a prerequisite for successful therapy outcome.

SUBMITTER: Wang L 

PROVIDER: S-EPMC7398503 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

Silencing Fc Domains in T cell-Engaging Bispecific Antibodies Improves T-cell Trafficking and Antitumor Potency.

Wang Linlin L   Hoseini Sayed Shahabuddin SS   Xu Hong H   Ponomarev Vladimir V   Cheung Nai-Kong NK  

Cancer immunology research 20191015 12


Bispecific antibodies (BsAb) that engage T cells bind to tumor cells via a tumor-associated antigen and to T cells through surface CD3. BsAbs have promising antitumor properties <i>in vivo</i> Here, we describe the effects of Fc silencing on BsAb-driven T-cell trafficking to solid tumors. We used BsAbs specific for disialoganglioside GD2 or oncoprotein ErbB2 (HER2) and built on the IgG(L)-scFv platform with or without Fc silencing. We studied the kinetics of T-cell infiltration from blood into s  ...[more]

Similar Datasets

| S-EPMC8154967 | biostudies-literature
| S-EPMC4492699 | biostudies-literature
| S-EPMC4485828 | biostudies-other
| S-EPMC7731630 | biostudies-literature
| S-EPMC8657033 | biostudies-literature
| S-EPMC10324450 | biostudies-literature
| S-EPMC7236391 | biostudies-literature
| S-EPMC8243740 | biostudies-literature
| S-EPMC9779728 | biostudies-literature