Silencing Fc domains in T cell-engaging bispecific antibodies improves t-cell trafficking and antitumor potency Journal Article
| Authors: | Wang, L.; Hoseini, S. S.; Xu, H.; Ponomarev, V.; Cheung, N. K. |
| Article Title: | 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-derivedGD2+ neuroblastoma or HER2+ breast cancer, and human CD3e 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. © 2019 American Association for Cancer Research. |
| Journal Title: | Cancer Immunology Research |
| Volume: | 7 |
| Issue: | 12 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-12-01 |
| Start Page: | 2013 |
| End Page: | 2024 |
| Language: | English |
| DOI: | 10.1158/2326-6066.Cir-19-0121 |
| PUBMED: | 31615814 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Source: Scopus |
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