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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MSK Authors
  1. Nai-Kong Cheung
    532 Cheung
  2. Vladimir Ponomarev
    101 Ponomarev
  3. Hong Xu
    27 Xu
  4. Linlin Wang
    2 Wang