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Retargeting T cells to GD2 pentasaccharide on human tumors using Bispecific humanized antibody.

Abstract
Anti-disialoganglioside GD2 IgG antibodies have shown clinical efficacy in solid tumors that lack human leukocyte antigens (e.g., neuroblastoma) by relying on Fc-dependent cytotoxicity. However, there are pain side effects secondary to complement activation. T-cell retargeting bispecific antibodies (BsAb) also have clinical potential, but it is thus far only effective against liquid tumors. In this study, a fully humanized hu3F8-BsAb was developed, in which the anti-CD3 huOKT3 single-chain Fv fragment (ScFv) was linked to the carboxyl end of the anti-GD2 hu3F8 IgG1 light chain, and was aglycosylated at N297 of Fc to prevent complement activation and cytokine storm. In vitro, hu3F8-BsAb activated T cells through classic immunologic synapses, inducing GD2-specific tumor cytotoxicity at femtomolar EC50 with >10⁵-fold selectivity over normal tissues, releasing Th1 cytokines (TNFα, IFNγ, and IL2) when GD2⁺ tumors were present. In separate murine neuroblastoma and melanoma xenograft models, intravenous hu3F8-BsAb activated T cells in situ and recruited intravenous T cells for tumor ablation, significantly prolonging survival from local recurrence or from metastatic disease. Hu3F8-BsAb, but not control BsAb, drove T cells and monocytes to infiltrate tumor stroma. These monocytes were necessary for sustained T-cell proliferation and/or survival and contributed significantly to the antitumor effect. The in vitro and in vivo antitumor properties of hu3F8-BsAb and its safety profile support its further clinical development as a cancer therapeutic, and provide the rationale for exploring aglycosylated IgG-scFv as a structural platform for retargeting human T cells.
AuthorsHong Xu, Ming Cheng, Hongfen Guo, Yuedan Chen, Morgan Huse, Nai-Kong V Cheung
JournalCancer immunology research (Cancer Immunol Res) Vol. 3 Issue 3 Pg. 266-77 (Mar 2015) ISSN: 2326-6074 [Electronic] United States
PMID25542634 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright©2014 American Association for Cancer Research.
Chemical References
  • Antibodies, Bispecific
  • CD3 Complex
  • Gangliosides
  • Immunoglobulin G
  • Single-Chain Antibodies
  • ganglioside, GD2
Topics
  • Animals
  • Antibodies, Bispecific (immunology)
  • CD3 Complex (immunology)
  • Cell Line, Tumor
  • Cell Proliferation (physiology)
  • Gangliosides (immunology)
  • Humans
  • Immunoglobulin G (immunology)
  • Melanoma (drug therapy)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Monocytes (immunology)
  • Neuroblastoma (drug therapy)
  • Single-Chain Antibodies (immunology)
  • T-Lymphocytes (immunology)
  • Xenograft Model Antitumor Assays

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