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Ref Type Journal Article
PMID (25542634)
Authors Xu H, Cheng M, Guo H, Chen Y, Huse M, Cheung NK
Title Retargeting T cells to GD2 pentasaccharide on human tumors using Bispecific humanized antibody.
Journal Cancer immunology research
Vol 3
Issue 3
Date 2015 Mar
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Hu3F8-BsAb hu3F8 x huOKT3 Bispecific Antibody Hu3F8-BsAb is a humanized bispecific antibody that targets CD3 and GD2, which may induce T-cell response against tumor cells expressing GD2 (PMID: 25542634).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown melanoma not applicable Hu3F8-BsAb Preclinical - Cell line xenograft Actionable In a preclinical study, Hu3F8-BsAb treatment induced cell killing in melanoma cell lines expressing GD2 in culture, and treatment with Hu3F8-BsAb plus human peripheral blood mononuclear cells inhibited tumor growth and improved survival in melanoma cell line xenograft models in combination with transplanted PBMCs (PMID: 25542634). 25542634
Unknown unknown neuroblastoma not applicable Hu3F8-BsAb Preclinical - Cell line xenograft Actionable In a preclinical study, Hu3F8-BsAb treatment induced cell killing in neuroblastoma cell lines expressing GD2 in culture, and treatment with Hu3F8-BsAb plus human peripheral blood mononuclear cells inhibited tumor growth in neuroblastoma cell line xenograft models (PMID: 25542634). 25542634