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|Ref Type||Journal Article|
|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|
|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.|
|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|