Retargeting T cells to GD2 pentasaccharide on human tumors using bispecific humanized antibody Journal Article
| Authors: | Xu, H.; Cheng, M.; Guo, H.; Chen, Y.; Huse, M.; Cheung, N. K. V. |
| Article Title: | 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 >10 -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. © 2014 American Association for Cancer Research. |
| Keywords: | cd3 antigen; cell proliferation; t lymphocyte; antigens, cd3; t-lymphocytes; mouse; animal; animals; mice; mice, knockout; melanoma; drug screening; xenograft model antitumor assays; cell line, tumor; mice, inbred balb c; physiology; immunology; bagg albino mouse; immunoglobulin g; neuroblastoma; tumor cell line; monocyte; monocytes; single chain fragment variable antibody; knockout mouse; gangliosides; ganglioside; ganglioside, gd2; antibodies, bispecific; bispecific antibody; humans; human; single-chain antibodies |
| Journal Title: | Cancer Immunology Research |
| Volume: | 3 |
| Issue: | 3 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2015-03-01 |
| Start Page: | 266 |
| End Page: | 277 |
| Language: | English |
| DOI: | 10.1158/2326-6066.cir-14-0230-t |
| PUBMED: | 25542634 |
| PROVIDER: | scopus |
| PMCID: | PMC4351131 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2016 -- Source: Scopus |
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