期刊
ONCOIMMUNOLOGY
卷 4, 期 4, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/2162402X.2014.989776
关键词
Bispecific antibody; BiTE; ganglioside; GD2; immunotherapy; melanoma; neuroblastoma; T-cell
资金
- NCI NIH HHS [P30 CA008748] Funding Source: Medline
Bispecific antibodies (BsAbs) have proven highly efficient T cell recruiters for cancer immunotherapy by virtue of one tumor antigen-reactive single chain variable fragment (scFv) and another that binds CD3. In order to enhance the antitumor potency of these tandem scFv BsAbs (tsc-BsAbs), we exploited the dimerization domain of the human transcription factor HNF1 alpha to enhance the avidity of a tsc-BsAb to the tumor antigen disialoganglioside GD2 while maintaining functional monovalency to CD3 to limit potential toxicity. The dimeric tsc-BsAb showed increased avidity to GD2, enhanced T cell mediated killing of neuroblastoma and melanoma cell lines in vitro (32-37 fold), exhibited a near 4-fold improvement in serum half-life, and enhanced tumor ablation in mouse xenograft models. We propose that the use of this HNF1 alpha-derived dimerization tag may be a novel and effective strategy to increase the potency of T-cell engaging antibodies for clinical cancer immunotherapy.
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