title: Human derived dimerization tag enhances tumor killing potency of a T-cell engaging bispecific antibody.
abstract: 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 HNF1α 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 linesin 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 HNF1α-derived dimerization tag may be a novel and effective strategy to increase the potency of T-cell engaging antibodies for clinical cancer immunotherapy.
authors.affiliation: Department of Pediatrics; Memorial Sloan Kettering Cancer Center ; New York, NY USA.
authors.forename: Mahiuddin
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Pediatrics; Memorial Sloan Kettering Cancer Center ; New York, NY USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics; Memorial Sloan Kettering Cancer Center ; New York, NY USA.
authors.forename: Irene Y
authors.initials: IY
authors.lastname: Cheung
authors.affiliation: Department of Pediatrics; Memorial Sloan Kettering Cancer Center ; New York, NY USA.
authors.forename: N K
authors.initials: NK
authors.lastname: Cheung
keywords: BiTE; BiTE, bispecific T-cell engager; Bispecific antibody; BsAb, bispecific antibody; GD2; HDD, HNF1α dimerization domain; T-cell; ganglioside; immunotherapy; melanoma; neuroblastoma; tsc-BsAb, tandem single-chain bispecific antibody