title: Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma.
abstract: We describe the application of a novel, bispecific antibody platform termed dual affinity retargeting (DART) to eradicate B-cell lymphoma through coengagement of the B cell-specific antigen CD19 and the TCR/CD3 complex on effector T cells. Comparison with a single-chain, bispecific antibody bearing identical CD19 and CD3 antibody Fv sequences revealed DART molecules to be more potent in directing B-cell lysis. The enhanced activity with the CD19xCD3 DART molecules was observed on all CD19-expressing target B cells evaluated using resting and prestimulated human PBMCs or purified effector T-cell populations. Characterization of a CD19xTCR bispecific DART molecule revealed equivalent potency with the CD19xCD3 DART molecule, demonstrating flexibility of the DART structure to support T-cell/B-cell associations for redirected T cell-killing applications. The enhanced level of killing mediated by DART molecules was not accompanied by any increase in nonspecific T-cell activation or lysis of CD19(-) cells. Cell-association studies indicated that the DART architecture is well suited for maintaining cell-to-cell contact, apparently contributing to the high level of target cell killing. Finally, the ability of the CD19xTCR DART to inhibit B-cell lymphoma in NOD/SCID mice when coadministered with human PBMCs supports further evaluation of DART molecules for the treatment of B-cell malignancies.
authors.affiliation: MacroGenics Inc, Rockville, MD, USA. moorep@macrogenics.com
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moore
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.forename: G Jonah
authors.initials: GJ
authors.lastname: Rainey
authors.forename: Steve
authors.initials: S
authors.lastname: Burke
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Sergey
authors.initials: S
authors.lastname: Gorlatov
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Veri
authors.forename: Sudeepta
authors.initials: S
authors.lastname: Aggarwal
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yang
authors.forename: Kalpana
authors.initials: K
authors.lastname: Shah
authors.forename: Linda
authors.initials: L
authors.lastname: Jin
authors.forename: Sunan
authors.initials: S
authors.lastname: Zhang
authors.forename: Leilei
authors.initials: L
authors.lastname: He
authors.forename: Tengfei
authors.initials: T
authors.lastname: Zhang
authors.forename: Valentina
authors.initials: V
authors.lastname: Ciccarone
authors.forename: Scott
authors.initials: S
authors.lastname: Koenig
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonvini
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology*; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008222:Lymphokines / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D012795:Sialoglycoproteins / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D017252:CD3 Complex; C089422:Fv protein, human; D008222:Lymphokines; D011948:Receptors, Antigen, T-Cell; D012795:Sialoglycoproteins