title: Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies.
abstract: Bispecific antibodies and antibody fragments in various formats have been explored as a means to recruit cytolytic T cells to kill tumor cells. Encouraging clinical data have been reported with molecules such as the anti-CD19/CD3 bispecific T cell engager (BiTE) blinatumomab. However, the clinical use of many reported T cell-recruiting bispecific modalities is limited by liabilities including unfavorable pharmacokinetics, potential immunogenicity, and manufacturing challenges. We describe a B cell-targeting anti-CD20/CD3 T cell-dependent bispecific antibody (CD20-TDB), which is a full-length, humanized immunoglobulin G1 molecule with near-native antibody architecture constructed using "knobs-into-holes" technology. CD20-TDB is highly active in killing CD20-expressing B cells, including primary patient leukemia and lymphoma cells both in vitro and in vivo. In cynomolgus monkeys, CD20-TDB potently depletes B cells in peripheral blood and lymphoid tissues at a single dose of 1 mg/kg while demonstrating pharmacokinetic properties similar to those of conventional monoclonal antibodies. CD20-TDB also exhibits activity in vitro and in vivo in the presence of competing CD20-targeting antibodies. These data provide rationale for the clinical testing of CD20-TDB for the treatment of CD20-expressing B cell malignancies.
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. sun.laura@gene.com.
authors.forename: Liping L
authors.initials: LL
authors.lastname: Sun
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Ellerman
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Mathieu
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Hristopoulos
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Yan
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Robyn
authors.initials: R
authors.lastname: Clark
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Reyes
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Stefanich
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Mai
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Young
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mahrukh
authors.initials: M
authors.lastname: Huseni
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Peiyin
authors.initials: P
authors.lastname: Wang
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Noel
authors.initials: N
authors.lastname: Dybdal
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Scheer
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Teemu
authors.initials: T
authors.lastname: Junttila
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Klara
authors.initials: K
authors.lastname: Totpal
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Ebens
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D006801:Humans; D015448:Leukemia, B-Cell / Q000276:immunology / Q000628:therapy*; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D018951:Antigens, CD20; D017252:CD3 Complex