title: Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells.
abstract: Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti-PD-L1 treatment. Thus, combining HER2-TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response.
authors.affiliation: Genentech, Inc., South San Francisco, California. junttila.teemu@gene.com.
authors.forename: Teemu T
authors.initials: TT
authors.lastname: Junttila
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johnston
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Maria
authors.initials: M
authors.lastname: Hristopoulos
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Robyn
authors.initials: R
authors.lastname: Clark
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Diego
authors.initials: D
authors.lastname: Ellerman
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Bu-Er
authors.initials: BE
authors.lastname: Wang
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Mary
authors.initials: M
authors.lastname: Mathieu
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Guangmin
authors.initials: G
authors.lastname: Li
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Judy
authors.initials: J
authors.lastname: Young
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Gail
authors.initials: G
authors.lastname: Lewis Phillips
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Stefanich
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Christoph
authors.initials: C
authors.lastname: Spiess
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Andrew
authors.initials: A
authors.lastname: Polson
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Bryan
authors.initials: B
authors.lastname: Irving
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Scheer
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Junttila
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Kelley
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Klara
authors.initials: K
authors.lastname: Totpal
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Allen
authors.initials: A
authors.lastname: Ebens
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D000068878:Trastuzumab
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human