title: Chemically Programmed Bispecific Antibodies in Diabody Format.
abstract: Chemically programmed bispecific antibodies (biAbs) endow target cell-binding small molecules with the ability to recruit and activate effector cells of the immune system. Here we report a platform of chemically programmed biAbs aimed at redirecting cytotoxic T cells to eliminate cancer cells. Two different antibody technologies were merged together to make a novel chemically programmed biAb. This was achieved by combining the humanized anti-hapten monoclonal antibody (mAb) h38C2 with the humanized anti-human CD3 mAb v9 in a clinically investigated diabody format known as Dual-Affinity Re-Targeting (DART). We show that h38C2 × v9 DARTs can readily be equipped with tumor-targeting hapten-derivatized small molecules without causing a systemic response harming healthy tissues. As a proof of concept, we chemically programmed h38C2 × v9 with hapten-folate and demonstrated its selectivity and potency against folate receptor 1 (FOLR1)-expressing ovarian cancer cells in vitro and in vivo Unlike conventional biAbs, chemically programmed biAbs in DART format are highly modular with broad utility in terms of both target and effector cell engagement. Most importantly, they provide tumor-targeting compounds access to the power of cancer immunotherapy.
authors.affiliation: From the Departments of Cancer Biology.
authors.forename: Even
authors.initials: E
authors.lastname: Walseng
authors.affiliation: the Chemical Biology Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Nelson
authors.affiliation: From the Departments of Cancer Biology.
authors.forename: Junpeng
authors.initials: J
authors.lastname: Qi
authors.affiliation: From the Departments of Cancer Biology, Chemistry, and.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Nanna
authors.affiliation: Chemistry, and.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.affiliation: the Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, and.
authors.forename: Rajib K
authors.initials: RK
authors.lastname: Goswami
authors.affiliation: the Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, and.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Sinha
authors.affiliation: the Chemical Biology Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.affiliation: From the Departments of Cancer Biology, Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, crader@scripps.edu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rader
mesh_terms: D018033:Antibodies, Bispecific / Q000737:chemistry* / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000737:chemistry* / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D058975:Folate Receptor 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D009363:Neoplasm Proteins
keywords: T-cell; antibody engineering; cancer therapy; chemical modification; folate; immunotherapy; ovarian cancer