title: Redirected T-cell killing of solid cancers targeted with an anti-CD3/Trop-2-bispecific antibody is enhanced in combination with interferon-α.
abstract: Trop-2 has limited presence on normal tissues but is highly expressed in diverse epithelial cancers. (E1)-3s is a T-cell-redirecting trivalent bispecific antibody (bsAb), comprising an anti-CD3 scFv covalently linked to a stabilized dimer of a Trop-2-targeting Fab using Dock-and-Lock. We show for the first time that bsAb-mediated bidirectional trogocytosis occurs between target and T cells and involves immunologic synapses. We studied the effects of interferon-α (INFα) on (E1)-3s-mediated T-cell killing of human gastric and pancreatic cancer cell lines. T-cell activation, cytokine induction, and cytotoxicity were evaluated ex vivo using peripheral blood mononuclear cells (PBMC) or T cells with NCI-N87 gastric cancer as target cells. In vivo activity was assayed with NCI-N87 and Capan-1 (pancreatic) xenografts. In the presence of target cells and PBMCs, (E1)-3s did not cause excess cytokine production. When combined with (E1)-3s, peginterferonalfa-2a--which alone did not increase T-cell activation or raise cytokine levels over baseline--increased CD69 expression but did not significantly increase cytokine induction. (E1) 3s mediated a highly potent T-cell lysis of NCI-N87 target cells in vitro. Inclusion of peginterferonalfa-2a or a more potent form of INFα, 20*-2b, significantly potentiated the activity of (E1)-3s by more than 2.5- or 7-fold, respectively. In vivo, combining peginterferonalfa-2a with (E1)-3s delayed Capan-1 growth longer than each single agent. Similarly, combination therapy delayed tumor proliferation of NCI-N87 compared with (E1)-3s or peginterferonalfa-2a single-treatment groups. (E1)-3s effectively induced T-cell-mediated killing of Trop-2-expressing pancreatic and gastric cancers, which was enhanced with INFα.
authors: Immunomedics, Inc., Morris Plains, New Jersey. IBC Pharmaceuticals, Inc., Morris Plains, New Jersey. erossi@immunomedics.com.
authors: Edmund A
authors: EA
authors: Rossi
authors: Immunomedics, Inc., Morris Plains, New Jersey.
authors: Diane L
authors: DL
authors: Rossi
authors: Immunomedics, Inc., Morris Plains, New Jersey.
authors: Thomas M
authors: TM
authors: Cardillo
authors: Immunomedics, Inc., Morris Plains, New Jersey. IBC Pharmaceuticals, Inc., Morris Plains, New Jersey.
authors: Chien-Hsing
authors: CH
authors: Chang
authors: Immunomedics, Inc., Morris Plains, New Jersey. IBC Pharmaceuticals, Inc., Morris Plains, New Jersey. Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, New Jersey.
authors: David M
authors: DM
authors: Goldenberg
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D016898:Interferon-alpha / Q000494:pharmacology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D011092:Polyethylene Glycols; D011994:Recombinant Proteins
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D016898:Interferon-alpha; D011994:Recombinant Proteins; C499380:TACSTD2 protein, human; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a