title: Antitumor activity of an anti-CD98 antibody.
abstract: CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Hayes
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chinn
authors.affiliation: School of Medicine, University of California-San Diego, La Jolla, CA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Cantor
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Cairns
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: Zoia
authors.initials: Z
authors.lastname: Levashova
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: Hoang
authors.initials: H
authors.lastname: Tran
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Velilla
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: Dana
authors.initials: D
authors.lastname: Duey
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: John
authors.initials: J
authors.lastname: Lippincott
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zachwieja
authors.affiliation: School of Medicine, University of California-San Diego, La Jolla, CA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
authors.affiliation: Pre-Clinical Development, Igenica Biotherapeutics, CA.
authors.forename: Edward
authors.initials: E
authors.lastname: H van der Horst
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001692:Biological Transport; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D003165:Complement System Proteins / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D027261:Fusion Regulatory Protein-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000596:Amino Acids; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D027261:Fusion Regulatory Protein-1; D003165:Complement System Proteins; D020169:Caspases
keywords: acute myeloid leukemia; anti-CD98 monoclonal antibody; multiple mechanism of action; non-small cell lung cancer; phenotypic screening