1. Antitumor activity of an anti‐CD98 antibody
- Author
-
Hayes, Gregory M, Chinn, Lawrence, Cantor, Joseph M, Cairns, Belinda, Levashova, Zoia, Tran, Hoang, Velilla, Timothy, Duey, Dana, Lippincott, John, Zachwieja, Joseph, Ginsberg, Mark H, and van der Horst, Edward H
- Subjects
Orphan Drug ,Lung ,Cancer ,Biotechnology ,Rare Diseases ,Hematology ,Lung Cancer ,Amino Acids ,Animals ,Antibodies ,Monoclonal ,Antibodies ,Monoclonal ,Humanized ,Antibody-Dependent Cell Cytotoxicity ,Antineoplastic Agents ,Biological Transport ,Caspases ,Cell Line ,Tumor ,Cell Membrane Permeability ,Complement System Proteins ,Cytotoxicity ,Immunologic ,Disease Models ,Animal ,Drug Evaluation ,Preclinical ,Female ,Fusion Regulatory Protein-1 ,Humans ,Lysosomes ,Mice ,Models ,Biological ,Protein Binding ,Tumor Burden ,Xenograft Model Antitumor Assays ,phenotypic screening ,anti-CD98 monoclonal antibody ,multiple mechanism of action ,acute myeloid leukemia ,non-small cell lung cancer ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - 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.
- Published
- 2015