Antitumor activity of an anti-CD98 antibody

作者：Hayes Gregory M; Chinn Lawrence; Cantor Joseph M; Cairns Belinda; Levashova Zoia; Hoang Tran; Velilla Timothy; Duey Dana; Lippincott John; Zachwieja Joseph; Gin**erg Mark H; van der Horst Edward H^*

来源：International Journal of Cancer, 2015, 137(3): 710-720.

DOI：10.1002/ijc.29415

• phenotypic screening
• anti-CD98 monoclonal antibody
• multiple mechanism of action
• acute myeloid leukemia
• non-small cell lung cancer

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.
What's new? The CD98 protein is overexpressed in a wide variety of cancers, and its expression levels show positive association with tumor progression and metastasis. Both the heavy and the light chains of CD98 are of therapeutic interest. The present study reports broad and potent anti-tumor activity of the anti-CD98 humanized monoclonal antibody IGN523 in leukemic cell-line-derived xenograft models and patient-derived non-small cell lung cancer xenografts. IGN523 exhibited multiple mechanisms of action, and in vitro demonstrated antibody-dependent cellular cytotoxicity, blocked amino acid transport, and led to tumor cell apoptosis mediated via caspase-3 and caspase-7 pathways.

• 出版日期2015-8-1