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.CD98 is a heterodimeric protein that comprises a heavy and light chain. The CD98 heavy chain is a type II transmembrane glycoprotein that forms a heterodimer via covalent linkage to one of 6 amino acid transporters. 1,2 CD98 is overexpressed on the cell surface of almost all tumor cells, regardless of tissue origin and increased expression of a CD98-light chain, L-type amino acid transporter 1 (LAT-1) occurs in many types of human cancers, including breast, colon, oral, ovarian, esophageal, glioma and leukemia. 3,4 Increased uptake of amino acids supports the high growth rate of cancer cells by providing the building blocks for protein synthesis. [4][5][6] Moreover, the higher expression of CD98 heavy chain and LAT-1 in metastatic vs. primary tumors suggests that over-expression of CD98/LAT-1 may facilitate progression and metastasis of human cancers.CD98 also regulates integrin signaling by association with integrin b-subunits, thereby controlling cell proliferation, survival, migration, epithelial adhesion and polarity. 3,7 The function of CD98 in regulating both amino acid transport and integrin signaling can contribute to the rapid proliferation and clonal expansion of lymphocytes and tumor cells. 3 The expression pattern and pleiotropic function of CD98 heavy and light chains suggest these proteins are promising targets for treatment of a variety of human cancers. Although small molecule inhibitors of LAT-1 activity have demonstrated preclinical antitumor activity in a number of cancer cell types, including NSCLC, colon cancer, oral cancer and breast cancer, development of antibodies against CD98 heavy chain has received less focus. 5,[8][9][10] Murine monoclonal antibodies to CD98 inhibit lymphocyte proliferation and the growth of bladder cancer, lymphoma, glioma, prostate and colon cancer cells in preclinical models. [11][12][13] To identify therapeutic anti-CD98 antibodies with significant antitumor activity, we ...

CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia

“…Both genetic deletion and mAb mediated blockade of CD98 suggest that CD98 inhibition impairs adhesion and survival of leukemia cells. We should note that previous work (Hayes et al, 2014) indicates that IGN523, which reduces CD98 expression, can also increase lysosomal membrane permeability, reduce amino acid transport and trigger antibody-dependent cellular cytotoxicity (ADCC). Thus, anti-CD98 mAb could act through multiple mechanisms that include defects in cell adhesion to the microenvironment, increased apoptosis and ADCC.…”

“…To this end we used a humanized CD98 antibody, IGN523 (Hayes et al, 2014). Treatment with IGN523 antibody (denoted as CD98 mAb) significantly impacted the adhesion of AML cells to endothelial cells (Figure S5H).…”

“…Because CD98 is particularly well-suited for antibody-mediated therapy, an anti-CD98 antibody (IGN523) has recently been developed (Hayes et al, 2014). Both genetic deletion and mAb mediated blockade of CD98 suggest that CD98 inhibition impairs adhesion and survival of leukemia cells.…”

Ubiquitination of CD98 limits cell proliferation and clonal expansion

“…Specifically, the 8×KR mutations do not affect the extracellular Cys residue that couples CD98 to the amino acid transporters or the transmembrane and membrane proximal cytoplasmic domain residues that support integrin signaling (Henderson et al, 2004). Genetic ablation of CD98 protects from autoimmunity and several cancers (Cantor and Ginsberg, 2012) and blocking CD98 can inhibit leukemias and lymphomas (Hayes et al, 2015). Thus, our finding that ubiquitylation regulates CD98 expression and clonal expansion pinpoints a new locus for intervention in either autoimmunity or hematologic malignancies.…”

Endothelial Cells Require CD98 for Efficient Angiogenesis—Brief Report

“…Antibodies specific for CD98hc have direct effects on growth and survival of human tumor cells 11 , but their effects on human endothelial cell angiogenesis are unknown. Two days after incubating HUVEC with cross-linked anti-CD98hc antibody, the level of surface CD98hc (Figure 2C) by flow cytometry and total CD98hc (Figure 2E) in cell lysates was significantly decreased as was the ability to form tube-like structures on Matrigel, a widely used model to study EC angiogenic activities in vitro (Figure 2D).…”