Novel Anti-CRR9/CLPTM1L Antibodies with Antitumorigenic Activity Inhibit Cell Surface Accumulation, PI3K Interaction, and Survival Signaling

• Published in: Molecular cancer therapeutics 2016-05, Vol.15 (5), p.985-997
• Main Authors: Puskás, László G, Mán, Imola, Szebeni, Gabor, Tiszlavicz, László, Tsai, Susan, James, Michael A
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Membrane - metabolism; Cell Proliferation; Cell Survival - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - metabolism; Disease Models, Animal; Drug Resistance, Neoplasm - genetics; Gene Expression; Humans; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - mortality; Neoplasms - pathology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Prognosis; Protein Binding; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-15-0717

We and others have recently shown cisplatin resistance-related protein 9 (CRR9)/Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L) to affect survival and proliferation in lung and pancreatic tumor cells. Our research has indicated that CLPTM1L affects multiple survival signaling pathways in tumor cells under oncogenic, genotoxic, and microenvironmental stress. We have confirmed the association of CLPTM1L with pancreatic cancer by demonstrating overexpression of CLPTM1L in pancreatic tumors and poor survival in patients with high tumor expression of CLPTM1L. Predicting a transmembrane structure, we determined that CLPTM1L could be targeted at the plasma membrane. Herein, we describe the development of mAbs targeting CLPTM1L. Lead antibodies inhibited surface accumulation of CLPTM1L, Akt phosphorylation, anchorage-independent growth, and chemotherapeutic resistance in lung and pancreatic tumor cells. Gemcitabine promoted a physical interaction between CLPTM1L and p110α in pancreatic tumor cells, which was inhibited by anti-CLPTM1L. In vivo treatment with anti-CLPTM1L robustly inhibited the growth of both lung and pancreatic adenocarcinoma xenografts. The efficacy of anti-CLPTM1L correlated with specific epitopes representing important targets in human cancers, particularly those driven by KRas, for which effective targeted therapies have been elusive. This study is the first to report cell-surface exposure of the tumor survival protein CLPTM1L and inhibition of the function of surface CLPTM1L with novel, systematically developed inhibitory mAbs establishing proof of concept of clinically practical agents inhibiting this compelling new tumor survival target in cancer. Mol Cancer Ther; 15(5); 985-97. ©2016 AACR.