Abstract

Survival of patients with lung cancer could be significantly prolonged should the disease be diagnosed early. Growing evidence indicates that the immune response in the form of autoantibodies to developing cancer is present before clinical presentation. We used a phage-displayed antibody library to select for recombinant scFvs that specifically bind to lung cancer-associated IgM autoantibodies. We selected for scFv recombinant antibodies reactive with circulating IgM autoantibodies found in the serum of patients with early stage lung adenocarcinoma but not matched controls. Discriminatory performance of 6 selected scFvs was validated in an independent set of serum from stage 1 adenocarcinoma and matching control groups using two independent novel methods developed for this application. The panel of 6 selected scFvs predicted cancer based on seroreactivity value with sensitivity of 0.8 and specificity of 0.87. Receiver Operative Characteristic curve (ROC) for combined 6 scFv has an AUC of 0.88 (95%CI, 0.76–1.0) as determined by fluorometric microvolume assay technology (FMAT) The ROC curve generated using a homogeneous bridging Mesa Scale Discovery (MSD) assay had an AUC of 0.72 (95% CI, 0.59–0.85). The panel of all 6 antibodies demonstrated better discriminative power than any single scFv alone. The scFv panel also demonstrated the association between a high score - based on seroreactivity - with poor survival. Selected scFvs were able to recognize lung cancer associated IgM autoantibodies in patient serum as early as 21 months before the clinical presentation of disease. The panel of antibodies discovered represents a potential unique non-invasive molecular tool to detect an immune response specific to lung adenocarcinoma at an early stage of disease.

Highlights

  • Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and, if not detected early, has a low cure rate

  • Growing evidence indicates that humoral immune response in the form of autoantibodies is present in cancer patients before clinical demonstration of disease [3,4]

  • Phage single chain fragment variable (scFv) remaining after cross absorption were panned against IgM isolated from early stage I adenocarcinoma lung cancer patients to obtain scFv specific for lung cancer autoantibodies

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Summary

Introduction

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and, if not detected early, has a low cure rate. Only 16% of patients are diagnosed at stage I [2] Early detection of lung cancer represents a critical and challenging need in the management of this deadly disease. Despite recent advances in molecular diagnostics, no specific biomarker for the early detection of lung cancer has reached the clinic. A promising approach to the early detection of cancer is to look for the immune response to the developing cancer. Growing evidence indicates that humoral immune response in the form of autoantibodies is present in cancer patients before clinical demonstration of disease [3,4]. Despite recent advance, current research has not achieved the final clinical goal of detecting biomarkers specific for the early detection of lung cancer

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