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(Chest. 2004;125:105S-106S.)
© 2004 American College of Chest Physicians

Efficient Identification and Use of Tumor-Associated Antibodies as Markers of Non-small Cell Lung Cancer*

Li Zhong, PhD; Xuejun Peng, MS; Giovana E. Hidalgo, BA; Dennis E. Doherty, MD, FCCP; Arnold S. Stromberg, PhD, FCCP and Edward A. Hirschowitz, MD, FCCP

* From the Lexington Veterans Affairs Medical Center, University of Kentucky, Chandler Medical Center, Lexington, KY.

Correspondence to: Edward A. Hirschowitz, MD, Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, 800 Rose St, MN614, Lexington, KY 40536-0084; e-mail: eahirs2{at}pop.uky.edu

Currently, only a limited number of tumor markers for non-small cell lung cancer (NSCLC) are available, and NSCLC heterogeneity makes the identification of a single sensitive and specific marker unlikely. Antibodies to tumor-associated proteins may expand the number of available tumor markers for lung cancer, and may be used together in a serum profile to enhance sensitivity and specificity. Using biopan enrichment techniques with serum from NSCLC patients and healthy individuals, we isolated 57 phage-expressed proteins from two NSCLC complementary DNA T-7 phage libraries, with 45 of these having a sequence identity with known or putative tumor-associated proteins. The immunochemical reactivity of patient serum with phage clones shows how the numbers of immunogenic phages were enriched by this process, and that antibodies were present in the sera of NSCLC patients but not in the sera of healthy persons.

Antibody affinity for several phage-expressed proteins was confirmed by limiting the dilution of the serum from individuals assayed by an enzyme-linked immunosorbent assay. Antibodies to five phage-expressed proteins were measured by enzyme-linked immunosorbent assay to validate the concept that combinations have greater predictive value than any single antibody alone. Logistic regression analysis showed that the combined measurements of five antibodies were better able to discriminate between the sera of healthy individuals and the sera of NSCLC patients than any single antibody alone, underscoring the importance of identifying multiple potential markers. Building on these concepts, we evaluated the ability of a fluorescent protein microarray to measure antibodies against multiple phage-expressed proteins simultaneously as a first step in developing a comprehensive and predictive assay that accommodates NSCLC heterogeneity. A custom protein biochip composed of phage-expressed proteins was tested for reactivity with antibodies in the sera of cancer patients and the sera of healthy subjects. Differences in fluorescent intensity showed an ability to distinguish between them. Our data show the feasibility of profiling antibody responses as markers of disease and are proof of the concept that supports the rationale for further development of this approach. The potential for efficient profiling of patient sera for tumor-associated antibodies makes this work both logical and timely.


   Footnotes
 
Abbreviation: NSCLC = non-small cell lung cancer

This study was supported by American Lung Association project No. RG-054-N and The Kentucky Lung Cancer Research Foundation and Veteran’s Affair’s Medical Center.





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