title: Discovery of lung cancer biomarkers by profiling the plasma proteome with monoclonal antibody libraries.
abstract: A challenge in the treatment of lung cancer is the lack of early diagnostics. Here, we describe the application of monoclonal antibody proteomics for discovery of a panel of biomarkers for early detection (stage I) of non-small cell lung cancer (NSCLC). We produced large monoclonal antibody libraries directed against the natural form of protein antigens present in the plasma of NSCLC patients. Plasma biomarkers associated with the presence of lung cancer were detected via high throughput ELISA. Differential profiling of plasma proteomes of four clinical cohorts, totaling 301 patients with lung cancer and 235 healthy controls, identified 13 lung cancer-associated (p < 0.05) monoclonal antibodies. The monoclonal antibodies recognize five different cognate proteins identified using immunoprecipitation followed by mass spectrometry. Four of the five antigens were present in non-small cell lung cancer cells in situ. The approach is capable of generating independent antibodies against different epitopes of the same proteins, allowing fast translation to multiplexed sandwich assays. Based on these results, we have verified in two independent clinical collections a panel of five biomarkers for classifying patient disease status with a diagnostics performance of 77% sensitivity and 87% specificity. Combining CYFRA, an established cancer marker, with the panel resulted in a performance of 83% sensitivity at 95% specificity for stage I NSCLC.
authors.affiliation: Biosystems International SAS, Evry, France. mariana.kuras@biosys-intl.com
authors.forename: Mariana
authors.initials: M
authors.lastname: Guergova-Kuras
authors.forename: István
authors.initials: I
authors.lastname: Kurucz
authors.forename: William
authors.initials: W
authors.lastname: Hempel
authors.forename: Nadège
authors.initials: N
authors.lastname: Tardieu
authors.forename: János
authors.initials: J
authors.lastname: Kádas
authors.forename: Carole
authors.initials: C
authors.lastname: Malderez-Bloes
authors.forename: Anne
authors.initials: A
authors.lastname: Jullien
authors.forename: Yann
authors.initials: Y
authors.lastname: Kieffer
authors.forename: Marina
authors.initials: M
authors.lastname: Hincapie
authors.forename: András
authors.initials: A
authors.lastname: Guttman
authors.forename: Eszter
authors.initials: E
authors.lastname: Csánky
authors.forename: Balázs
authors.initials: B
authors.lastname: Dezso
authors.forename: Barry L
authors.initials: BL
authors.lastname: Karger
authors.forename: László
authors.initials: L
authors.lastname: Takács
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism*; D000918:Antibody Specificity; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood* / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000175:diagnosis; D016022:Case-Control Studies; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D006023:Glycoproteins / Q000097:blood / Q000276:immunology; D006242:Haptoglobins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007118:Immunoassay / Q000379:methods; D008175:Lung Neoplasms / Q000097:blood* / Q000175:diagnosis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D012372:ROC Curve; D055815:Young Adult; D000514:alpha 1-Antichymotrypsin / Q000097:blood / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C493495:CFH protein, human; D006023:Glycoproteins; D006242:Haptoglobins; C015246:LRG1 protein, human; D020543:Proteome; D000514:alpha 1-Antichymotrypsin; D017242:Complement Factor H