By serologic identification of antigens by recombinant expression cloning (SEREX) analysis using an autologous lung adenocarcinoma cell line, OU-LU-6, as a cDNA library source, we demonstrated that XAGE-1 was the dominant antigen recognized by serum from a patient. By immunoscreening, we obtained 38 positive cDNA clones consisting of 16 genes designated as OY-LC-1 to -OY-LC-16. OY-LC-1, represented by 18 clones, was identical to XAGE-1. OY-LC-2 to -16, represented by either a single or 2 clones, were identical to known genes shown to be ubiquitously expressed in various normal tissues. RT-PCR analysis showed that of 4 XAGE-1 transcripts—XAGE-1a, b, c and d—XAGE-1b was expressed in OU-LU-6 dominantly. Furthermore, XAGE-1b mRNA was expressed in 4 of 10 lung cancer tissues, whereas no expression was observed in normal tissues. Of 4 XAGE-1b mRNA positive cancer tissues, 3 were adenocarcinoma and one was poorly differentiated squamous cell carcinoma. Of 32 sera from lung cancer patients, 8 sera were reactive with the XAGE-1b product. Those 8 sera were from patients with adenocarcinoma. These findings indicated strong immunogenicity of XAGE-1b in lung adenocarcinoma and suggested its potential use as a target for vaccine-based immunotherapies. © 2003 Wiley-Liss, Inc.