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EphA2 overexpression and its non-canonical signaling lead to oncogenic transformation, metabolic reprogramming, resistance to treatments, and metastasis. Therefore, strategies targeting EphA2 have been evaluated in clinical trials. However, the clinical effects were not sufficient. An anti-EphA2 monoclonal antibody (mAb), Ea2Mab-7 (mouse IgG1, \u03ba), demonstrated high affinity and specificity among Eph receptors. In this study, we produced recombinant class-switched Ea2Mab-7 variants, including Ea2Mab-7-mG2a (mouse IgG2a) and Ea2Mab-7-hG1 (human IgG1). Both Ea2Mab-7-mG2a and Ea2Mab-7-hG1 recognized human triple-negative breast cancer MDA-MB-231, pancreatic cancer MIA PaCa-2, and colorectal cancer HCT-15 in flow cytometry. Furthermore, both Ea2Mab-7-mG2a and Ea2Mab-7-hG1 exerted significant antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against these tumors. In mouse xenograft models of breast, pancreatic, and colorectal cancers, both mAbs demonstrated antitumor activity. These results indicate the potential of Ea2Mab-7 variants for the treatment of EphA2-positive cancers.<\/jats:p>","DOI":"10.3390\/ijms27073221","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T11:51:03Z","timestamp":1775130663000},"page":"3221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antitumor Activities of Chimeric Anti-EphA2 Antibodies in Xenograft Models of Breast, Pancreatic, and Colorectal Cancers"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7984-5414","authenticated-orcid":false,"given":"Guanjie","family":"Li","sequence":"first","affiliation":[{"name":"Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2646-5132","authenticated-orcid":false,"given":"Hiroyuki","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9039-4474","authenticated-orcid":false,"given":"Tomokazu","family":"Ohishi","sequence":"additional","affiliation":[{"name":"Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8524-7322","authenticated-orcid":false,"given":"Hiroyuki","family":"Satofuka","sequence":"additional","affiliation":[{"name":"Department of Antibody Drug 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