Antitumor Activities of Chimeric Anti-EphA2 Antibodies in Xenograft Models of Breast, Pancreatic, and Colorectal Cancers

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Abstract
Erythropoietin-producing hepatocellular receptor A2 (EphA2) has emerged as a key mediator that promotes tumor malignant progression. 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, κ), 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.
Funding Information
  • Japan Agency for Medical Research and Development (JP25am0521010)
  • Japan Agency for Medical Research and Development (JP25ama121008)
  • Japan Agency for Medical Research and Development (JP25ama221153)
  • Japan Agency for Medical Research and Development (JP25ama221339)
  • Japan Agency for Medical Research and Development (JP25bm1123027)
  • Japan Society for the Promotion of Science (25K18843)
  • Japan Society for the Promotion of Science (24K11652)
  • Japan Society for the Promotion of Science (24K18268)
  • Japan Society for the Promotion of Science (25K10553)

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