Abstract 2729: Suppression of hematogenous metastasis by mouse and murine/human chimeric anti-Aggrus/podoplanin antibodies

Tumor cell-induced platelet aggregation has been known to facilitate hematogenous metastasis by increasing the arrest of tumor cell emboli in the microvasculature. We have previously established metastatic variants of cancer cells and identified Aggrus (also known as podoplanin, T1alpha, gp36) as a platelet aggregation-inducing factor expressed on the surface of highly metastatic variants. Aggrus, a type-I transmembrane sialomucin-like glycoprotein, induced platelet activation via interaction with one of its counter receptor CLEC-2 (C-type lectin-like receptor 2) expressed on platelet surface. Thus, Aggrus-induced platelet aggregation did not require any plasma components. Moreover, Aggrus has been shown to be up-regulated in many different types of cancers and to be associated with poor outcome. Thus, Aggrus must be a useful cancer specific antigen in addition to a useful therapeutic target for developing hematogenous metastasis inhibitors. In this study, we established an anti-human Aggrus monoclonal antibody, designated as P2-0, and investigated its potential as a hematogenous metastasis inhibitor. We observed that P2-0 antibody could inhibit Aggrus-CLEC-2 interaction detected by in vitro competition assay and could suppress Aggrus-induced platelet aggregation in a concentration-dependent manner. Moreover, P2-0 antibody decreased the number of Aggrus-mediated pulmonary metastatic foci in in vivo experimental mouse model. We then cloned complementarity-determining region of P2-0 antibody and generated murine/human chimeric P2-0 antibody. We revealed that chimeric P2-0 antibody retained Aggrus-neutralizing activity and inhibited the experimental pulmonary metastasis of cancer cells that endogenously expressed Aggrus on their surface. These data indicate that P2-0 antibody and its chimeric antibody are useful as inhibitors of Aggrus-mediated hematogenous metastasis and expected to be applied for the clinical examination of Aggrus-targeted cancer therapy. This study was supported in part by a grant from the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, Japan. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2729. doi:1538-7445.AM2012-2729