Abstract
Lymphoma is the most common hematological cancer in dogs. Canine diffuse large B cell lymphoma shows a relatively good response to treatment with multi-agent cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy; however, the 2-year survival rate is as low as 20%. For human B cell type lymphoma, the anti-CD20 chimeric antibody, rituximab, was developed two decades ago. The combination of rituximab and CHOP chemotherapy was highly successful in improving patient prognosis. However, no anti-canine CD20 antibody is available for the treatment of canine lymphoma. During this study, a rat anti-canine CD20 monoclonal antibody was established. We also generated a rat-canine chimeric antibody against canine CD20 designed for clinical application. This chimeric antibody (4E1-7-B) showed in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against the canine B cell lymphoma cell line CLBL-1. Moreover, to obtain stronger ADCC activity, a defucosylated 4E1-7-B antibody (4E1-7-B_f) was also generated, and it showed tenfold stronger ADCC activity compared with 4E1-7-B. 4E1-7-B_f as well as 4E1-7-B suppressed the growth of CLBL-1 tumors in an immunodeficient xenotransplant mouse model. Finally, a single administration of 4E1-7-B_f induced considerable peripheral B cell depletion in healthy beagles. Thus, 4E1-7-B_f is a good antibody drug candidate for canine B cell type lymphoma.
Highlights
Lymphoma is one of the most common hematological cancers in dogs, and is important as a point of comparison for human lymphoma[1]
B cell lymphoma, the most common type which is similar to human diffused large B cell lymphoma (DLBCL), has a favorable prognosis compared to T cell lymphoma because the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen of chemotherapy leads to remission in most cases
By immunization with NRK/cCD20 cells, an anticanine CD20 monoclonal antibody was obtained, and its subclass was determined to be rat IgG2a by flow cytometry. 4E1-7 reacted with NRK/cCD20 cells, but not parental NRK cells (Fig. 1A)
Summary
Lymphoma is one of the most common hematological cancers in dogs, and is important as a point of comparison for human lymphoma[1]. Rituximab binds to human CD20 molecules and directly induces apoptotic cell death in addition to its function through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)[5] It has been used alongside multiple drug CHOP chemotherapy (R-CHOP) in the treatment of B cell type lymphoid tumors, including non-Hodgkin B cell lymphoma, with dramatic s uccess[6,7]. Rue et al developed an anti-canine CD20 antibody (clone 1E4) and generated a chimeric antibody for therapeutic use[17] They observed the in vitro cytotoxicity of this antibody via CDC and a decrease in the number of peripheral B cells in vivo in healthy beagles; the clinical efficacy in dogs with canine B cell lymphoma remain unknown. We generated a rat-canine chimeric version of this antibody and verified its function in vitro and in vivo
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