A novel hemolytic complement-sufficient NSG mouse model supports studies of complement-mediated antitumor activity in vivo

作者：Verma Mohit K; Clemens Julia; Burzenski Lisa; Sampson Stephen B; Brehm Michael A; Greiner Dale L; Shultz Leonard D^*

来源：Journal of Immunological Methods, 2017, 446: 47-53.

DOI：10.1016/j.jim.2017.03.021

• Immunotherapy
• Complement-dependent cytotoxicity (CDC)
• Patient-derived xenograft (PDX)
• NSG mice
• Monoclonal antibody (mAb)

Monoclonal antibodies (mAbs) have emerged as a mainstream therapeutic option against cancer. mAbs mediate tumor cell-killing through several mechanisms including complement-dependent cytotoxicity (CDC). However, studies of mAb-mediated CDC against tumor cells remain largely dependent on in vitro systems. Previously developed and widely used NOD-scid IL2r gamma(null) (NSG) mice support enhanced engraftment of many primary human tumors. However, NSG mice have a 2-bp deletion in the coding region of the hemolytic complement (Hc) gene, and it is not possible to evaluate CDC activity in NSG mice. To address this limitation, we generated a novel strain of NSG mice-NSG-Hc(1)w that have an intact complement system able to generate the membrane attack complex. Utilizing the Daudi Burkitt's human lymphoma cell line, and the anti-human CD20 mAb rituximab, we further demonstrated that the complement system in NSG-Hcz mice is fully functional. NSG-Hc(1) mice expressed CDC activity against Daudi cells in vivo following rituximab treatment and showed longer overall survival compared with rituximab-treated NSG mice that lack hemolytic complement. Our results validate the NSG-Hc(1) mouse model as a platform for testing mechanisms underlying CDC in vivo and suggest its potential use to compare complement-dependent and complement-independent cytotoxic activity mediated by therapeutic mAbs.

• 出版日期2017-7