title: A novel hemolytic complement-sufficient NSG mouse model supports studies of complement-mediated antitumor activity in vivo.
abstract: 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 IL2rγnull(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-Hc1-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-Hc1mice is fully functional. NSG-Hc1mice 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-Hc1mouse 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States.
authors.forename: Mohit K
authors.initials: MK
authors.lastname: Verma
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Clemens
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Burzenski
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Sampson
authors.affiliation: Diabetes Center of Excellence™, Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.affiliation: Diabetes Center of Excellence™, Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, United States.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States. Electronic address: lenny.shultz@jax.org.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D018951:Antigens, CD20; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D064593:Heterografts; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000069283:Rituximab; D003165:Complement System Proteins
keywords: Complement-dependent cytotoxicity (CDC); Immunotherapy; Monoclonal antibody (mAb); NSG mice; Patient-derived xenograft (PDX)