Complement-mediated mechanisms in anti-GD2 monoclonal antibody therapy of murine metastatic cancer.
The role of complement in antibody therapy of cancer is in general poorly understood. We used the EL4 syngeneic mouse model of metastatic lymphoma to investigate the role of complement in immunotherapy directed against GD2, a target of clinical relevance. IgG2a and IgM anti-GD2 therapy protected EL4-challenged mice from metastases and prolonged survival. Expression of CD59, an inhibitor of direct complement-mediated cytotoxicity (CMC), effectively protected EL4 cells from CMC in vitro but did not affect the outcome of monoclonal antibody therapy. Protection by IgG therapy was also unaffected in mice deficient in C3 or complement receptor 3 (CR3) but was almost completely abrogated in FcgammaR I/III-deficient mice. These data indicate a crucial role for antibody-dependent cell-mediated cytoxicity (ADCC). However, at lower doses of IgG, therapeutic effect was partially abrogated in C3-deficient mice, indicating complement-mediated enhancement of ADCC at limiting IgG concentration. In contrast to IgG, the therapeutic effect of IgM was completely abrogated in C3-deficient mice. High level expression of CD59 on EL4 did not influence IgM therapy, suggesting IgM functions by complement-dependent cell-mediated cytotoxicity (CDCC), a mechanism thought to be inactive against tumor cells. Thus, IgG and IgM can operate via different primary mechanisms of action, and CDCC and complement-dependent enhancement of ADCC mechanisms are operative in vivo. The effects of complement can be supplemental to other antibody-mediated mechanisms and likely have increased significance at limiting antibody concentration or low antigen density.
Imai
Masaki
M
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29424, USA.
Landen
Charles
C
Ohta
Rieko
R
Cheung
Nai-Kong V
NK
Tomlinson
Stephen
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D018801:CD2 Antigens / Q000276:immunology*; D018957:CD59 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D003176:Complement C3 / Q000276:immunology / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology / Q000494:pharmacology; D008223:Lymphoma / Q000276:immunology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017452:Receptors, IgG / Q000276:immunology
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D018957:CD59 Antigens; D003176:Complement C3; D007075:Immunoglobulin M; D017452:Receptors, IgG; D003165:Complement System Proteins