| Abstract: |
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 Fc-yR 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. ©2005 American Association for Cancer Research. |
| Keywords: |
cancer survival; controlled study; treatment outcome; unclassified drug; nonhuman; antigen expression; animal cell; mouse; animals; mice; animal tissue; cancer immunotherapy; cancer prevention; chemoprophylaxis; metastasis; animal experiment; animal model; cell line, tumor; tumor antigen; mice, inbred c57bl; antibodies, monoclonal; immunoglobulin g; lymphoma; fc receptor; receptors, igg; cell protection; complement dependent cytotoxicity; immunoglobulin m antibody; immunoglobulin m; cell mediated cytotoxicity; cancer antibody; complement component c3; complement component c3 receptor; immunoglobulin g2a antibody; tumor antigen el4; antigens, cd2; antigens, cd59; complement c3; complement system proteins
|
