Molecular Immunology 40 (2003) 109–123 Review Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors Z. Fishelson a,∗ , N. Donin a , S. Zell b , S. Schultz b , M. Kirschfink b a Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel b Institute of Immunology, University of Heidelberg, Heidelberg, Germany Abstract Monoclonal antibodies (mAbs) are being increasingly used in cancer therapy owing to their ability to recognize specifically cancer cells and to activate complement- and cell-mediated cytotoxicity and/or to induce growth arrest or apoptosis. The therapeutic potential of anticancer antibodies is significantly limited due to the ability of cancer cells to block killing by complement. Of the multiple resistance strategies exploited by cancer cells, the expression of membrane complement regulatory proteins (mCRPs), such as CD46 (membrane cofactor protein (MCP)), CD55 (decay-accelerating factor (DAF)), CD35 (complement receptor type-1 (CR1)) and CD59, has received most attention. CD46, CD55 and CD35 block the complement cascade at the C3 activation stage and CD59 prevents assembly of the membrane attack complex of complement (MAC). These proteins protect normal tissues from accidental injury by activated complement, but also confer resistance on cancer cells, thereby limiting the effect of complement-fixing monoclonal antibodies. Expression of mCRPs on malignant cells is highly variable, yet there is clear indication that certain tumors express higher mCRP levels than the normal tissue from which they have evolved. mCRP level of expression and cellular location may also vary during malignant transformation and between differentiated and undifferentiated tumors. Neutralizing anti-mCRP mAbs have been used in vitro to elucidate the significance of mCRP expression to the tumor complement resistance phenotype. In general, CD59 appears to be the most effective mCRP protecting tumor cells from complement-mediated lysis. Nevertheless, it acts additively, and in certain tumors even synergistically, with CD55 and CD46. It is envisaged that treatment of cancer patients with mCRP blocking antibodies targeted specifically to cancer cells in combination with anticancer complement-fixing antibodies will improve the therapeutic efficacy. © 2003 Elsevier Ltd. All rights reserved. Keywords: Complement; mCRP; CD46; CD55; CD59; Cancer; Immunotherapy 1. Introduction: complement and its regulation by membrane complement regulatory proteins (mCRPs) The complement system is a major component of the innate immune system. It efficiently protects the host from pathogenic microorganisms, contributes to immune com- plex regulation and represents an important link between the innate and the specific immune system (for review, see Walport, 2001a,b). Complement comprises a group of more than 30 proteins, which participate in a cascade-like activa- tion process, serve as control proteins or act as cellular re- ceptors. Activation of the central component, C3, may occur through three different pathways, the antibody-dependent classical pathway as well as the two phylogenetically older Abbreviations: GPI, glycosyl phosphatidylinositol; mAb, monoclonal antibody; MAC, membrane attack complex of complement; mCRP, mem- brane complement regulatory protein. ∗ Corresponding author. Tel.: +972-3-6409620; fax: +972-3-6407432. E-mail address: lifish@post.tau.ac.il (Z. Fishelson). antibody-independent pathways, the alternative and the lectin pathways. Each of the activation pathways leads to formation of the terminal C5b-9 membrane attack complex of complement (MAC) (Muller-Eberhard, 1986). During MAC formation it is inserted into the surface membrane, leading either to cell destruction or, in sublytic doses, to cell activation (Morgan, 1989; Jurianz et al., 1999b). Comple- ment activation elicits a number of biological effects, such as recruitment and degranulation of leukocytes, smooth muscle contraction, and increase of vascular permeability. Complement activation also induces proinflammatory con- ditions that affect cell surface molecules on leukocytes as well as on endothelial cells. Thus, effector functions arising from complement activation may harm the host by induc- ing inflammatory tissue destruction. Complement activation links to antibody-dependent cellular cytotoxicity (ADCC) through the interaction of iC3b with CR3 (CD11b/CD18) on mononuclear phagocytes and natural killer (NK) cells and activation of complement-dependent cellular cytotoxicity (CDCC) (Perlmann et al., 1981; Bara and Lint, 1987). 0161-5890/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0161-5890(03)00112-3