Homologous restriction of complement-mediated cell lysis can be markedly enhanced by blocking decay-accelerating factor.
Regulation of complement (C') dependent lysis of cells is attributed to certain membrane proteins. One of these is decay-accelerating factor (DAF), CD55, a 70kD glycosylated protein which functions to protect host cells from damage by autologous C'. We hypothesized that blockade of DAF function by a monoclonal antibody (mAb) could augment C'-dependent lysis mediated by another mAb to a cell surface antigen expressed on leukaemia cells. Thus, we tested the effects of the anti-DAF mAb 1C6 on the ability of both rabbit and human C' to lyse human leukaemia cells through activation by complement-fixing murine mAb. DAF antigen was highly expressed on most leukaemia cell lines and primary acute leukaemia blast cells tested. Murine mAb to CD15 (PM-81) and to gp 120 (AML-1-99), both IgM, also bound to the majority of myeloid and lymphoid leukaemia cells. Using human serum as a source of C', the addition of mAb 1C6 reduced by an additional 85-94% the numbers of clonogenic HL-60 (myeloid leukaemia) cells lysed by mAb PM-81 alone. Similarly, the addition of mAb 1C6 reduced by an additional 87% the numbers of HL-60 colonies eliminated by mAb AML-1-99 alone. Similar results were observed in an experimental purging model using the myeloid leukaemia cell lines HL-60, U937 or NB4 cells as targets. These results show that mAb 1C6 can effectively block the actions of DAF. In the presence of mAb 1C6, the cytotoxic activity mediated by human C' was similar to that of rabbit C'. These results show that increased tumour cell killing can be achieved through DAF blockade. This finding has relevance to clinical trials using C'-fixing mAb for purging bone marrow of occult tumour cells prior to autologous transplantation.
Division of Hematology/Bone Marrow Transplantation, University of Pittsburgh Medical Center, PA 15213, USA.
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D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D018958:CD55 Antigens / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D003165:Complement System Proteins / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007938:Leukemia / Q000378:metabolism* / Q000628:therapy; D007945:Leukemia, Lymphoid / Q000378:metabolism / Q000628:therapy; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000628:therapy; D011817:Rabbits; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018958:CD55 Antigens; D003165:Complement System Proteins