A NOVEL CLASS OF ANTITUMOR ANTIBODIES - NUCLEOSOME-RESTRICTED ANTINUCLEAR AUTOANTIBODIES (ANA) FROM HEALTHY AGED NONAUTOIMMUNE MICE

Antinuclear autoantibodies (ANAs) of healthy aged mice were recently f ound to specifically interact with the surface of various tumor vs. no rmal cells. We characterize the specificity of three monoclonal ANAs f rom healthy aged Balb/c mice by indirect immunofluorescent staining of fixed Hep-2 cells, ELISA assays, and Western blotting analysis. Two o f these monoclonal antibodies, 2C5 and 1G3, exhibited specificity for nucleosomes. Subsequent flow cytometry experiments demonstrated that t he 2C5 antibody recognizes nucleosomes on the surface of mouse EL4 T-l ymphoma cells because antibody binding could be eliminated by pretreat ment of these cells with DNase or heparin and approximately 10-fold in creased after preincubation of cells with nucleosomes. The injection o f monoclonal antibody 2C5 into ANA-negative young mice 1 day before tu mor cell inoculation and on days 1, 3, and 5 thereafter significantly suppressed tumor development and increased survival. The antitumor act ivity of the 2C5 antibody is demonstrated for two syngeneic mouse tumo r models, EL4 T-lymphoma and B16 melanoma. In vitro analyses revealed antibody-dependent cellular cytotoxicity (ADCC) as one antitumor mecha nism of the 2C5 antibody. Based on these results, we postulate a benef icial role of antinucleosome autoantibodies as tumor-protective agents for an aging host or for antibody-mediated cancer therapy, and furthe r speculate that the presence of such antibodies represents a so far u nrecognized mechanism of immune surveillance against tumors.