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RI, CD89) and Tumor Antigens Efficiently Promote Cell-Mediated Cytotoxicity of Tumor Targets in Whole Blood
*
Medarex, Inc., Annandale, NJ 08801; and
Department of Microbiology, Dartmouth Medical School, Lebanon, NH 03756
The FcR for IgA (Fc
RI, CD89) is primarily expressed on cytotoxic
immune effector cells. By chemically cross-linking F(ab') fragments of
the FcR for IgA (FcRI)-specific mAb (A77) with tumor Ag-specific mAb
(anti-HER2/neu and anti-epidermal growth factor
receptor), we have developed bispecific molecules (BSM) that
simultaneously bind to respective tumor Ags and FcRI-expressing
effector cells in whole blood. These BSM mediated up to 55% of
specific lysis of appropriate tumor Ag-expressing target cells (from a
variety of tumors) with purified polymorphonuclear leukocytes,
monocytes, or whole blood effector cells without preactivation with
exogenous cytokines. To our knowledge, this is the first demonstration
of Ab-dependent cell-mediated cytotoxic activity via FcRI in whole
blood. Also, monocyte-derived macrophages mediated phagocytosis of
HER2/neu-expressing tumor cells (>95% tumor cell loss).
These BSM-mediated cytotoxic activities were completely inhibited by
F(ab')2 of A77, demonstrating the specific role of FcRI
as a trigger molecule. Furthermore, the binding of these BSM to
monocytes or polymorphonuclear leukocytes in whole blood did not induce
modulation of FcRI in the absence of the target Ag. Therefore,
immune effector cells may be "armed" with FcRI-directed BSM in
whole blood. These FcRI-directed BSM may offer new treatment options
for various malignancies and other disease conditions.
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