CD64 (FcgammaRI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of
tumors in the presence of appropriate
monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')(2) (BsAb) in retargeting
granulocyte-colony-stimulating factor (
G-CSF)-activated PMN against syngeneic
B-cell lymphomas is reported. This model allows careful analysis of the individual elements of the therapeutic process. BsAb were directed against
immunoglobulin-idiotype (Id), major histocompatibility class II (MHC II), or CD19 on the
tumors and huCD64 on the effectors. In vitro cytotoxicity assays and in vivo
tumor tracking showed that, provided effectors were activated with
G-CSF, all 3 derivatives destroyed and cleared
lymphoma cells, with (huCD64 x MHC II) proving by far the most cytotoxic in vitro. However, though all derivatives delivered some survival advantage, only the [huCD64 x Id] BsAb provided long-term protection to
tumor-bearing animals. These results demonstrate that CD64-recruited cytotoxic effectors operate in vivo but that the (huCD64 x Id) conferred an additional anti-
tumor function essential for long-term protection. T-cell depletion studies demonstrated that this extra therapeutic activity with [huCD64 x Id] was totally dependent on CD4 and CD8 T cells and that mice, once "cured" with BsAb, were resistant to
tumor rechallenge. These findings indicate that CD64 is an effective trigger molecule for delivering
cytokine-activated PMN against
tumor in vivo and that, provided
tumor targets are selected appropriately, CD64-based BsAb can establish long-term T-cell immunity.