Therapeutic efficacy of FcγRI/CD64-directed bispecific antibodies in B-cell lymphoma

CD64 (Fc gamma RI) 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 effecters. In vitro cytotoxicity assays and in vivo tumor tracking showed that, provided effecters 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 longterm protection to tumor-bearing animals. These results demonstrate that CD64-recruited cytotoxic effecters 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 Idl 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. (C) 2000 by The American Society of Hematology.