Therapeutic efficacy of Fc gamma RI/CD64-directed bispecific antibodies inB-cell lymphoma

CD64 (Fc gamma RI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tum ors in the presence of appropriate monoclonal antibodies. An huCD64 transge nic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')(2) (BsAb) in retargeting granulocyte-colony-stimulating f actor (G-CSF)-activated PMN against syngeneic B-cell lymphomas is reported. This model allows careful analysis of the individual elements of the thera peutic process. BsAb were directed against immunoglobulin-idiotype (Id), ma jor histocompatibility class II (MHC II), or CD19 on the tumors and huCD64 on the effecters. In vitro cytotoxicity assays and in vivo tumor tracking s howed that, provided effecters were activated with G-CSF, all 3 derivatives destroyed and cleared lymphoma cells, with (huCD64 x MHC II) proving by fa r the most cytotoxic in vitro. However, though all derivatives delivered so me survival advantage, only the [huCD64 x Id] BsAb provided longterm protec tion to tumor-bearing animals. These results demonstrate that CD64-recruite d cytotoxic effecters operate in vivo but that the (huCD64 x Id) conferred an additional anti-tumor function essential for long-term protection. T-cel l depletion studies demonstrated that this extra therapeutic activity with [huCD64 x Idl was totally dependent on CD4 and CD8 T cells and that mice, o nce "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 s elected appropriately, CD64-based BsAb can: establish long-term T-cell immu nity. (C) 2000 by The American Society of Hematology.