Triggering FCα-receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antibody therapy

CD20 Abs induce clinical responses in lymphoma patients, but there are considerable differences between individual patients, In Cr-51 release assays with whole blood as effector source, RAJI cells were effectively killed by a mouse/human chimeric IgG1 construct of CD20 Ab 1F5, whereas ARH-77 proved resistant to killing by this Ab, When whole blood was fractionated into plasma, mononuclear cells, or granulocytic effector cells, RAJI cells were effectively killed in the presence of complement-containing plasma, whereas the mature B cell line ARH-77 proved complement resistant. However, with a bispecific Ab (BsAb) against the myeloid receptor for IgA (CD89; Fc alpha RI) and CD20, a broad range of B cell lines were effectively killed, Fc alpha RI is expressed on monocytes/macrophages, neutrophils, and eosinophils. As the numbers of these effector cells and their functional activity ran be enhanced by application of G-CSF or GM-CSF, lysis via (Fc alpha RI x CD20) BsAb was significantly enhanced in blood from patients during therapy with these myeloid growth factors. Interestingly, the major effector cell population for this BsAb were polymorphonuclear neutrophils, which proved ineffective in killing malignant B cells with murine, chimeric IgG1, or Fc gamma RI- or Fc gamma RIII-directed BsAbs against CD20, Experiments with blood from human Fc alpha RI/Fc gamma RI double-transgenic mice showed corresponding results, allowing the establishment of relevant syngenic animal models in these mice. In conclusion, the combination of myeloid growth factors and an (Fc alpha RI x CD20) BsAb may represent a promising approach to improve effector cell recruitment for CD20-directed lymphoma therapy.