HLA CLASS-II AS POTENTIAL TARGET ANTIGEN ON MALIGNANT B-CELLS FOR THERAPY WITH BISPECIFIC ANTIBODIES IN COMBINATION WITH GRANULOCYTE-COLONY-STIMULATING FACTOR

We have investigated the capacity of polymorphonuclear phagocytes (PMN ) to lyse malignant B-cell lines using antibodies and antibody derivat es to a range of different B-cell antigens. PMN were found to mediate lysis of all tested B-cell lines in the presence of HLA class II antib odies L227, L243, F3.3, and CR3/43. Target cell lysis was significantl y enhanced when PMN isolated during granulocyte colony-stimulating fac tor (G-CSF) treatment were compared with PMN from healthy donors. Only G-CSF primed PMN, expressing Fc gamma RI (CD64), lysed B cells in the presence of monoclonal antibody (MoAb) 1D10 or Lym-1 to HLA class II related epitopes. Remarkably, PMN were consistently unable to kill mal ignant B cells with antibodies to the B-cell related antigens CD19, CD 20, CD21, CD37, and CD38. This target antigen restriction was not obse rved with mononuclear effector cells, which mediated cytotoxicity with antibodies to HLA class II, but also with mouse/human chimeric constr ucts to CD19, CD37, and CD38. Blocking studies with Fc gamma R antibod ies and reverse antibody-dependent cellular cytotoxicity (ADCC) experi ments against Fc gamma R antibody expressing hybridoma targets confirm ed the pivotal role of Fc gamma RI in enhanced killing by G-CSF primed neutrophils. Bispecific antibodies (BsAb) with one specificity for Fc gamma RI, and another for a tumor associated antigen, offer an intere sting approach to improve effector cell recruitment for immunotherapy. In our studies, very effective lysis was observed with G-CSF primed P MN and an [HLA class II x Fc gamma RI] BsAb. The therapeutic implicati ons of these findings and the possible use of BsAb in combination with G-CSF are discussed. (C) 1996 by The American Society of Hematology.