BISPECIFIC AB THERAPY OF B-CELL LYMPHOMA - TARGET-CELL SPECIFICITY OFANTIBODY DERIVATIVES APPEARS CRITICAL IN DETERMINING THERAPEUTIC OUTCOME

Despite the success of mAb and bispecific (bs)Ab in the treatment of c ertain malignancies, there is still considerable uncertainty about the most appropriate format in which they should be used. In the current work we have investigated a panel of bsAb [IgG and F(ab)(2)] with dual specificity for T cells and neoplastic B cells. Throughout this work, anti-CD2 or anti-CD3 were used to bind the mouse T cells, and antibod ies to surface IgM idiotype (Id), CD19, CD22, or MHC class IT were use d to target mouse B cell lymphomas BCL1 or A31. In vitro, killing was measured in a conventional cytotoxicity assay using Cr-51-labelled A31 and BCL1 cells as targets and activated mouse splenocytes as effecter s. bsAb showed a wide range of cytotoxic activities, which could be ra nked in the following order: [anti-CD3 x anti-class-II] > [anti-CD3 x anti-CD19] > [anti-CD3 x anti-Id] > [anti-CD3 x anti-CD22], with the [ anti-CD2 x anti-Id] derivative showing relatively little cytotoxic act ivity. This hierarchy of activity indicates some correlation with the binding activity of the bsAb on target cells, but showed a much strong er parallel with the tendency of the anti-(target cells) mAb to underg o antigenic modulation (less modulation, more killing). In vivo, the s ituation was completely different and only the anti-id derivatives, [a nti-CD3 x anti-ld] and [anti-CD2 x anti-ld], were effective in prolong ing the survival of tumour-bearing animals. Under optimal conditions I d-positive tumour was eradicated with a single treatment of bsAb. We c onclude from this work that the target cell specificity of a bsAb is c ritical in determining therapeutic outcome and that in vitro cytotoxic ity assays do not predict in vivo activity.