1760 DJ Flavell et al NK cells into tissues is in some way impaired in these animals. The latter would prevent NK cells coming into direct contact with HSB- 2 cells in extra-splenic tissue locations and thus prevent the engage- ment of NK cell surface FcγRIII with the Fc domain of antibody coating the target leukaemia cell, a step that is an absolute require- ment for cellular cytotoxicity. This study has not attempted to examine the distribution of NK1.1 cells in other NOD/SCID tissues other than spleen and it is therefore not possible to draw any firm conclusions regarding these various possibilities at this stage, though it is the opinion of the authors that it is the impairment in NOD/SCID NK cell lytic function that more likely accounts for the apparent lack of in vivo directed ADCC against HSB-2 cells. We also demonstrated in the present study that the anti-CD7 IT HB2-SAPORIN was therapeutically significantly less effective in vivo against HSB-2 cells xenografted into NOD/SCID mice in comparison to the therapeutic effects obtained in SCID mice. We observed in one experiment that 70% of NOD/SCID-HSB-2 mice treated with IT developed signs and symptoms of leukaemia cell growth at virtually the same rate as PBS sham-treated controls, and achieved ultimately only a 30% disease-free survival rate. This compares with an 80% survival rate in equivalent SCID mice treated with the same IT. This was even more pronounced in a second experiment where HB2-SAPORIN was almost completely ineffective, giving only a very modest increase in the time taken to develop symptoms compared with PBS sham-treated controls and with all animals in this treatment group eventually showing demon- strable leukaemia cell growth. The HB2-F(ab)2-SAPORIN IT. which is incapable of recruiting NK cells due to its lack of an Fc domain, performed in a near identical fashion to HB2-SAPORIN. These findings in NOD/SCID mice are remarkably similar to the observed outcome when standard SCID mice bearing HSB-2 leukaemia are depleted of their NK cells with anti-asialo GM1 anti- body and then treated with HB2-SAPORIN IT (Flavell et al, 1998). Here the therapeutic effect of HB2-SAPORIN was significantly reduced in NK cell-depleted animals in comparison to NK cell- intact animals. Just as in NOD/SCID-HSB-2 mice treated with the IT HB2-SAPORIN in the present study, the majority of SCID- HSB-2 mice depleted of their NK cells with anti-asialo GM1 anti- body also died at a similar rate as sham-treated controls (Flavell et al, 1998). This allowed us to draw the conclusion that ADCC medi- ated by NK or NK-like cells contributed additively to the overall therapeutic effect of HB2-SAPORIN in the SCID-HSB-2 model. The present study would seem to provide further support for this hypothesis, that is to say that it is the absence of effective in vivo ADCC in NOD/SCID-HSB-2 mice that reduces the therapeutic effect of the IT HB2-SAPORIN. The cautionary lesson to be learned here is simply that the non-adaptive immune status of immunodeprived mice can significantly influence the therapeutic evaluation of antibody-based drugs like HB2-SAPORIN and give a misleading overestimate of their intrinsic anti-tumour potency. On the positive side such in vivo animal models also provide a means of delineating and defining contributory additivities between mech- anistically different antibody-mediated anti-tumour activities and provide us with valuable insights that may eventually assist us in the development of multi-modal targeted approaches for the treat- ment of human malignancies. ACKNOWLEDGEMENTS This work was supported by the children’s leukaemia research charity Leukaemia Busters. 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