Host-mediated antibody-dependent cellular cytotoxicity contributes to the in vivo therapeutic efficacy of an anti-CD7-saporin immunotoxin in a severe combined immunodeficient mouse model of human T-cell acute lymphoblastic leukemia.

We have investigated the anti-leukemia effect that is exerted by the murine anti-CD7 antibody HB2 in a severe combined immunodeficient (SCID) mouse model of human T-cell acute lymphoblastic leukemia (T-ALL) and determined the contribution that this antibody effect makes to the therapeutic potency of a saporin immunotoxin (IT) constructed with the same antibody. The anti-leukemia effect is not exerted through complement-mediated lysis or through direct growth-inhibitory signaling after binding of antibody to the CD7 molecule on the T-ALL cell surface but rather through antibody-dependent cellular cytotoxicity (ADCC). Thus, the in vivo depletion of SCID mice of their natural killer cells almost completely abolishes the therapeutic effect of native HB2 anti-CD7 antibody and moreover significantly reduces the in vivo therapeutic performance of the anti-CD7 HB2-SAPORIN IT. Furthermore, an IT constructed with the F(ab')2 fragment of the same anti-CD7 antibody (HB2-F(ab')2-SAPORIN), which is incapable of recruiting natural killer cells, performed significantly less well therapeutically than HB2-SAPORIN IT. There was also a significant improvement in the therapeutic performance of the HB2-F(ab')2-SAPORIN IT in SCID-HSB-2 mice when used in combination with intact HB2 antibody, presumably through restoration of an ADCC attack on the target HSB-2 cell. These combined data indicate that ADCC in the SCID mouse does contribute additively together with toxin to the in vivo therapeutic potency of the HB2-SAPORIN IT directed against this human T-ALL cell line and that this has potentially important implications for the utility of this and other related classes of immunotherapeutic in human therapy.