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.
Flavell
D J
DJ
The Simon Flavell Leukaemia Research Unit, University Pathology, Southampton General Hospital, Hampshire, United Kingdom.
Warnes
S
S
Noss
A
A
Flavell
S U
SU
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000920:Antibody-Dependent Cell Cytotoxicity; D019011:Antigens, CD7 / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D018796:Immunoconjugates / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D016130:Immunophenotyping; D000922:Immunotoxins / Q000008:administration & dosage*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000008:administration & dosage*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013154:Spleen / Q000166:cytology
D000906:Antibodies; D019011:Antigens, CD7; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D010940:Plant Proteins; D011500:Protein Synthesis Inhibitors; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins