Therapy of human B‐cell lymphoma bearing scid mice is more effective with anti‐CD19‐and anti‐CD38‐saporin immunotoxins used in combination than with either immunotoxin used alone

Abstract

The CD19+ CD38+ human Burkitt's lymphoma cell line Ramos grows aggressively when injected intravenously (i.v.) into severe combined immunodeficient (SCID) mice, killing 100% of animals within a 33-42 day period with widely disseminated disease. Treatment commencing 7 days after i.v. injection of Ramos cells, with 3 doses of an anti-CD19 immunotoxin (IT; BU12-SAPORIN) or an anti-CD38IT (OKT10-SAPORIN) led to a significant prolongation of survival compared with sham-treated controls; the anti-CD38 IT gave the greatest prolongation of survival, but all treated animals eventually succumbed to disease. When both ITs were used in combination at equivalent dose levels, the therapeutic outcome was significantly improved over that obtained for single IT therapy, with 20% of animals surviving disease-free to 300 days. When anti-CD38 IT was given in combination with anti-CD19 antibody there was no therapeutic improvement over anti-CD38 IT used alone. However, when anti-CD19 IT was given in combination with CD38 antibody, a significant prolongation of survival ensued over that obtained with anti-CD19 IT alone, though this was not as significantly pronounced as that obtained when both ITs were used in combination and was only as good as the survival obtained with OKT10 antibody used alone. CD19 and CD38 are expressed on the surface of the vast majority of B-cell lymphoma and common acute lymphoblastic leukaemia cells, and our findings provide a sound rationale for a combination immunotoxin trial in these diseases directed against both these target molecules.

Therapy of human T-cell acute lymphoblastic leukaemia with a combination of anti-CD7 and anti-CD38-SAPORIN immunotoxins is significantly better than therapy with each individual immunotoxin

“…The present study has confirmed in a different model tumour system very similar findings, which we originally made with the human B-cell lymphoma cell line Ramos when targeted against with a combination of anti-CD19 and -CD38-saporin ITs (Flavell et al, 1995). In the instance of the SCID-Ramos model it was found that the improved therapeutic benefit was entirely due to an immunotoxin-mediated effect, as combination pairs of IT + antibody (i.e.…”

“…Both of these naked antibodies probably mediate their in vivo therapeutic effects via ADCC and the in vitro chromium release results presented here show demonstrably that both antibodies and ITs can evoke ADCC. These results are very similar to those obtained with the anti-CD19 antibody BU12 and same anti-CD38 antibody in SCID mice bearing the CD19+ CD38+ human B-cell lymphoma cell line Ramos (Flavell et al, 1995). In both described tumour systems it therefore appears that anti-CD38 antibody performs therapeutically better than either the anti-CD19 antibody in the SCIDRamos model, or the anti-CD7 antibody in the SCID-CEM system.…”

“…These findings allow us to feel optimistic that such a therapeutic approach may be of real practical benefit in achieving better and more robust response rates in patients with this type of immunotherapeutic and justify further preclinical evaluation. In the present study we demonstrate that a combination of anti-CD7 and anti-CD38-saporin ITs are significantly more effective therapeutically in SCID mice xenografted with the human CD7+ CD38+ T-ALL cell line CCRF CEM than the individual ITs when used individually, thus confirming in a completely different tumour system our original findings with the B-cell lymphoma cell line Ramos (Flavell et al, 1995(Flavell et al, , 1997 and therefore further reinforcing the rationale for developing this approach for clinical trials.…”

“…previously shown that therapy outcome in SCID mice xenografted with the human B-cell lymphoma cell line Ramos is significantly improved when a combination of anti-CD19 and anti-CD38 saporin ITs are used compared with when either IT is used individually (Flavell et al, 1995). Indeed we have further shown that a 3 IT combination with anti-CD19, -CD22 and -CD38 specificities can completely cure SCID-Ramos mice (Flavell et al, 1997).…”

“…The ability of each IT, native antibody or saporin to inhibit protein synthesis in target CCRF CEM cells was evaluated by a [ 3 H]-leucine incorporation assay as described previously (Flavell et al, 1995) (CN Pharmaceuticals Ltd, Basingstoke).…”