PRECLINICAL STUDIES WITH THE ANTI-CD19-SAPORIN IMMUNOTOXIN BU12-SAPORIN FOR THE TREATMENT OF HUMAN-B-CELL TUMORS

The immunotoxin BU12-SAPORIN was constructed by covalently coupling th e single-chain ribosome-inactivating protein saporin to the anti-CD19 monoclonal antibody BU12 via a disulphide linker using the heterobifun ctional reagent SPDP. The immunoreactivity and specificity of BU12-SAP ORIN was identical to that of unmodified native BU12 antibody. BU12-SA PORIN was selectively cytotoxic in vitro in a dose-dependent manner fo r the CD19(+) human common acute lymphoblastic leukaemia (cALL) cell l ine NALM-6 but exhibited no toxicity for the CD19(-) T-cell acute lymp hoblastic leukaemia (T-ALL) cell line HSB-2. The survival of severe co mbined immunodeficient (SCID) mice with disseminated NALM-6 leukaemia was significantly prolonged compared with sham-treated control animals by a course of therapy with BU12-SAPORIN but not with the irrelevant anti-CD7 immunotoxin HB2-SAPORIN. BU12-SAPORIN had no therapeutic effe ct in SCID mice with disseminated CD19(-) HSB-2 leukaemia. These precl inical studies have clearly demonstrated the selective cytotoxicity of BU12-SAPORIN for CD19(+) target cells both in vitro and in vivo. This , taken together with the lack of expression of the CD19 molecule by a ny normal life-sustaining tissue and its ubiquitous and homogeneous ex pression by the majority of cALL and B-NHL cells, provides the rationa le for undertaking a phase I trial of systemic therapy with BU12-SAPOR IN.