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.
We have investigated the cytotoxic performance of two different anti-CD7/anti-saporin BsAb's (HB2 x DB7-18 and Q1.1), three anti-CD38/anti-saporin BsAb's (OKT10 x RabSap, OKT10 x DB7-18 and Q4.1) and an anti-CD7 (HB2-Sap) and anti-CD38-saporin (OKT10-Sap) immunotoxin for delivering the ribosome inactivating protein (rip) to the human T-cell acute lymphoblastic leukemia cell line HSB-2. In the case of CD7 as target molecule the immunotoxin outperformed both anti-CD7 BsAb's being six times more effective than HB2 x DB7-18 and 98 times more so than Q1.1 at effectively inhibiting protein synthesis in a dose dependent manner. The chemically constructed HB2 x DB7-18 BsAb was more effective at inhibiting protein synthesis and cell growth in target HSB-2 cells in a dose dependent manner than the quadroma produced BsAb Q1.1. Both BsAb demonstrated a prozone effect used at concentrations above 0.1 nM though this was more pronounced for Q1.1 than for HB2 x DB7-18. The prozone effect was partially though not completely reversed by increasing the concentration of saporin in the system. In the case of CD38 as target molecule the anti-CD38 IT OKT10-Sap performed poorly, never actually achieving its IC50. Two BsAb's constructed with monoclonal anti-saporin Fab arms each recognizing a different epitope on the saporin molecule also performed poorly. In contrast the BsAb OKT10 x RabSap constructed with Fab derived from a rabbit polyclonal anti-saporin antiserum performed in a dose dependent manner achieving its IC50 at a concentration of 1.3 nM. This BsAb also exhibited a prozone effect. These results exemplify the importance of cross linking adjacent target molecules on the cell surface in order to achieve effective delivery of saporin to the cell interior.
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