HIGHLY POTENT CD22-RECOMBINANT RICIN A RESULTS IN COMPLETE CURE OF DISSEMINATED MALIGNANT B-CELL XENOGRAFTS IN SCID MICE BUT FAILS TO CURE SOLID XENOGRAFTS IN NUDE-MICE

The highly specific cytotoxic action of ribosome-inactivating protein (RIP) containing immunotoxins (ITs) makes IT therapy a promising appro ach to eliminating residual malignant cells. We investigated the cytot oxicity of the IT CD22-recombinant ricin A to the B-cell line Ramos in vitro and in vivo. Cytotoxicity of CD22-recombinant ricin A in vitro was very high as expressed by the very low 50% inhibition dose (ID50) of 3.5x10(-11) M. Cytotoxicity was increased 7 times in the presence o f the cytotoxicity enhancer NH4Cl. The ultimate kill of Ramos cells by CD22-recombinant ricin A was high (2.7-log kill) and was increased st rongly in the presence of NH4Cl (4.2-log kill). Anti-tumor activity in vivo was investigated by i.v. treatment of solid s.c. Ramos xenograft s in nude BALB/c mice. A single dose did not inhibit tumor growth. Tre atment on 5 consecutive days resulted in evident tumor reduction. In o ne mouse, tumor could no longer be detected on the 6th day after start ing treatment. However, after 8 days tumor volumes increased again. An ti-tumor activity was more pronounced in a disseminated tumor model in SCID mice. IT treatment (i.v.) 7 days after i.v. inoculation with Ram os cells resulted in cure of all mice. Non-specific toxicity was low. Alanine aminotransferase (ALAT) levels in serum were elevated temporar ily. Serum values of gamma-glutamyl transferase (gamma-GT), bilirubin and creatinin did not change. Body weight was also transiently reduced . The LD(50) in SCID mice after i.v. administration was high (0.626 mg IT per mouse). The clearance rate in SCID mice, as determined by ELIS A, was biphasic. (C) 1996 Wiley-Liss, Inc.