A mouse
IgG2b anti-pan
carcinoma monoclonal antibody, NR-LU-10, was shown to bind homogeneously to
ascites xenografts of both ovarian and colon
carcinoma. Following linkage to a highly potent holotoxin, Pseudomonas
exotoxin A (PE), NR-LU-10 demonstrated high potency and selectivity in vitro (ID50 = 100 pg/ml; elimination of greater than or equal to 4.5 logs of cells). The conjugate was evaluated for therapeutic efficacy against a human colon
tumor (HT-29) transplantable in the peritoneal cavity of nude mice. Beginning 3 days after HT-29 injection, mice received either three or six i.p.
injections of 0.5 micrograms of unconjugated NR-LU-10 or
immunotoxin conjugate (NR-LU-10/PE) every other day. Mice that received three or six treatments of NR-LU-10 alone had median survival times (MSTs) of 39 and 40 days, respectively, which did not differ significantly from the MST observed for the untreated control groups (MST = 35 days). In contrast, treatment with three or six
injections of 0.5 micrograms NR-LU-10/PE exhibited significantly increased MSTs (P = 0.002) of 50 and 60 days, respectively. Coinjection of unconjugated NR-LU-10 (20 micrograms) and 0.5 micrograms of NR-LU-10/PE blocked the
therapeutic effect of the
immunotoxin (MST = 33 days). The therapeutic efficacy of NR-LU-10/PE was further enhanced against HT-29 when administered i.p. during and after cytoreductive
chemotherapy. The i.p. administration of 300 mg/lg of
cyclophosphamide plus 100 mg/kg of the chemoprotective
drug,
WR-2721, 10 and 17 days posttumor cell inoculation induced a significant increase in MST from 36 days to 59 days (P = 0.002). Interestingly, groups of mice that received either two, four, or seven treatments of NR-LU-10/PE following cytoreductive
therapy exhibited a further significant increase (P = 0.001) in MSTs of 89, 97, and 105 days, respectively. Therefore, the use of
immunotoxin therapy following cytoreductive
chemotherapy significantly prolonged survival time of mice bearing the HT-29 colon
tumor over that observed with
chemotherapy or NR-LU-10/PE alone.