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Administration of disulfide‐stabilized Fv‐immunotoxins B1(dsFv)‐PE38 and B3(dsFv)‐PE38 by continuous infusion increases their efficacy in curing large tumor xenografts in nude mice
Author(s) -
Benhar Itai,
Reiter Yoram,
Pai Lee H.,
Pastan Ira
Publication year - 1995
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910620320
Subject(s) - immunotoxin , ricin , chemistry , ratón , disulfide bond , pharmacology , medicine , endocrinology , toxin , biochemistry , monoclonal antibody , immunology , antibody
B1 (dsFv)‐PE38 and B3(dsFv)‐PE38 are recombinant immunotoxins in which the Fv fragments of MAbs B1 and B3, respectively, are stabilized by an engineered interchain disulfide bond and are fused at their C‐termini to a modified Pseudomonas exotoxin from which the cell‐binding domain has been deleted (PE38). Both immunotoxins have been shown to be specifically cytotoxic toward human cancer cell lines which express Le Y ‐related carbohydrates on their surface, and when given i.v., eradicated 30‐to 50‐mm 3 s.c. A431 tumors growing in nude mice. A major advantage of dsFv‐immunotoxins is their stability at 37°C compared with the relatively unstable single‐chain Fvs. This allows them to be given continuously by osmotic pumps placed in the peritoneal cavity. In an attempt to increase the therapeutic index of the immunotoxins, we have now delivered them continuously for 6 days through mini‐osmotic pumps placed in the peritoneal cavity of tumor‐bearing nude mice. Using this mode of administration, we were able to maintain a constant level of immunotoxin in the serum which was non‐toxic to the mice, but caused complete regressions of large 150‐to 200‐mm 3 tumors which lasted for over a month at 1/11 of the LD 50 with B1(dsFv)‐PE38 and 1/6 of the LD 50 with B3(dsFv)‐PE38. Complete regression of tumors of similar size could also be achieved by i.v. bolus injections of these immunotoxins at 1/7 of the LD, o with B1 (dsFv)‐PE38) and 1/3 of the LD 50 with B3(dsFv)‐PE38. These results suggest that in patients it may be advantageous to administer dsFv‐immunotoxins by continuous infusion, since a larger therapeutic index is achieved. © 1995 Wiley‐Liss Inc.