Preclinical testing of an anti-erbB-2 recombinant toxin.
The performance of OLX-209 indicates it should enter phase I clinical testing. OLX-209 is a recombinant toxin targeting the erbB-2 oncoprotein. The design of OLX-209 takes advantage of improvements in immunotoxin technology to produce a molecule that is smaller and more potent than a conventional chemically linked antibody-toxin conjugate. The targeting portion of OLX-209 is a single chain antibody structure derived from the anti-erbB-2 hybridoma, e23. This antibody has unusual specificity in that it does not bind to most normal tissue including peripheral nerve or kidney tissue. Preclinical testing shows in vitro activity against breast cancer cell lines in the pM range. Efficacy testing in five models of human cancer indicates that a dose of 43 micrograms/kg causes reproducible tumor regressions. Efficacy can be achieved on a variety of schedules of administration. The effective dose results in no measurable change in serum liver enzymes when delivered to mice or primates. The LD10 is over twice the effective dose in mice. The pharmacokinetics indicate a t 1/2 of 50 minutes for both mice and cynomolgus monkeys. Serum concentrations of more than ten times those observed at the effective dose can be achieved in monkeys with no evidence of toxicity. Antigenicity of OLX-209 is surprisingly low. These results form the basis for the clinical testing phase for OLX-209.
King
C R
CR
Oncologix, Inc., Gaithersburg, MD, USA.
Kasprzyk
P G
PG
Fischer
P H
PH
Bird
R E
RE
Turner
N A
NA
D000818:Animals; D000906:Antibodies; D005098:Exotoxins; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology* / Q000633:toxicity; D009369:Neoplasms / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000633:toxicity; D057127:Single-Chain Antibodies; D014407:Tumor Cells, Cultured
D000906:Antibodies; D005098:Exotoxins; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C089922:OLX 209