NHS76/PEP2, a fully human vasopermeability-enhancing agent to increase the uptake and efficacy of cancer chemotherapy.
OBJECTIVE
Previously, we have shown that the attachment of interleukin 2 (IL-2) to a tumor-targeting antibody can produce a 4-fold enhancement in the uptake of antibodies and drugs in tumors. More recently, we discovered that a 37-amino-acid linear sequence of IL-2 designated vasopermeability-enhancing peptide (PEP), contained the vasopermeability activity of IL-2, and could be used after linkage to tumor-targeting antibodies to produce the same enhancement of drugs and antibodies in tumors. We now describe the generation of a fully human antibody fusion protein, designated NHS76/PEP(2), which can be used in patients to enhance the therapeutic potential of chemotherapy.


METHODS
NHS76/PEP(2) was expressed in NS0 cells using the glutamine synthetase gene amplification system. To show its clinical potential as a pretreatment to chemotherapy, NHS76/PEP(2) was given i.v. 2 hours before the injection of suboptimal doses of etoposide, doxorubicin, Taxol, Taxotere, 5-fluorouracil, or vinblastine in mice bearing established solid tumors. Results were recorded by measuring tumor volumes thrice per week.


RESULTS
Compared with drug treatment alone, NHS76/PEP(2) pretreatment substantially improved the effectiveness of chemotherapeutic agents in solid tumor models. Tumor suppression was most pronounced in those groups of mice bearing tumors known to be sensitive to the specific drug under study. However, in certain instances, tumors previously known to be resistant to specific single chemotherapeutic agents were shown to respond by the addition of NHS76/PEP(2) pretreatment.


CONCLUSIONS
NHS76/PEP(2) seems an excellent candidate to improve the value of standard chemotherapy drug treatment by virtue of its ability to increase the uptake of drugs in solid tumors selectively.
Khawli
Leslie A
LA
Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
Hu
Peisheng
P
Epstein
Alan L
AL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000627:therapeutic use; D005047:Etoposide / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology*; D043823:Taxoids / Q000493:pharmacokinetics / Q000627:therapeutic use; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome; D014747:Vinblastine / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C503143:NHS76-PEP2; D010446:Peptide Fragments; D043823:Taxoids; D000077143:Docetaxel; D014747:Vinblastine; D005047:Etoposide; D004317:Doxorubicin; D017239:Paclitaxel; D005472:Fluorouracil