NHS76/PEP2, a Fully Human Vasopermeability-Enhancing Agent to Increase The Uptake and Efficacy of Cancer Chemotherapy

Abstract

Purpose: Previously, we have shown that the attachment of interleukin 2 (IL-2) to a tumortargeting 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.

Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice

“…Its fusion protein with antibody NHS76 (NHS76/PEP) showed an increased uptake compared with NHS76 alone. Pretreatment of animals with NHS/PEP also augmented the therapeutic effect of several drugs (doxorubicin, Taxol, vinblastine, etoposide, and 5-fluorouracil) within a 2-hour interval (27).…”

Antibody tumor penetration: Transport opposed by systemic and antigen-mediated clearance

“…These signaling molecules increase the physical permeability of vasculature by inducing the formation of fenestrations within endothelial cells or increasing the size of intercellular gaps [133][134][135]. Epstein and coworkers have demonstrated that systemic administration of IL-2 peptides fused to tumor targeting antibodies can specifically increase permeability of the tumor vasculature leading to increased tumor uptake and therapeutic efficacy of subsequently administered drugs [136,137]. In contrast, Halin et al found that pretreatment of tumor bearing mice with a tumor targeting scFv-VEGF fusion only improved uptake of subsequently administered drugs moderately and at high concentrations [138].…”

Approaches to improve tumor accumulation and interactions between monoclonal antibodies and immune cells

“…Using a 2-h pretreatment, an optimal dose of NHS76/PEP2 (30 μg) induced greatly increased and specific tumor accumulation of the mAb B72.3. 86 This approach increased also tumor accumulation and therapeutic efficacy of the chemotherapeutic drugs etoposide, doxorubicin, paclitaxel (Taxol ® ), docetaxel (Taxotere ® ), 5-fluorouracil, or vinblastine. The same group had previously shown that conjugation of tumor necrosis factor (TNF)-α to the tumor necrosis-targeting mAb TNT-1 caused a three-fold increase of the tumor uptake of the F(ab') 2 fragment of the same antibody.…”