Genetically designing a more potent antipancreatic cancer agent by simultaneously co-targeting human IL13 and EGF receptors in a mouse xenograft model.
OBJECTIVE
Investigators are currently interested in the epidermal growth factor receptor (EGFR) and interleukin 13 receptor (IL13R) as potential targets in the development of new biologicals for pancreatic cancer. Attempts to develop successful agents have met with difficulty. The novel approach used here was to target these receptors simultaneously with EGF and IL13 cloned on the same bispecific single-chain molecule with truncated diphtheria toxin (DT(390)) to determine if co-targeting with DTEGF13 had any advantages.


METHODS
Proliferation experiments were performed to measure the potency and selectivity of bispecific DTEGF13 and its monospecific counterparts against pancreatic cancer cell lines PANC-1 and MiaPaCa-2 in vitro. DTEGF13 was then administered intratumourally to nude mice with MiaPaCa-2 flank tumours to measure efficacy and toxicity (weight loss).


RESULTS
In vitro, bispecific DTEGF13 was 2800-fold more toxic than monospecific DTEGF or DTIL13 against PANC-1. A similar enhancement was observed in vitro when MiaPaCa-2 pancreatic cancer cells or H2981-T3 lung adenocarcinoma cells were studied. DTEGF13 activity was blockable with recombinant EGF13. DTEGF13 was potent (IC(50) = 0.00017 nM) against MiaPaCa-2, receptor specific and significantly inhibited MiaPaCa-2 tumours in nude mice (p<0.008).


CONCLUSIONS
In vitro studies show that the presence of both ligands on the same bispecific molecule is responsible for the superior activity of DTEGF13. Intratumoural administration showed that DTEGF13 was highly effective in checking aggressive tumour progression in mice. Lack of weight loss in these mice indicated that the drug was tolerated and a therapeutic index exists in an "on target" model in which DTEGF13 is cross-reactive with native mouse receptors.
Vallera
D A
DA
University of Minnesota Cancer Center, Department of Therapeutic Radiology-Radiation Oncology, Minneapolis, MN 55455, USA. valle001@umn.edu
Stish
B J
BJ
Shu
Y
Y
Chen
H
H
Saluja
A
A
Buchsbaum
D J
DJ
Vickers
S M
SM
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D053660:Receptors, Interleukin-13 / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C525855:DTEGF13 cytotoxin; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors