Genetically designing a more potent antipancreatic cancer agent by simultaneously co-targeting human IL13 and EGF receptors in a mouse xenograft model

D. A. Vallera, B. J. Stish, Y. Shu, H. Chen, Ashok Saluja, D. J. Buchsbaum, S. M. Vickers

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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. Design: 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.

Original languageEnglish (US)
Pages (from-to)634-641
Number of pages8
JournalGut
Volume57
Issue number5
DOIs
StatePublished - May 1 2008
Externally publishedYes

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Interleukin-13
Heterografts
Pancreatic Neoplasms
Nude Mice
Weight Loss
Neoplasms
Interleukin-13 Receptors
Diphtheria Toxin
Poisons
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Research Personnel
Ligands
Cell Line
In Vitro Techniques
ErbB Receptors
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Genetically designing a more potent antipancreatic cancer agent by simultaneously co-targeting human IL13 and EGF receptors in a mouse xenograft model. / Vallera, D. A.; Stish, B. J.; Shu, Y.; Chen, H.; Saluja, Ashok; Buchsbaum, D. J.; Vickers, S. M.

In: Gut, Vol. 57, No. 5, 01.05.2008, p. 634-641.

Research output: Contribution to journalArticle

Vallera, D. A. ; Stish, B. J. ; Shu, Y. ; Chen, H. ; Saluja, Ashok ; Buchsbaum, D. J. ; Vickers, S. M. / Genetically designing a more potent antipancreatic cancer agent by simultaneously co-targeting human IL13 and EGF receptors in a mouse xenograft model. In: Gut. 2008 ; Vol. 57, No. 5. pp. 634-641.
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AU - Vallera, D. A.

AU - Stish, B. J.

AU - Shu, Y.

AU - Chen, H.

AU - Saluja, Ashok

AU - Buchsbaum, D. J.

AU - Vickers, S. M.

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N2 - 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. Design: 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.

AB - 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. Design: 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.

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