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Clin Cancer Res. 2012 Feb 1;18(3):839-49. doi: 10.1158/1078-0432.CCR-11-1116. Epub 2011 Dec 15.

Pharmacokinetically stabilized cystine knot peptides that bind alpha-v-beta-6 integrin with single-digit nanomolar affinities for detection of pancreatic cancer.

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  • 1Canary Center for Cancer, Early Detection, Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, California 94305, USA.

Abstract

PURPOSE:

Detection of pancreatic cancer remains a high priority and effective diagnostic tools are needed for clinical applications. Many cancer cells overexpress integrin α(v)β(6), a cell surface receptor being evaluated as a novel clinical biomarker.

EXPERIMENTAL DESIGN:

To validate this molecular target, several highly stable cystine knot peptides were engineered by directed evolution to bind specifically and with high affinity (3-6 nmol/L) to integrin α(v)β(6). The binders do not cross-react with related integrin α(v)β(5), integrin α(5)β(1), or tumor-angiogenesis-associated integrin, α(v)β(3).

RESULTS:

Positron emission tomography showed that these disulfide-stabilized peptides rapidly accumulate at tumors expressing integrin α(v)β(6). Clinically relevant tumor-to-muscle ratios of 7.7 ± 2.4 to 11.3 ± 3.0 were achieved within 1 hour after radiotracer injection. Minimization of off-target dosing was achieved by reformatting α(v)β(6)-binding activities across various natural and pharmacokinetically stabilized cystine knot scaffolds with different amino acid content. We show that the primary sequence of a peptide scaffold directs its pharmacokinetics. Scaffolds with high arginine or glutamic acid content suffered high renal retention of more than 75% injected dose per gram (%ID/g). Substitution of these amino acids with renally cleared amino acids, notably serine, led to significant decreases in renal accumulation of less than 20%ID/g 1 hour postinjection (P < 0.05, n = 3).

CONCLUSIONS:

We have engineered highly stable cystine knot peptides with potent and specific integrin α(v)β(6)-binding activities for cancer detection. Pharmacokinetic engineering of scaffold primary sequence led to significant decreases in off-target radiotracer accumulation. Optimization of binding affinity, specificity, stability, and pharmacokinetics will facilitate translation of cystine knots for cancer molecular imaging.

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