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


ABSTRACT: Detection of pancreatic cancer remains a high priority and effective diagnostic tools are needed for clinical applications. Many cancer cells overexpress integrin ?(v)?(6), a cell surface receptor being evaluated as a novel clinical biomarker.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 ?(v)?(6). The binders do not cross-react with related integrin ?(v)?(5), integrin ?(5)?(1), or tumor-angiogenesis-associated integrin, ?(v)?(3).Positron emission tomography showed that these disulfide-stabilized peptides rapidly accumulate at tumors expressing integrin ?(v)?(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 ?(v)?(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).We have engineered highly stable cystine knot peptides with potent and specific integrin ?(v)?(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.

SUBMITTER: Kimura RH 

PROVIDER: S-EPMC3271184 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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

Kimura Richard H RH   Teed Robert R   Hackel Benjamin J BJ   Pysz Marybeth A MA   Chuang Courtney Z CZ   Sathirachinda Ataya A   Willmann Jürgen K JK   Gambhir Sanjiv S SS  

Clinical cancer research : an official journal of the American Association for Cancer Research 20111215 3


<h4>Purpose</h4>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.<h4>Experimental design</h4>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 no  ...[more]

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