Preclinical development and first-in-human imaging of the integrin a v b 6 with [ 18 F]a v b 6 -binding peptide in metastatic carcinoma

Sven H. Hausner, Richard J Bold, Lina Y. Cheuy, Helen K Chew, Megan E Daly, Ryan A. Davis, Cameron C Foster, Edward Kim, Julie Sutcliffe

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4 Citations (Scopus)

Abstract

Purpose: The study was undertaken to develop and evaluate the potential of an integrin a v b 6 -binding peptide (a v b 6 -BP) for noninvasive imaging of a diverse range of malignancies with PET. Experimental Design: The peptide a v b 6 -BP was prepared on solid phase and radiolabeled with 4-[ 18 F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired a v b 6 -expressing and a v b 6 -null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired a v b 6 -expressing and a v b 6 -null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer. Results: [ 18 F]a v b 6 -BP displayed excellent affinity and selectivity for the integrin a v b 6 in vitro [IC 50 (a v b 6 ) ¼ 1.2 nmol/L vs IC 50 (a v b 3 ) >10 mmol/L] in addition to rapid target-specific cell binding and internalization (72.5% 0.9% binding and 52.5% 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [ 18 F]a v b 6 -BP was rapid, primarily via the kidneys. In patients, [ 18 F]a v b 6 -BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [ 18 F]a v b 6 -BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung. Conclusions: The clinical impact of [ 18 F]a v b 6 -BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.

Original languageEnglish (US)
Pages (from-to)1206-1215
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number4
DOIs
StatePublished - Feb 15 2019

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Integrins
Null Lymphocytes
Carcinoma
Peptides
Neoplasm Metastasis
Neoplasms
Lung
Autoradiography
Pancreatic Neoplasms
Heterografts
Colonic Neoplasms
Research Design
Enzyme-Linked Immunosorbent Assay
Breast Neoplasms
Kidney
Bone and Bones
Cell Line
Acids
Liver
Brain

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{ac5163bf42bc4d5988c6a95cb0affef5,
title = "Preclinical development and first-in-human imaging of the integrin a v b 6 with [ 18 F]a v b 6 -binding peptide in metastatic carcinoma",
abstract = "Purpose: The study was undertaken to develop and evaluate the potential of an integrin a v b 6 -binding peptide (a v b 6 -BP) for noninvasive imaging of a diverse range of malignancies with PET. Experimental Design: The peptide a v b 6 -BP was prepared on solid phase and radiolabeled with 4-[ 18 F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired a v b 6 -expressing and a v b 6 -null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired a v b 6 -expressing and a v b 6 -null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer. Results: [ 18 F]a v b 6 -BP displayed excellent affinity and selectivity for the integrin a v b 6 in vitro [IC 50 (a v b 6 ) ¼ 1.2 nmol/L vs IC 50 (a v b 3 ) >10 mmol/L] in addition to rapid target-specific cell binding and internalization (72.5{\%} 0.9{\%} binding and 52.5{\%} 1.8{\%}, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [ 18 F]a v b 6 -BP was rapid, primarily via the kidneys. In patients, [ 18 F]a v b 6 -BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [ 18 F]a v b 6 -BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung. Conclusions: The clinical impact of [ 18 F]a v b 6 -BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.",
author = "Hausner, {Sven H.} and Bold, {Richard J} and Cheuy, {Lina Y.} and Chew, {Helen K} and Daly, {Megan E} and Davis, {Ryan A.} and Foster, {Cameron C} and Edward Kim and Julie Sutcliffe",
year = "2019",
month = "2",
day = "15",
doi = "10.1158/1078-0432.CCR-18-2665",
language = "English (US)",
volume = "25",
pages = "1206--1215",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "4",

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TY - JOUR

T1 - Preclinical development and first-in-human imaging of the integrin a v b 6 with [ 18 F]a v b 6 -binding peptide in metastatic carcinoma

AU - Hausner, Sven H.

AU - Bold, Richard J

AU - Cheuy, Lina Y.

AU - Chew, Helen K

AU - Daly, Megan E

AU - Davis, Ryan A.

AU - Foster, Cameron C

AU - Kim, Edward

AU - Sutcliffe, Julie

PY - 2019/2/15

Y1 - 2019/2/15

N2 - Purpose: The study was undertaken to develop and evaluate the potential of an integrin a v b 6 -binding peptide (a v b 6 -BP) for noninvasive imaging of a diverse range of malignancies with PET. Experimental Design: The peptide a v b 6 -BP was prepared on solid phase and radiolabeled with 4-[ 18 F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired a v b 6 -expressing and a v b 6 -null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired a v b 6 -expressing and a v b 6 -null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer. Results: [ 18 F]a v b 6 -BP displayed excellent affinity and selectivity for the integrin a v b 6 in vitro [IC 50 (a v b 6 ) ¼ 1.2 nmol/L vs IC 50 (a v b 3 ) >10 mmol/L] in addition to rapid target-specific cell binding and internalization (72.5% 0.9% binding and 52.5% 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [ 18 F]a v b 6 -BP was rapid, primarily via the kidneys. In patients, [ 18 F]a v b 6 -BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [ 18 F]a v b 6 -BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung. Conclusions: The clinical impact of [ 18 F]a v b 6 -BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.

AB - Purpose: The study was undertaken to develop and evaluate the potential of an integrin a v b 6 -binding peptide (a v b 6 -BP) for noninvasive imaging of a diverse range of malignancies with PET. Experimental Design: The peptide a v b 6 -BP was prepared on solid phase and radiolabeled with 4-[ 18 F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired a v b 6 -expressing and a v b 6 -null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired a v b 6 -expressing and a v b 6 -null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer. Results: [ 18 F]a v b 6 -BP displayed excellent affinity and selectivity for the integrin a v b 6 in vitro [IC 50 (a v b 6 ) ¼ 1.2 nmol/L vs IC 50 (a v b 3 ) >10 mmol/L] in addition to rapid target-specific cell binding and internalization (72.5% 0.9% binding and 52.5% 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [ 18 F]a v b 6 -BP was rapid, primarily via the kidneys. In patients, [ 18 F]a v b 6 -BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [ 18 F]a v b 6 -BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung. Conclusions: The clinical impact of [ 18 F]a v b 6 -BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.

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U2 - 10.1158/1078-0432.CCR-18-2665

DO - 10.1158/1078-0432.CCR-18-2665

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