Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

Jimson W D'Souza; Harvey Hensley; Mohan Doss; Charles Beigarten; Michael Torgov; Tove Olafsen; Jian Q Yu; Matthew K Robinson

doi:10.2967/jnumed.116.178780

Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

Jimson W D'Souza, Harvey Hensley, Mohan Doss, Charles Beigarten, Michael Torgov, Tove Olafsen, Jian Q Yu, Matthew K Robinson

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

UNLABELLED: Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers.

METHODS: The anti-prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI.

RESULTS: 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy.

CONCLUSION: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance.

Original language	English
Pages (from-to)	175-180
Number of pages	6
Journal	Journal of Nuclear Medicine
Volume	58
Issue number	1
DOIs	https://doi.org/10.2967/jnumed.116.178780
State	Published - Dec 2017

Keywords

Animals
Antibodies, Monoclonal/pharmacokinetics
Cell Line, Tumor
Drug Evaluation, Preclinical/methods
Humans
Luminescent Measurements/methods
Male
Mice
Molecular Imaging/methods
Positron-Emission Tomography/methods
Prostatic Neoplasms/diagnostic imaging
Radiopharmaceuticals/pharmacokinetics
Reproducibility of Results
Sensitivity and Specificity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.2967/jnumed.116.178780

Cite this

@article{aaef854c935d4c6eaedd72a42b74ab98,

title = "Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers",

abstract = "UNLABELLED: Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers.METHODS: The anti-prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI.RESULTS: 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy.CONCLUSION: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance.",

keywords = "Animals, Antibodies, Monoclonal/pharmacokinetics, Cell Line, Tumor, Drug Evaluation, Preclinical/methods, Humans, Luminescent Measurements/methods, Male, Mice, Molecular Imaging/methods, Positron-Emission Tomography/methods, Prostatic Neoplasms/diagnostic imaging, Radiopharmaceuticals/pharmacokinetics, Reproducibility of Results, Sensitivity and Specificity",

author = "D'Souza, \{Jimson W\} and Harvey Hensley and Mohan Doss and Charles Beigarten and Michael Torgov and Tove Olafsen and Yu, \{Jian Q\} and Robinson, \{Matthew K\}",

note = "{\textcopyright} 2017 by the Society of Nuclear Medicine and Molecular Imaging.",

year = "2017",

month = dec,

doi = "10.2967/jnumed.116.178780",

language = "English",

volume = "58",

pages = "175--180",

journal = "Journal of Nuclear Medicine",

issn = "0161-5505",

publisher = "Society of Nuclear Medicine Inc.",

number = "1",

}

TY - JOUR

T1 - Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

AU - D'Souza, Jimson W

AU - Hensley, Harvey

AU - Doss, Mohan

AU - Beigarten, Charles

AU - Torgov, Michael

AU - Olafsen, Tove

AU - Yu, Jian Q

AU - Robinson, Matthew K

PY - 2017/12

Y1 - 2017/12

N2 - UNLABELLED: Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers.METHODS: The anti-prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI.RESULTS: 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy.CONCLUSION: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance.

AB - UNLABELLED: Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers.METHODS: The anti-prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI.RESULTS: 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy.CONCLUSION: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance.

KW - Animals

KW - Antibodies, Monoclonal/pharmacokinetics

KW - Cell Line, Tumor

KW - Drug Evaluation, Preclinical/methods

KW - Humans

KW - Luminescent Measurements/methods

KW - Male

KW - Mice

KW - Molecular Imaging/methods

KW - Positron-Emission Tomography/methods

KW - Prostatic Neoplasms/diagnostic imaging

KW - Radiopharmaceuticals/pharmacokinetics

KW - Reproducibility of Results

KW - Sensitivity and Specificity

UR - https://www.scopus.com/pages/publications/85009152902

U2 - 10.2967/jnumed.116.178780

DO - 10.2967/jnumed.116.178780

M3 - Article

C2 - 27539844

SN - 0161-5505

VL - 58

SP - 175

EP - 180

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

IS - 1

ER -

Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this