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EJNMMI Research
Published in: EJNMMI Research 1/2017

Open Access 01-12-2017 | Original research

Pharmacokinetics, microscale distribution, and dosimetry of alpha-emitter-labeled anti-PD-L1 antibodies in an immune competent transgenic breast cancer model

Authors: Jessie R. Nedrow, Anders Josefsson, Sunju Park, Tom Bäck, Robert F. Hobbs, Cory Brayton, Frank Bruchertseifer, Alfred Morgenstern, George Sgouros

Published in: EJNMMI Research | Issue 1/2017

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Abstract

Background

Studies combining immune checkpoint inhibitors with external beam radiation have shown a therapeutic advantage over each modality alone. The purpose of these works is to evaluate the potential of targeted delivery of high LET radiation to the tumor microenvironment via an immune checkpoint inhibitor.

Methods

The impact of protein concentration on the distribution of 111In-DTPA-anti-PD-L1-BC, an 111In-antibody conjugate targeted to PD-L1, was evaluated in an immunocompetent mouse model of breast cancer. 225Ac-DOTA-anti-PD-L1-BC was evaluated by both macroscale (ex vivo biodistribution) and microscale (alpha-camera images at a protein concentration determined by the 111In data.

Results

The evaluation of 111In-DTPA-anti-PD-L1-BC at 1, 3, and 10 mg/kg highlighted the impact of protein concentration on the distribution of the labeled antibody, particularly in the blood, spleen, thymus, and tumor. Alpha-camera images for the microscale distribution of 225Ac-DOTA-anti-PD-L1-BC showed a uniform distribution in the liver while highly non-uniform distributions were obtained in the thymus, spleen, kidney, and tumor. At an antibody dose of 3 mg/kg, the liver was dose-limiting with an absorbed dose of 738 mGy/kBq; based upon blood activity concentration measurements, the marrow absorbed dose was 29 mGy/kBq.

Conclusions

These studies demonstrate that 225Ac-DOTA-anti-PD-L1-BC is capable of delivering high LET radiation to PD-L1 tumors. The use of a surrogate SPECT agent, 111In-DTPA-anti-PD-L1-BC, is beneficial in optimizing the dose delivered to the tumor sites. Furthermore, an accounting of the microscale distribution of the antibody in preclinical studies was essential to the proper interpretation of organ absorbed doses and their likely relation to biologic effect.
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Metadata
Title
Pharmacokinetics, microscale distribution, and dosimetry of alpha-emitter-labeled anti-PD-L1 antibodies in an immune competent transgenic breast cancer model
Authors
Jessie R. Nedrow
Anders Josefsson
Sunju Park
Tom Bäck
Robert F. Hobbs
Cory Brayton
Frank Bruchertseifer
Alfred Morgenstern
George Sgouros
Publication date
01-12-2017
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2017
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-017-0303-2

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