TY - JOUR
T1 - Pharmacokinetics, microscale distribution, and dosimetry of alpha-emitter-labeled anti-PD-L1 antibodies in an immune competent transgenic breast cancer model
AU - Nedrow, Jessie R.
AU - Josefsson, Anders
AU - Park, Sunju
AU - Bäck, Tom
AU - Hobbs, Robert F.
AU - Brayton, Cory
AU - Bruchertseifer, Frank
AU - Morgenstern, Alfred
AU - Sgouros, George
N1 - Funding Information:
This study was funded by National Institute of Health grant R01 CA 187037.
Publisher Copyright:
© 2017, The Author(s).
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Alpha-particle emitting radioimmunotherapy
KW - Anti-PD-L1 antibodies
KW - Dosimetry
KW - Immune checkpoint inhibition
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=85025083016&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85025083016&partnerID=8YFLogxK
U2 - 10.1186/s13550-017-0303-2
DO - 10.1186/s13550-017-0303-2
M3 - Article
C2 - 28721684
AN - SCOPUS:85025083016
SN - 2191-219X
VL - 7
JO - EJNMMI Research
JF - EJNMMI Research
M1 - 57
ER -