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

Abstract

BackgroundStudies 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.MethodsThe 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.ResultsThe 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.ConclusionsThese 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.

Radioimmunoimaging and targeting treatment in an immunocompetent murine model of triple‐negative breast cancer using radiolabeled anti–programmed death‐ligand 1 monoclonal antibody

“…This research revealed that radionuclide‐labeled anti‐PD‐L1 mAb yielded tolerable projected marrow doses, further supporting its use for radiopharmaceutical therapy . Nedrow JR modified an anti‐PD‐L1 mAb to deliver 225 Ac for potential targeted α‐particle therapy . The biodistribution and imaging results indicated its capability of delivering high linear energy transfer radiation to PD‐L1‐expressing tumors.…”

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

“…A 89 Zr-labeled mAb against mouse PD-L1 was used to show increased tracer uptake in a syngeneic head and neck tumor model after fractionated radiotherapy (Kikuchi et al 2017). Other research teams have also successfully employed mAbs for imaging of PD-L1 using different radionuclides, including 89 Zr, 111 In, 64 Cu and 131 I (Hettich et al 2016;Chatterjee et al 2016;Josefsson et al 2016;Nedrow et al 2017aNedrow et al , 2017bLesniak et al 2016;Li et al 2018;Moroz et al 2018;Truillet et al 2018;Pang et al 2018).…”

212Pb-Labeled Antibody 225.28 Targeted to Chondroitin Sulfate Proteoglycan 4 for Triple-Negative Breast Cancer Therapy in Mouse Models

“…Due to the inability of 223 Ra to accumulate in primary tumors or non-skeletal metastases, alternative radionuclides and targeting strategies are required to be effective against primary TNBC and metastases to other organs. Many monoclonal antibodies (mAbs) that specifically bind to antigens overexpressed on malignant cells have been used as carriers for α-particle emitting nuclides in targeted radioimmunotherapy (RIT) studies against preclinical in vitro and in vivo models of breast cancer [ 11 , 12 , 14 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. However, no existing mAbs or radioimmunoconjugates (RICs) that simultaneously target differentiated, bulk tumor cells and CICs are approved for TNBC or other types of breast cancer.…”