Imaging, Biodistribution, and Dosimetry of Radionuclide-Labeled PD-L1 Antibody in an Immunocompetent Mouse Model of Breast Cancer

Abstract

The programmed cell death ligand 1 (PD-L1) participates in an immune checkpoint system involved in preventing autoimmunity. PD-L1 is expressed on tumor cells, tumor-associated macrophages, and other cells in the tumor microenvironment. Anti-PD-L1 antibodies are active against a variety of cancers, and combined anti-PD-L1 therapy with external beam radiotherapy has been shown to increase therapeutic efficacy. PD-L1 expression status is an important indicator of prognosis and therapy responsiveness, but methods to precisely capture the dynamics of PD-L1 expression in the tumor microenvironment are still limited. In this study, we developed a murine anti-PD-L1 antibody conjugated to the radioactive isotope Indium-111 (111In) for imaging and biodistribution studies in an immune-intact mouse model of breast cancer. The distribution of 111In-DTPA-anti-PD-L1 in tumors as well as the spleen, liver, thymus, heart, and lungs peaked 72 hours after injection. Co-injection of labeled and 100-fold unlabeled antibody significantly reduced spleen uptake at 24 hours, indicating that an excess of unlabeled antibody effectively blocked PD-L1 sites in the spleen, thus shifting the concentration of 111In-DTPA-anti-PD-L1 into the blood stream and potentially increasing tumor uptake. Clearance of 111In-DTPA-anti-PD-L1 from all organs occurred at 144 hours. Moreover, dosimetry calculations revealed that radionuclide-labeled anti-PD-L1 antibody yielded tolerable projected marrow doses, further supporting its use for radiopharmaceutical therapy. Taken together, these studies demonstrate the feasibility of using anti-PD-L1 antibody for radionuclide imaging and radioimmunotherapy, and highlight a new opportunity to optimize and monitor the efficacy of immune checkpoint inhibition therapy.

Peptide-Based 68Ga-PET Radiotracer for Imaging PD-L1 Expression in Cancer

“…8−10,12,13,35 All those agents provide PD-L1 specific images albeit requiring longer clearance times that span days to hours in contrast to our small peptides that require <60 min. Additionally, the advantage of small peptides and the potential to modify their biodistribution was evident in the different pharmacokinetics and image contrast shown by [ 64 Cu] and [ 68 Ga] labeled WL12.…”

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

“…In this respect, binding to PD-L1-expressing cells in blood or other tissue may prevent antibody extravasation and accumulation at the site of the tumor. 13 , 14 Moreover, lack of tumor-selectivity appears to result in generalized activation of antigen-experienced T cells, including functionally silenced auto-reactive T cells. The latter aspect is evidenced by the frequent occurrence of severe autoimmune-related adverse events during and after treatment with PD-L1-blocking antibodies.…”

Practical Immuno-PET Radiotracer Design Considerations for Human Immune Checkpoint Imaging

“…Antibody-based imaging agents have several advantages including their naturally high avidity, antigen specificity, and ease of production. For these reasons, early attempts at immune checkpoint imaging have used antibody scaffolds including 3 111 In radiotracers directed against murine and human PD-L1 for SPECT imaging of breast and non-small cell lung cancer (23)(24)(25). Our laboratory has also developed a murine anti-PD1 monoclonal antibody radiolabeled with 64 Cu for imaging PD-1 expression on tumor-infiltrating lymphocytes (26).…”