Imaging of Programmed Cell Death Ligand 1: Impact of Protein Concentration on Distribution of Anti-PD-L1 SPECT Agents in an Immunocompetent Murine Model of Melanoma

Abstract

Programmed cell death ligand 1 (PD-L1) is part of an immune checkpoint system that is essential for preventing autoimmunity and cancer. Recent approaches in immunotherapy that target immune checkpoints have shown great promise in a variety of cancers, including metastatic melanoma. The use of targeted molecular imaging would help identify patients who will best respond to anti-PD-L1 treatment while potentially providing key information to limit immune-related adverse effects. Recently, we developed an antibody-based PD-L1-targeted SPECT agent-In-diethylenetriaminepentaacetic acid (DTPA)-anti-PD-L1-to identify PD-L1-positive tumors in vivo. To best use such PD-L1-targeted imaging agents, it is important, as a first step, to understand how the signal is affected by different parameters. We evaluated the impact of protein concentration on the distribution ofIn-DTPA-anti-PD-L1 in a murine model of aggressive melanoma. In-DTPA-anti-PD-L1 (dissociation constant, 0.6 ± 0.1 nM) demonstrated increased uptake in B16F10 tumors at protein concentrations equaling or exceeding 1 mg/kg at 24 h and 3 mg/kg at 72 h. At 24 h, the PD-L1-rich spleen and lungs demonstrated decreasing uptake with increasing protein concentration. At 72 h, uptake in the thymus was significantly increased at protein concentrations of 3 mg/kg or greater. Both time points demonstrated increased tracer amounts remaining in circulation as the amount of cold antibody was increased. These studies demonstrate that In-DTPA-anti-PD-L1 is capable of identifying tumors that overexpresses PD-L1 and monitoring the impact of PD-L1-rich organs on the distribution of anti-PD-L1 antibodies.

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.…”

Role of medical imaging for immune checkpoint blockade therapy: From response assessment to prognosis prediction

“…Preclinical studies showed that immuno‐PET monitoring of CD8+ T cells could serve as a predictive and prognostic biomarker for immune checkpoint therapy . Currently, effective efforts are underway to define PD‐L1 or PD‐1 expression using noninvasive molecular probes, of which a large number of studies focused on the feasibility of antibody‐based tracers in immunotherapy …”

“…For instance, Natarajan et al developed 89 Zr‐keytruda and 64 Cu‐keytruda to visualize PD‐1 expression on human tumor infiltrating lymphocytes within tumors and lymphoid tissues . With regard to SPECT/CT‐based molecular imaging, several studies showed the capacity of 111 In labeled anti‐PD‐L1 antibodies for imaging PD‐L1 expression in triple‐negative breast cancer (TNBC) and NSCLC . Furthermore, Pang et al demonstrated that 131 I‐PD‐L1 monoclonal antibody (mAb) could be a potential tool for noninvasively visualizing PD‐L1 expression in primary tumors and metastases .…”

“…71,72 Currently, effective efforts are underway to define PD-L1 or PD-1 expression using noninvasive molecular probes, of which a large number of studies focused on the feasibility of antibody-based tracers in immunotherapy. [73][74][75][76][77][78][79][80][81][82] For PET/CT-based molecular imaging, 64 Cu and 89 Zr are the most common radionuclides used in immuno-oncology. HTXM-MST 64 Cu-, 89 Zr-labeled antibodies 74,77,79 PD-L1 expression -HTXM-MST 89 Zr-, 64 Cu-labeled antibodies 81,82 PD-1 expression -HTXM-MST 89 Zr-labeled antibody 83 TR; PFS, OS…”

“…82 With regard to SPECT/CT-based molecular imaging, several studies showed the capacity of 111 In labeled anti-PD-L1 antibodies for imaging PD-L1 expression in triple-negative breast cancer (TNBC) and NSCLC. 73,75,76 Furthermore, Pang et al demonstrated that 131 I-PD-L1 monoclonal antibody (mAb) could be a potential tool for noninvasively visualizing PD-L1 expression in primary tumors and metastases. 78 More recently, Bensch et al conducted a first-inhuman study to assess the potential of 89 Zr-atezolizumab in predicting the treatment response to PD-L1 blockade in 22 patients across three tumors types (bladder cancer, NSCLC, and TNBC).…”