Abstract
Recent advancements in the field of immune-oncology have led to a significant increase in life expectancy of patients with diverse forms of cancer, such as hematologic malignancies, melanoma and lung cancer. Unfortunately, these encouraging results are not observed in the majority of patients, who remain unresponsive and/or encounter adverse events. Currently, researchers are collecting more insight into the cellular and molecular mechanisms that underlie these variable responses. As an example, the human lymphocyte activation gene-3 (huLAG-3), an inhibitory immune checkpoint receptor, is increasingly studied as a therapeutic target in immune-oncology. Noninvasive molecular imaging of the immune checkpoint programmed death protein-1 (PD-1) or its ligand PD-L1 has shown its value as a strategy to guide and monitor PD-1/PD-L1-targeted immune checkpoint therapy. Yet, radiotracers that allow dynamic, whole body imaging of huLAG-3 expression are not yet described. We here developed single-domain antibodies (sdAbs) that bind huLAG-3 and showed that these sdAbs can image huLAG-3 in tumors, therefore representing promising tools for further development into clinically applicable radiotracers.
Highlights
Cancer immunotherapy has become a standard treatment in oncology owing to the success of immune checkpoint blocking drugs [1,2,3]
We reported that mouse LAG-3-specific single-domain antibodies (sdAbs) can be used to quantitatively and noninvasively image moLAG-3 expression on tumor-infiltrating lymphocytes at baseline and and after induction by PD-1-blocking therapy, showing predictive value for subsequent LAG-3 blocking therapy [16, 37]
Phage-displayed sdAbs were evaluated over four rounds of biopanning for their ability to bind recombinant moLAG-3 or human lymphocyte activation gene-3 (huLAG-3) proteins immobilized on immunosorbent plates
Summary
Cancer immunotherapy has become a standard treatment in oncology owing to the success of immune checkpoint blocking drugs [1,2,3]. Monocloncal antibodies (mAbs) that block CTLA-4, PD-1 or its ligand PD-L1 have proven benefit in various cancer types [4,5,6,7,8]. These mAbs work by reinvigorating exhausted anticancer T cells and other immune cells by releasing the brake on their activation status, proliferation and cancer-infiltrating capacity [9]. The response of cancer patients after treatment with immune checkpoint blocking drugs remains mixed and unpredictable. It remains a key challenge to evaluate ongoing treatment responses and stratify patients
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