ABSTRACT
Despite advances in immunotherapy for the treatment of cancers,not all patients can benefit from programmed cell death ligand 1(PD-L1)immune checkpoint blockade therapy.Anti-PD-L1 therapeutic effects reportedly correlate with the PD-L1 expression level;hence,accurate detection of PD-L1 expression can guide immunotherapy to achieve better therapeutic effects.Therefore,based on the high affinity antibody Nb109,a new site-specifically radiolabeled tracer,68Ga-NODA-cysteine,aspartic acid,and valine(CDV)-Nb109,was designed and synthesized to accurately monitor PD-L1 expression.The tracer 68Ga-NODA-CDV-Nb109 was obtained using a site-specific conjugation strategy with a radiochemical yield of about 95％and radiochemical purity of 97％.It showed high affinity for PD-L1 with a dissociation constant of 12.34±1.65 nM.Both the cell uptake assay and positron emission tomography(PET)imaging revealed higher tracer uptake in PD-L1-positive A375-hPD-L1 and U87 tumor cells than in PD-L1-negative A375 tumor cells.Meanwhile,dynamic PET imaging of a NC1-H1299 xenograft indicated that doxorubicin could upregulate PD-L1 expression,allowing timely interventional immunotherapy.In conclusion,this tracer could sensitively and dynamically monitor changes in PD-L1 expression levels in different cancers and help screen patients who can benefit from anti-PD-L1 immunotherapy.
ABSTRACT
JS001 (toripalimab) is a humanized IgG monoclonal antibody which strongly inhibits programmed cell death protein 1 (PD1). In this study, we used a different iodine isotype (I) to label JS001 probes to target the human PD1 (hPD1) antigen. , the half maximal effective concentration (EC) value of I-JS001 did not significantly differ from that of JS001. The uptake of I-JS001 by activated T cells was 5.63 times higher than that by nonactivated T cells after 2 h of incubation. The binding affinity of I-JS001 to T cells of different lineages after phytohemagglutinin (PHA) stimulation reached 4.26 nmol/L. Humanized C57BL/6 mice bearing mouse sarcoma S180 cell tumors were validated for immuno-positron emission tomography (immuno-PET) imaging. Pathological staining was used to assess the expression of PD1 in tumor tissues. The homologous Ihuman IgG (IhIgG) group or blocking group was used as a control group. Immuno-PET imaging showed that the uptake in the tumor area of the I-JS001 group at different time points was significantly higher than that of the blocking group or the I-hIgG group in the humanized mouse model. Taken together, these results suggest that this radiotracer has potential for noninvasive monitoring and directing tumor-specific personalized immunotherapy in PD1-positive tumors.