TY - JOUR
T1 - Peptide-Based 68 Ga-PET Radiotracer for Imaging PD-L1 Expression in Cancer
AU - De Silva, Ravindra A.
AU - Kumar, Dhiraj
AU - Lisok, Ala
AU - Chatterjee, Samit
AU - Wharram, Bryan
AU - Venkateswara Rao, Kalagadda
AU - Mease, Ronnie
AU - Dannals, Robert F.
AU - Pomper, Martin G.
AU - Nimmagadda, Sridhar
N1 - Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/9/4
Y1 - 2018/9/4
N2 - Tumors create and maintain an immunosuppressive microenvironment that promotes cancer cell escape from immune surveillance. The immune checkpoint protein programmed death-ligand 1 (PD-L1) is expressed in many cancers and is an important contributor to the maintenance of the immunosuppressive tumor microenvironment. PD-L1 is a prominent target for cancer immunotherapy. Guidance of anti-PD-L1 therapy is currently effected through measurement of PD-L1 through biopsy and immunohistochemistry. Here, we report a peptide-based imaging agent, [ 68 Ga]WL12, to detect PD-L1 expression in tumors noninvasively by positron emission tomography (PET). WL12, a cyclic peptide comprising 14 amino acids, binds to PD-L1 with high affinity (IC50 23 nM). Synthesis of [ 68 Ga]WL12 provided radiochemical purity >99% after purification. Biodistribution in immunocompetent mice demonstrated 11.56 ± 3.18, 4.97 ± 0.8, 1.9 ± 0.1, and 1.33 ± 0.21 percentage of injected dose per gram (%ID/g) in hPD-L1, MDAMB231, SUM149, and CHO tumors, respectively, at 1 h postinjection, with high binding specificity noted with coinjection of excess, nonradiolabeled WL12. PET imaging demonstrated high tissue contrast in all tumor models tested.
AB - Tumors create and maintain an immunosuppressive microenvironment that promotes cancer cell escape from immune surveillance. The immune checkpoint protein programmed death-ligand 1 (PD-L1) is expressed in many cancers and is an important contributor to the maintenance of the immunosuppressive tumor microenvironment. PD-L1 is a prominent target for cancer immunotherapy. Guidance of anti-PD-L1 therapy is currently effected through measurement of PD-L1 through biopsy and immunohistochemistry. Here, we report a peptide-based imaging agent, [ 68 Ga]WL12, to detect PD-L1 expression in tumors noninvasively by positron emission tomography (PET). WL12, a cyclic peptide comprising 14 amino acids, binds to PD-L1 with high affinity (IC50 23 nM). Synthesis of [ 68 Ga]WL12 provided radiochemical purity >99% after purification. Biodistribution in immunocompetent mice demonstrated 11.56 ± 3.18, 4.97 ± 0.8, 1.9 ± 0.1, and 1.33 ± 0.21 percentage of injected dose per gram (%ID/g) in hPD-L1, MDAMB231, SUM149, and CHO tumors, respectively, at 1 h postinjection, with high binding specificity noted with coinjection of excess, nonradiolabeled WL12. PET imaging demonstrated high tissue contrast in all tumor models tested.
KW - NSCLC
KW - PD-1
KW - TNBC
KW - immune checkpoint therapy
KW - peptide
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U2 - 10.1021/acs.molpharmaceut.8b00399
DO - 10.1021/acs.molpharmaceut.8b00399
M3 - Article
C2 - 30037229
AN - SCOPUS:85050813107
SN - 1543-8384
VL - 15
SP - 3946
EP - 3952
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 9
ER -