{"doi":"10.1136/jitc-2024-008794","title":"Preclinical development of novel PD-L1 tracers and first-in-human study of [<sup>68</sup>Ga]Ga-NOTA-RW102 in patients with lung cancers","abstract":"Background The programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells’ immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors’ immunotherapy landscape. Methods By immunizing an alpaca with recombinant human PD-L1, three clones of the v ariable domain of the h eavy chain of h eavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([ 68 Ga]Ga-NOTA-RW102, [ 68 Ga]Ga-NOTA-ABDRW102, [ 64 Cu]Cu-NOTA-ABDRW102, and [ 89 Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [ 68 Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC). Results While RW102 has a high binding affinity to PD-L1 with an excellent K D value of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent K D value of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have different in vivo circulation times. In preclinical studies, [ 68 Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [ 64 Cu]Cu-NOTA-ABDRW102 and [ 89 Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [ 68 Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies. Conclusions We developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [ 68 Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments. 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