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Wissler HL , Ehlerding EB , Lyu Z , Zhao Y , Zhang S , Eshraghi A , Buuh ZY , McGuth JC , Guan Y , Engle JW , Bartlett SJ , Voelz VA , Cai W , Wang RE
Site-Specific Immuno-PET Tracer to Image PD-L1
Mol Pharm. 2019 May 6;16(5) :2028-2036
PMID: 30875232 PMCID: PMC6521698 URL: https://www.ncbi.nlm.nih.gov/pubmed/30875232
AbstractThe rapid ascension of immune checkpoint blockade treatments has placed an emphasis on the need for viable, robust, and noninvasive imaging methods for immune checkpoint proteins, which could be of diagnostic value. Immunoconjugate-based positron emission tomography (immuno-PET) allows for sensitive and quantitative imaging of target levels and has promising potential for the noninvasive evaluation of immune checkpoint proteins. However, the advancement of immuno-PET is currently limited by available imaging tools, which heavily rely on full-length IgGs with Fc-mediated effects and are heterogeneous mixtures upon random conjugation with chelators for imaging. Herein, we have developed a site-specific alphaPD-L1 Fab conjugate with the chelator 1,4,7-triazacyclononane- N, N', N''-triacetic acid (NOTA), enabling radiolabeling for PET imaging, using the amber suppression-mediated genetic incorporation of unnatural amino acid (UAA), p-azidophenylalanine. This Fab conjugate is homogeneous and demonstrated tight binding toward the PD-L1 antigen in vitro. The radiolabeled version, (64)Cu-NOTA-alphaPD-L1, has been employed in PET imaging to allow for effective visualization and mapping of the biodistribution of PD-L1 in two normal mouse models, including the capturing of different PD-L1 expression levels in the spleens of the different mouse types. Follow-up in vivo blocking studies and ex vivo fluorescent staining further validated specific tissue uptakes of the imaging agent. This approach illustrates the utility of UAA-based site-specific Fab conjugation as a general strategy for making sensitive PET imaging probes, which could facilitate the elucidation of the roles of a wide variety of immune checkpoint proteins in immunotherapy.
Notes1543-8392 Wissler, Haley L Ehlerding, Emily B Lyu, Zhigang Zhao, Yue Zhang, Si Eshraghi, Anisa Buuh, Zakey Yusuf McGuth, Jeffrey C Guan, Yifu Engle, Jonathan W Bartlett, Sarah J Voelz, Vincent A ORCID: http://orcid.org/0000-0002-1054-2124 Cai, Weibo ORCID: http://orcid.org/0000-0003-4641-0833 Wang, Rongsheng E ORCID: http://orcid.org/0000-0002-5749-7447 Journal Article United States Mol Pharm. 2019 Mar 25. doi: 10.1021/acs.molpharmaceut.9b00010.