Peptide-based PET quantifies target engagement of PD-L1 therapeutics

Abstract

Authorship note: DK and AL contributed equally to this work. Conflict of interest: DK, SC, WGL, MGP, and SN are co-inventors on a pending US patent (PCT/US2017/068025) covering [ 64 Cu]WL12 and as such are entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict-of-interest policies. DK, SC, WGL, SN, JTP, CMR, and MGP are inventors on patent applications not related to this work. CMR serves on the Scientific Advisory Board of Harpoon Therapeutics, and has consulted on oncology drug development for AbbVie, Amgen, Ascentage, BMS, Celgene, Daiichi Sankyo, Genentech, Loxo, and Pharmamar. Under a licensing agreement between EMJ, Aduro Biotech Inc., and Johns Hopkins University, the University is entitled to milestone payments and royalties on sales of certain cancer vaccine products. EMJ serves on the Scientific Advisory Board of Genocea, Adaptive Biotech, DragonFly, and CSTONE and received grants from Aduro Biotech, Amgen, BMS, Hertix, and Corvus.

Multiplexed Non-invasive in vivo Imaging to Assess Metabolism and Receptor Engagement in Tumor Xenografts

“…Overall, this body of work ascertains the utility of QC-1 as an effective FRET acceptor for the monitoring of receptor-ligand interactions, i.e. drug-target engagement, in vitro 6 and in vivo with the benefit of opening a wide range of opportunities to monitor multiplexed ligands or antibodies biodistribution and internalization using MFLI-FRET whole body imaging in preclinical studies. Importantly, multiplexing of NIR FRET with 2-DG imaging provides invaluable insight into the drug binding and metabolic drug response in real time to optimize tumor drug delivery.…”

“…[1][2][3] However, a major challenge in preclinical molecular imaging is the lack of multiplexing approaches that can directly assess intracellular anti-cancer drug delivery while also reporting on drug efficacy via tumor metabolic signatures in live animal models non-invasively and longitudinally. [4][5][6][7] Indeed, current standard approaches are either destructive or incapable to discriminate between cell-associated drugs and unbound drugs residing in the extracellular space. [8][9][10][11] Monitoring drug biodistribution and quantification in preclinical in vivo studies greatly benefits from Fluorescence Lifetime Imaging (FLI).…”

Biomarkers for Response to Immune Checkpoint Blockade

“…Technical limitations in assessing PD-L1 expression could be overcome by alternative assays, such as mRNA (messenger RNA) measurement by RNA sequencing or reverse transcriptase polymerase chain reaction (RT-PCR) (Conroy et al 2019, Erber et al 2017; however, addressing potential biological limitations will remain challenging. New approaches for evaluating PD-L1 expression that are being developed include noninvasive nuclear imaging approaches, which may allow unbiased whole-body imaging of PD-L1 expression that can be followed over time (Kumar et al 2019, Niemeijer et al 2018. Initial studies using zirconium 89-labeled atezolizumab (Bensch et al 2018) suggest that this approach may be more predictive than IHC-or RT-PCR-based assays.…”

A screening platform based on epitope editing for drug discovery

“…Recently, blocking the PD-1/PD-L1 pathway has become one of the most promising strategies in cancer therapy and several monoclonal antibodies are currently on the market or in the process of FDA approval. 32,33 Anti-PD-L1 antibody , which targets the specific extracellular domain of Phe19-Thr239 of PD-L1, and two classes of reported PD-L1 inhibitors 20 include small molecule BMS-202 and peptide WL12 were selected for the testing. 32,33 As shown in Fig.6e-h, the readout of WL12 significantly decreased while BMS-202 displayed no obvious change compared to the blank control.…”

“…32,33 Anti-PD-L1 antibody , which targets the specific extracellular domain of Phe19-Thr239 of PD-L1, and two classes of reported PD-L1 inhibitors 20 include small molecule BMS-202 and peptide WL12 were selected for the testing. 32,33 As shown in Fig.6e-h, the readout of WL12 significantly decreased while BMS-202 displayed no obvious change compared to the blank control. This may arise from the flat and large interface of antibody-antigen interaction that makes it even more difficult for small molecular inhibitors to compete the binding.…”