National Institutes of Health/National Cancer Institute (NIH/NCI)
P41 CA196276
United States
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01 CA258427
United States
Citation
Journal: Nat Chem Biol / Year: 2024 Title: Discovery of VH domains that allosterically inhibit ENPP1. Authors: Paige E Solomon / Colton J Bracken / Jacqueline A Carozza / Haoqing Wang / Elizabeth P Young / Alon Wellner / Chang C Liu / E Alejandro Sweet-Cordero / Lingyin Li / James A Wells / Abstract: Ectodomain phosphatase/phosphodiesterase-1 (ENPP1) is overexpressed on cancer cells and functions as an innate immune checkpoint by hydrolyzing extracellular cyclic guanosine monophosphate adenosine ...Ectodomain phosphatase/phosphodiesterase-1 (ENPP1) is overexpressed on cancer cells and functions as an innate immune checkpoint by hydrolyzing extracellular cyclic guanosine monophosphate adenosine monophosphate (cGAMP). Biologic inhibitors have not yet been reported and could have substantial therapeutic advantages over current small molecules because they can be recombinantly engineered into multifunctional formats and immunotherapies. Here we used phage and yeast display coupled with in cellulo evolution to generate variable heavy (VH) single-domain antibodies against ENPP1 and discovered a VH domain that allosterically inhibited the hydrolysis of cGAMP and adenosine triphosphate (ATP). We solved a 3.2 Å-resolution cryo-electron microscopy structure for the VH inhibitor complexed with ENPP1 that confirmed its new allosteric binding pose. Finally, we engineered the VH domain into multispecific formats and immunotherapies, including a bispecific fusion with an anti-PD-L1 checkpoint inhibitor that showed potent cellular activity.
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