{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:59:43Z","timestamp":1791413983453,"version":"4.3.3"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"18","license":[{"start":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T00:00:00Z","timestamp":1588032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,5,5]]},"abstract":"<jats:p>\n                    Genetic polymorphisms in the region of the trimeric serine hydrolase high-temperature requirement 1 (\n                    <jats:italic>HTRA1<\/jats:italic>\n                    ) are associated with increased risk of age-related macular degeneration (AMD) and disease progression, but the precise biological function of HtrA1 in the eye and its contribution to disease etiologies remain undefined. In this study, we have developed an HtrA1-blocking Fab fragment to test the therapeutic hypothesis that HtrA1 protease activity is involved in the progression of AMD. Next, we generated an activity-based small-molecule probe (ABP) to track target engagement in vivo. In addition, we used N-terminomic proteomic profiling in preclinical models to elucidate the in vivo repertoire of HtrA1-specific substrates, and identified substrates that can serve as robust pharmacodynamic biomarkers of HtrA1 activity. One of these HtrA1 substrates, Dickkopf-related protein 3 (DKK3), was successfully used as a biomarker to demonstrate the inhibition of HtrA1 activity in patients with AMD who were treated with the HtrA1-blocking Fab fragment. This pharmacodynamic biomarker provides important information on HtrA1 activity and pharmacological inhibition within the ocular compartment.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1917608117","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T16:45:27Z","timestamp":1588092327000},"page":"9952-9963","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":51,"title":["Development of a therapeutic anti-HtrA1 antibody and the identification of DKK3 as a pharmacodynamic biomarker in geographic atrophy"],"prefix":"10.1073","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9011-1913","authenticated-orcid":false,"given":"Irene","family":"Tom","sequence":"first","affiliation":[{"name":"OMNI Biomarker Development, Genentech, Inc., South San Francisco, CA 94080;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria C.","family":"Pham","sequence":"additional","affiliation":[{"name":"Department of Microchemistry, Proteomics &amp; 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Sci."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s11095-019-2569-8","article-title":"Review of biomarkers in ocular matrices: Challenges and opportunities","volume":"36","author":"Tamhane M.","year":"2019","unstructured":"M. Tamhane, S. Cabrera-Ghayouri, G. Abelian, V. Viswanath, Review of biomarkers in ocular matrices: Challenges and opportunities. Pharm. Res. 36, 40 (2019).","journal-title":"Pharm. Res."},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/0161-5890(89)90139-9","article-title":"A serum protein SP40,40 modulates the formation of membrane attack complex of complement on erythrocytes","volume":"26","author":"Choi N. H.","year":"1989","unstructured":"N. H. Choi, T. Mazda, M. Tomita, A serum protein SP40,40 modulates the formation of membrane attack complex of complement on erythrocytes. Mol. Immunol. 26, 835\u2013840 (1989).","journal-title":"Mol. 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Altered expression of clusterin mRNA. FEBS Lett. 300, 279\u2013282 (1992).","journal-title":"FEBS Lett."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"e1700321","DOI":"10.1002\/pmic.201700321","article-title":"A proteomics approach to identify candidate proteins secreted by M\u00fcller glia that protect ganglion cells in the retina","volume":"18","author":"Ruzafa N.","year":"2018","unstructured":"N. Ruzafa, X. Pereiro, M. F. Lepper, S. M. Hauck, E. Vecino, A proteomics approach to identify candidate proteins secreted by M\u00fcller glia that protect ganglion cells in the retina. Proteomics 18, e1700321 (2018).","journal-title":"Proteomics"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.exer.2015.02.017","article-title":"Structure and function of the interphotoreceptor matrix surrounding retinal photoreceptor cells","volume":"133","author":"Ishikawa M.","year":"2015","unstructured":"M. Ishikawa, Y. Sawada, T. 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Chem."},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.exer.2014.01.002","article-title":"Thiol-dependent antioxidant activity of interphotoreceptor retinoid-binding protein","volume":"120","author":"Gonzalez-Fernandez F.","year":"2014","unstructured":"F. Gonzalez-Fernandez, D. Sung, K. M. Haswell, A. Tsin, D. Ghosh, Thiol-dependent antioxidant activity of interphotoreceptor retinoid-binding protein. Exp. Eye Res. 120, 167\u2013174 (2014).","journal-title":"Exp. Eye Res."},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1167\/iovs.08-2497","article-title":"A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa","volume":"50","author":"den Hollander A. I.","year":"2009","unstructured":"A. I. den Hollander ., A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa. Invest. Ophthalmol. Vis. 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Arterioscler. Thromb. Vasc. Biol. 38, 425\u2013437 (2018).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"292","DOI":"10.3389\/fncel.2018.00292","article-title":"Dickkopf-3 causes neuroprotection by inducing vascular endothelial growth factor","volume":"12","author":"Busceti C. L.","year":"2018","unstructured":"C. L. Busceti ., Dickkopf-3 causes neuroprotection by inducing vascular endothelial growth factor. Front. Cell. Neurosci. 12, 292 (2018).","journal-title":"Front. Cell. Neurosci."},{"key":"e_1_3_4_32_2","unstructured":"J. Mones Inhibiting VEGF and PDGF to treat AMD. https:\/\/www.reviewofophthalmology.com\/article\/inhibiting-vegf-and-pdgf-to-treat-amd. Accessed 8 April 2020."},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1093\/hmg\/11.11.1333","article-title":"Protein localization in the human eye and genetic screen of opticin","volume":"11","author":"Friedman J. 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