{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T13:50:05Z","timestamp":1792245005453,"version":"4.4.0"},"reference-count":30,"publisher":"The Endocrine Society","issue":"9","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion from a pituitary adenoma. Pegvisomant is the only approved GH receptor antagonist (GHRA) and is administered via daily subcutaneous injections, which limits real-world effectiveness. Here, we report the discovery and characterization of MAR002, a novel, half-life extended monoclonal antibody GHRA. MAR002 was identified by immunizing transgenic mice with the extracellular domain of human and cynomolgus monkey GH receptor (GHR) and engineered with Fc modifications to limit effector function and extend serum half-life. MAR002 was benchmarked against pegvisomant in biophysical assays, cellular signaling inhibition studies, and a head-to-head pharmacokinetic\/pharmacodynamic study in cynomolgus monkeys. MAR002 exhibited higher binding affinity to GHR and &amp;gt;100-fold more potent inhibition of GH-induced GHR signaling than pegvisomant (human half-maximal inhibitory concentration [IC50] 1.05\u2005nM vs 122\u2005nM). Epitope binning demonstrated simultaneous binding of MAR002 and GH to GHR, consistent with an allosteric, noncompetitive mechanism; notably, MAR002 inhibitory activity was maintained at supraphysiological GH concentrations, whereas pegvisomant activity was competitively reduced. In cynomolgus monkeys, a single 10\u2005mg\/kg intravenous dose of MAR002 sustained \u226550% IGF-1 suppression for 36 days compared with 15 days for an equimolar pegvisomant dose, with comparable maximal lowering (\u223c80%). These findings support clinical evaluation of MAR002 as a next-generation long-acting GHRA for acromegaly, with potential for reduced dosing frequency and more consistent suppression of the GH\u2013IGF-1 axis.<\/jats:p>","DOI":"10.1210\/endocr\/bqag090","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:57:05Z","timestamp":1786017425000},"source":"Crossref","is-referenced-by-count":2,"title":["Development and characterization of a long-acting allosteric growth hormone receptor antagonist for acromegaly"],"prefix":"10.1210","volume":"167","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7248-5078","authenticated-orcid":false,"given":"Katherine","family":"Kurylo","sequence":"first","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5528-1941","authenticated-orcid":false,"given":"Page R","family":"Bouchard","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0972-0908","authenticated-orcid":false,"given":"Mark N","family":"Milton","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3200-5917","authenticated-orcid":false,"given":"Peter F","family":"Moesta","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6989-2308","authenticated-orcid":false,"given":"Laura E","family":"Dichtel","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]},{"name":"Mass General Brigham Innovation Fellows Program, Massachusetts General Hospital\/Third Rock Ventures , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"Gromada","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vyas","family":"Ramanan","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Vincent","sequence":"additional","affiliation":[{"name":"Alloy Therapeutics , Waltham, MA 02451 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda","family":"Smith","sequence":"additional","affiliation":[{"name":"Alloy Therapeutics , Waltham, MA 02451 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chew Shun","family":"Chang","sequence":"additional","affiliation":[{"name":"Alloy Therapeutics , Waltham, MA 02451 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7589-7268","authenticated-orcid":false,"given":"Jack","family":"McGuire","sequence":"additional","affiliation":[{"name":"Alloy Therapeutics , Waltham, MA 02451 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Shimkets","sequence":"additional","affiliation":[{"name":"Alloy Therapeutics , Waltham, MA 02451 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark P","family":"Joing","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1196-7307","authenticated-orcid":false,"given":"Joshua","family":"Lehrer-Graiwer","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-1646","authenticated-orcid":false,"given":"Beryl B","family":"Cummings","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9936-5816","authenticated-orcid":false,"given":"Ethan J","family":"Weiss","sequence":"additional","affiliation":[{"name":"Marea Therapeutics , South San Francisco, CA 94080 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receptor ligand treatments: a meta-analysis","volume":"99","author":"Carmichael","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2026081803165125500_bqag090-B4","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.mayocp.2021.11.007","article-title":"Diagnosis and treatment of acromegaly: an update","volume":"97","author":"Ershadinia","year":"2022","journal-title":"Mayo Clin Proc"},{"issue":"5","key":"2026081803165125500_bqag090-B5","doi-asserted-by":"crossref","first-page":"e36411","DOI":"10.1371\/journal.pone.0036411","article-title":"Meta-analysis on the effects of octreotide on tumor mass in acromegaly","volume":"7","author":"Giustina","year":"2012","journal-title":"PLoS One"},{"issue":"12","key":"2026081803165125500_bqag090-B6","doi-asserted-by":"crossref","first-page":"R274","DOI":"10.1530\/EC-20-0433","article-title":"Novel therapies for acromegaly","volume":"9","author":"Maia","year":"2020","journal-title":"Endocr 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Endocrinol"},{"issue":"3","key":"2026081803165125500_bqag090-B13","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s11102-026-01673-x","article-title":"Long-term safety and efficacy of pegvisomant monotherapy for acromegaly: final data from the full ACROSTUDY cohort","volume":"29","author":"Yuen","year":"2026","journal-title":"Pituitary"},{"issue":"1","key":"2026081803165125500_bqag090-B14","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/imr.13379","article-title":"Living in LALA land? Forty years of attenuating Fc effector functions","volume":"328","author":"Hale","year":"2024","journal-title":"Immunol Rev"},{"issue":"1","key":"2026081803165125500_bqag090-B15","doi-asserted-by":"crossref","first-page":"2402701","DOI":"10.1080\/19420862.2024.2402701","article-title":"Systematic analysis of Fc mutations designed to reduce binding to Fc-gamma receptors","volume":"16","author":"Hale","year":"2024","journal-title":"MAbs"},{"issue":"2","key":"2026081803165125500_bqag090-B16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/nbt.1601","article-title":"Enhanced antibody half-life improves in vivo activity","volume":"28","author":"Zalevsky","year":"2010","journal-title":"Nat Biotechnol"},{"key":"2026081803165125500_bqag090-B17","volume-title":"Guide for the Care and Use of Laboratory Animals","author":"National Research Council (NRC)","year":"2011","edition":"8th ed"},{"issue":"2","key":"2026081803165125500_bqag090-B18","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1210\/er.2005-0006","article-title":"Somatotropic and gonadotropic axes linkages in infancy, childhood, and the puberty-adult transition","volume":"27","author":"Veldhuis","year":"2006","journal-title":"Endocr Rev"},{"issue":"11","key":"2026081803165125500_bqag090-B19","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1210\/me.2006-0007","article-title":"Growth hormone regulation of sex-dependent liver gene expression","volume":"20","author":"Waxman","year":"2006","journal-title":"Mol Endocrinol"},{"issue":"1","key":"2026081803165125500_bqag090-B20","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1210\/jc.2009-1630","article-title":"The exon 3-deleted growth hormone receptor is associated with better response to pegvisomant therapy in acromegaly","volume":"95","author":"Bernabeu","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2026081803165125500_bqag090-B21","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1210\/edrv-12-3-235","article-title":"The prolactin\/growth hormone receptor family","volume":"12","author":"Kelly","year":"1991","journal-title":"Endocr Rev"},{"issue":"5042","key":"2026081803165125500_bqag090-B22","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1126\/science.1549776","article-title":"Human growth hormone and extracellular domain of its receptor: crystal structure of the complex","volume":"255","author":"de Vos","year":"1992","journal-title":"Science"},{"key":"2026081803165125500_bqag090-B23","unstructured":"Kurylo K, Bouchard PR, Milton MN, et al \u00a02026. Serum IGF-1 and GH pharmacodynamic data in cynomolgus monkeys following a single intravenous dose of MAR002. Figshare. 10.6084\/m9.figshare.33131693."},{"issue":"24","key":"2026081803165125500_bqag090-B24","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1056\/NEJMra062453","article-title":"Medical progress: acromegaly","volume":"355","author":"Melmed","year":"2006","journal-title":"N Engl J Med"},{"issue":"3","key":"2026081803165125500_bqag090-B25","doi-asserted-by":"crossref","first-page":"e230247","DOI":"10.1530\/EC-23-0247","article-title":"Factors associated with disease control failure in acromegaly patients treated with pegvisomant: an ACROSTUDY analysis","volume":"13","author":"Giampietro","year":"2024","journal-title":"Endocr Connect"},{"issue":"5","key":"2026081803165125500_bqag090-B26","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s40618-017-0773-0","article-title":"How to improve effectiveness of pegvisomant treatment in acromegalic patients","volume":"41","author":"Ragonese","year":"2018","journal-title":"J Endocrinol Invest"},{"issue":"1","key":"2026081803165125500_bqag090-B27","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/cen.12239","article-title":"Circulating levels of pegvisomant and endogenous growth hormone during prolonged pegvisomant therapy in patients with acromegaly","volume":"80","author":"Madsen","year":"2014","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"6185","key":"2026081803165125500_bqag090-B28","doi-asserted-by":"crossref","first-page":"1249783","DOI":"10.1126\/science.1249783","article-title":"Mechanism of activation of protein kinase JAK2 by the growth hormone receptor","volume":"344","author":"Brooks","year":"2014","journal-title":"Science"},{"issue":"11","key":"2026081803165125500_bqag090-B29","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/S2213-8587(22)00244-3","article-title":"Acromegaly: pathogenesis, diagnosis, and management","volume":"10","author":"Fleseriu","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"9","key":"2026081803165125500_bqag090-B30","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/s41574-018-0058-5","article-title":"A consensus statement on acromegaly therapeutic outcomes","volume":"14","author":"Melmed","year":"2018","journal-title":"Nat Rev Endocrinol"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqag090\/70514228\/bqag090.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/167\/9\/bqag090\/70514228\/bqag090.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/167\/9\/bqag090\/70514228\/bqag090.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T07:17:01Z","timestamp":1787037421000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqag090\/8753753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":30,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,8,3]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqag090","relation":{},"ISSN":["1945-7170"],"issn-type":[{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,8,3]]},"article-number":"bqag090"}}