{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:07:35Z","timestamp":1792523255934,"version":"4.5.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Pre-existing anti-adeno-associated virus (AAV) neutralizing antibodies (NAbs) can impair AAV-mediated gene delivery. VTX-PID (imlifidase) is a streptococcal protease that specifically cleaves immunoglobulin G (IgG) antibodies. NAVIgATE was a first-in-human study of VTX-PID.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This double-blind controlled study (EUCT number: 2023-503892-83-00) randomized 35 healthy men, stratified by baseline anti-AAV3B NAb levels (intermediate [\u2264 1:45] or high [&amp;gt;1:45]) to receive ascending VTX-PID doses (0.075-0.6 mg\/kg) or placebo. The primary endpoint was safety. Key secondary endpoints included levels of anti-AAV3B NAbs and total antibodies (TAbs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>VTX-PID resulted in substantial reductions in total IgG, undigested IgG, anti-AAV3B TAb and NAb levels across all doses, followed by gradual full recovery, with effects being sustained longer (2\u20135 days) at the highest doses. All participants with intermediate NAb levels achieved durable noninhibitory NAb levels (titer \u22641:5), while those with high NAb levels showed reduction but did not reach the noninhibitory level. Most participants experienced VTX-PID-related treatment\u2212emergent adverse events, primarily musculoskeletal complaints of predominately mild to moderate intensity and fully reversible. Transient mild to moderate infusion-associated reactions occurred in four participants, and reversible liver function test elevations in three.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>VTX-PID effectively depleted anti-AAV3B NAbs, with a dose-dependent effect in magnitude and duration. The safety profile was manageable, with few temporary inflammatory events and self-resolving liver enzyme elevations. VTX-PID 0.3 mg\/kg was identified as the appropriate dose based on its safety and efficacy profile. In the population with intermediate NAb levels, the 2- to 5-day depletion in anti-AAV3B NAbs supports VTX\u2212PID as a promising pretreatment approach to open a window of opportunity of up to 5 days, broadening eligibility for systemic AAV-based gene therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1824802","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T13:30:10Z","timestamp":1779283810000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["VTX-PID as a novel recombinant immunoglobulin G\u2013degrading enzyme (IdeS) for efficient AAV-based gene therapy in participants with neutralizing antibodies: results of the phase I first-in-human NAVIgATE study"],"prefix":"10.3389","volume":"17","author":[{"given":"Bernard","family":"Benichou","sequence":"first","affiliation":[{"name":"Vivet Therapeutics SAS","place":["Paris, 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