{"id":2080,"date":"2026-05-26T07:00:00","date_gmt":"2026-05-26T07:00:00","guid":{"rendered":"https:\/\/wickedsister.evit.com.au\/index.php\/2026\/05\/26\/changing-arms-for-natalizumab-does-it-affect-the-crap-gap\/"},"modified":"2026-05-26T07:00:00","modified_gmt":"2026-05-26T07:00:00","slug":"changing-arms-for-natalizumab-does-it-affect-the-crap-gap","status":"publish","type":"post","link":"https:\/\/wickedsister.evit.com.au\/index.php\/2026\/05\/26\/changing-arms-for-natalizumab-does-it-affect-the-crap-gap\/","title":{"rendered":"Changing Arms for Natalizumab. Does it affect the crap-gap?"},"content":{"rendered":"<div class=\"twitter-share\"><a href=\"https:\/\/twitter.com\/intent\/tweet?url=https%3A%2F%2Fmultiple-sclerosis-research.org%2F2026%2F05%2Fchanging-arms-for-natalizumab-does-it-affect-the-crap-gap%2F&amp;via=the_MSBlog\" class=\"twitter-share-button\" data-size=\"large\">Tweet<\/a><\/div>\n<p class=\"wp-block-paragraph\">Natalizumab exchanges its arms so the left arm doesn&#8217;t know what the right arm is doing. When an IgG1 antibody is made it has two arms called Fragment Antigen Binding or Fab. Each arm of the Fab binds to the same target so they can cross link the targets together, this is thought to be what mediates the killing activity of ofatumumab, which cross links CD20 pairs together. Most therapeutic antibodies that deplete are made on the IgG1 backbone the Fab parts bind to the target and the rest gives the killing activity. IgG4 antibodies block function and they were used to produce natalizumab. But when you inject natalizumab into a human the therapeutic switches its arms with other circulating IgG4 so one arm binds the natalizumab target and the other binds to something else. This is not controlled.<\/p>\n<p class=\"wp-block-paragraph\">van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Mart\u00ednez-Mart\u00ednez P, Vermeulen E, den Bleker TH, Wiegman L, Vink T, Aarden LA, De Baets MH, van de Winkel JG, Aalberse RC, Parren PW. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007 Sep 14;317(5844):1554-7.<\/p>\n<p class=\"wp-block-paragraph\">I am sure if this was properly understood when it was made they would have made the antibody on an IgG1 background but engineered it so it would not kill. Alternatively, you stabilize the hinge between the Fab arms (the <strong>S228P mutation<\/strong>) to lock the hinge bonds and prevent arm exchange. Within 5 days of infusion over 95% of natalizumab has switched its arms according to data reported when the biosimilar antibody was being produced. So if you give it more time between doses you would expect that there was more time to do an exchange this process of extended dosing removes PML risk&#8230;.But here it is thought that this allows cells into the brain that gets rid of the JC virus, whilst keeping the MS at bay. Here they suggest that Fab exchange associates with the crap-gap. But say more study is needed&#8230; I say go do it then, but I am not so sure. Let&#8217;s see what they come up with.<\/p>\n<p class=\"wp-block-paragraph\">Gelissen LMY, van den Berg SPH, Toorop AA, Wijburg MT, Tallantyre EC, Derksen NIL, Loeff FC, Killestein J, Rispens T, van Kempen ZLE; NEXT-MS study group. Clinical implications of natalizumab Fab-arm exchange in patients with multiple sclerosis. Front Immunol. 2026 ;17:1796273. doi: 10.3389\/fimmu.2026.1796273.&nbsp;<\/p>\n<p class=\"wp-block-paragraph\">Natalizumab, a monoclonal antibody used to treat multiple sclerosis, can undergo <em>Fab-arm exchange<\/em> (FAE) with endogenous IgG4, resulting in a monovalent form with reduced avidity and presumed lower potency than the parental bivalent form. <strong>Levels of bivalent and monovalent natalizumab depend on the ratio of endogenous IgG4 to total natalizumab<\/strong>, which varies substantially between individuals. The clinical relevance of natalizumab FAE remains unknown. This study investigated the potential clinical implications of bivalent and monovalent natalizumab levels regarding progressive multifocal leukoencephalopathy (PML), extended interval dosing (EID) and wearing-off symptoms, using multiple cohorts of natalizumab-treated patients. Seven natalizumab-associated PML cases were each matched to two controls. Contrary to the hypothesis that higher bivalent levels might increase PML risk, cases showed a trend toward lower bivalent natalizumab levels, although definite conclusions were limited by small sample size. <strong>In patients receiving EID<\/strong>, <strong>both total and bivalent natalizumab levels decreased compared to standard interval dosing<\/strong>, with a greater median individual decrease in bivalent natalizumab than in total natalizumab (94% versus 78%). Notably, in <strong>more than half of patients receiving EID, bivalent natalizumab levels fell below the quantification limit (&lt;0.1 \u00b5g\/mL<\/strong>). Finally, patients experiencing <strong>wearing-off symptoms during natalizumab treatment had lower bivalent natalizumab levels, <\/strong>although this warrants validation in larger cohorts.<\/p>\n<p><em>Source: <a href=\"https:\/\/multiple-sclerosis-research.org\/2026\/05\/changing-arms-for-natalizumab-does-it-affect-the-crap-gap\/?utm_source=rss&amp;utm_medium=rss&amp;utm_campaign=changing-arms-for-natalizumab-does-it-affect-the-crap-gap\" rel=\"nofollow noopener\" target=\"_blank\">multiple-sclerosis-research.org<\/a><\/em><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tweet Natalizumab exchanges its arms so the left arm doesn&#8217;t know what the right arm is doing. When an IgG1 antibody is made it has two arms called Fragment Antigen Binding or Fab. Each arm of the Fab binds to the same target so they&hellip;<\/p>\n","protected":false},"author":0,"featured_media":0,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4],"tags":[11,15,9,8,13,14,12,10],"class_list":["post-2080","post","type-post","status-publish","format-standard","hentry","category-multiple-sclerosis-research","tag-brain-repair","tag-marburg-type-ms","tag-ms","tag-multiple-sclerosis","tag-myelin","tag-neuroregeneration","tag-oligodendrocyte","tag-remyelination"],"_links":{"self":[{"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/posts\/2080","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/types\/post"}],"replies":[{"embeddable":true,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/comments?post=2080"}],"version-history":[{"count":0,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/posts\/2080\/revisions"}],"wp:attachment":[{"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/media?parent=2080"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/categories?post=2080"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/tags?post=2080"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}