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These FLCs undergo a process of misfolding and aggregation into amyloid fibrils, that can cause irreversible system\u2010wide damage. Current treatments that focus on depleting the underlying plasma cell clone are often poorly tolerated, particularly in patients with severe cardiac involvement, meaning patient prognosis is poor. An alternative treatment approach currently being explored is the inhibition of FLC aggregation by stabilisation of the native conformer. Here, we aimed to identify and characterise antibody fragments that target FLC domains and promote their stabilisation. Using phage\u2010display screening methods, we identified a variable heavy (VH) domain, termed VH1, targeted towards the FLC. Using differential scanning fluorimetry and surface plasmon resonance, VH1 was characterised to bind and kinetically stabilise an amyloidogenic FLC, whereby a &gt;\u20095.5\u2009\u00b0C increase in thermal stability was noted. This improved stability corresponded to the inhibition of fibril formation, where 10\u2009:\u20091 LC\u2009:\u2009VH1 concentration reduced aggregation to baseline levels. X\u2010ray crystallographic structures of the LC\u2009:\u2009VH1 complex at atomic resolution revealed binding in a 1\u2009:\u20091 ratio, mimicking the dimeric antigen binding sites of the native immunoglobulin molecule and the native LC homodimer.<\/jats:p>","DOI":"10.1111\/febs.17223","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T02:41:02Z","timestamp":1720579262000},"page":"4913-4929","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enhanced stabilisation and reduced fibril forming potential of an amyloidogenic light chain using a variable heavy domain to mimic the homodimer complex"],"prefix":"10.1111","volume":"291","author":[{"given":"Alana","family":"Maerivoet","sequence":"first","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology University of Liverpool  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Price","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology University of Liverpool  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9cile","family":"Galmiche","sequence":"additional","affiliation":[{"name":"UCB Pharma  Slough UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Scott\u2010Tucker","sequence":"additional","affiliation":[{"name":"UCB Pharma  Slough UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff","family":"Kennedy","sequence":"additional","affiliation":[{"name":"UCB Pharma  Slough UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Crabbe","sequence":"additional","affiliation":[{"name":"UCB Pharma  Slough UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Antonyuk","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology University of Liverpool  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9963-5871","authenticated-orcid":false,"given":"Jillian","family":"Madine","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology University of Liverpool  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,7,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12286"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V128.22.4448.4448"},{"key":"e_1_2_11_4_1","article-title":"Systemic AL amyloidosis: current approaches to diagnosis and management","volume":"4","author":"Fotiou D","year":"2020","journal-title":"Hema"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009039"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-159801"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.16_suppl.TPS8076"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109229200"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3675"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121005109"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1817567116"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00339"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560040309"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10906-w"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0206167"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dci.2005.06.010"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.039"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)54718-9"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.8.3.509"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182661eb1"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1805689"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1998.2425"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1080\/13506120802676781"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"e_1_2_11_26_1","unstructured":"EvansR O'NeillM PritzelA AntropovaN SeniorA GreenT \u017d\u00eddekA BatesR BlackwellS YimJet\u00a0al. 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