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Here, we report an alternative therapeutic strategy using targeted protein degradation to eliminate pathogenic autoantibodies while leaving the rest of the immune system intact. We previously discovered autoimmune vitamin B12 central deficiency (ABCD), a neurologic condition in which autoantibodies targeting the transcobalamin receptor (CD320) impair the transport of cobalamin (B12) from the blood into the central nervous system (CNS). Combining scanning alanine mutagenesis by phage display, cryo-electron microscopy, and computational modeling, we elucidated a highly conserved anti-CD320 epitope and defined the structural determinants of antigen-autoantibody binding. Next, we synthesized a lysosome-targeting chimera (LYTAC) comprising the lysosome targeting glycan, triGalNAc, fused to the antigenic epitope of CD320 as autoantibody bait.\n                  <jats:italic>In vitro<\/jats:italic>\n                  , this LYTAC promoted the specific lysosomal internalization and extracellular clearance of anti-CD320, restoring homeostatic cellular uptake of B12. In a passive transfer mouse model of ABCD, LYTAC treatment rapidly cleared anti-CD320 from circulation and prevented penetration of anti-CD320 into the CNS. These findings uncover the mechanism of autoantibody-antigen binding in ABCD and demonstrate targeted autoantibody degradation as a therapeutic strategy that may be generalizable to other autoimmune neurologic diseases.\n                <\/jats:p>","DOI":"10.64898\/2026.02.01.703132","type":"posted-content","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T20:45:17Z","timestamp":1770151517000},"source":"Crossref","is-referenced-by-count":0,"title":["Structure-guided design of a targeted autoantibody degrader for neurologic disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1981-1244","authenticated-orcid":false,"given":"Marcell","family":"Zimanyi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Dayao","sequence":"additional","affiliation":[{"name":"Chan Zuckerberg Biohub, San Francisco, CA, USA"},{"name":"Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andoni I.","family":"Asencor","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF, San Francisco, CA, USA"},{"name":"Weill Institute for Neurosciences, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sravani","family":"Kondapavulur","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Asaki","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Graduate Program, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista","family":"McCutcheon","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF, San Francisco, CA, USA"},{"name":"Weill Institute for Neurosciences, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Dabaco","sequence":"additional","affiliation":[{"name":"Tetrad Graduate Program, UCSF, San Francisco, CA, USA"},{"name":"Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Bodansky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles S.","family":"Craik","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8599-1613","authenticated-orcid":false,"given":"Samuel J.","family":"Pleasure","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF, San Francisco, CA, USA"},{"name":"Weill Institute for Neurosciences, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph L.","family":"DeRisi","sequence":"additional","affiliation":[{"name":"Chan Zuckerberg Biohub, San Francisco, CA, USA"},{"name":"Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-0369","authenticated-orcid":false,"given":"Yifan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA"},{"name":"Howard Hughes Medical Institute, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8705-5084","authenticated-orcid":false,"given":"Michael R.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF, San Francisco, CA, USA"},{"name":"Weill Institute for Neurosciences, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John V.","family":"Pluvinage","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCSF, San Francisco, CA, USA"},{"name":"Weill Institute for Neurosciences, UCSF, San Francisco, CA, USA"},{"name":"Arc Institute, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020601003754000_2026.02.01.703132v1.1","doi-asserted-by":"crossref","unstructured":"Y. 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