{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T01:24:47Z","timestamp":1782523487959,"version":"3.54.5"},"reference-count":74,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,19]],"date-time":"2025-04-19T00:00:00Z","timestamp":1745020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NIAID Autoimmune Center of Excellence","award":["2UM1AI144292-06"],"award-info":[{"award-number":["2UM1AI144292-06"]}]},{"name":"NIH NIAID Autoimmune Center of Excellence","award":["NIH NCATS 9R44 TR005293-02"],"award-info":[{"award-number":["NIH NCATS 9R44 TR005293-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. The therapeutic landscape for MS has evolved significantly since the 1990s, with the development of more than 20 different disease-modifying therapies (DMTs). These therapies effectively manage relapses and inflammation, but most have failed to meaningfully prevent disease progression. While classically understood as a T cell-mediated condition, the most effective DMTs in slowing progression also target B cells. Novel classes of MS therapies in development, including anti-CD40L monoclonal antibodies, CD19 chimeric antigen receptor (CAR) T cells, and Bruton\u2019s tyrosine kinase (BTK) inhibitors show greater capacity to target and eliminate B cells in the brain\/CNS, as well as impacting T-cell and innate immune compartments. These approaches may help tackle the disease at its immunopathological core, addressing both peripheral and central immune responses that drive MS progression. Another emerging therapeutic strategy is to use bispecific antibodies, which have the potential for dual-targeting various disease aspects such as immune activation and neurodegeneration. As such, the next generation of MS therapies may be the first to reduce both inflammatory demyelination and disease progression in a clinically meaningful way. Their ability to target specific immune cell populations while minimizing broad immune suppression could also lead to better safety profiles. Here, we explore the biological rationale, advantages, limitations, and clinical progress of these emerging immunotherapies for relapsing\u2013remitting and progressive forms of MS.<\/jats:p>","DOI":"10.3390\/ijms26083880","type":"journal-article","created":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T20:24:16Z","timestamp":1745180656000},"page":"3880","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["New Frontiers in Multiple Sclerosis Treatment: From Targeting Costimulatory Molecules to Bispecific Antibodies"],"prefix":"10.3390","volume":"26","author":[{"given":"Megan","family":"Reidy","sequence":"first","affiliation":[{"name":"Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meerah","family":"Khan","sequence":"additional","affiliation":[{"name":"Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Mills","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Drug Discovery Foundation, 57 West 57th Street, Suite 904, New York, NY 10019, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4549-1224","authenticated-orcid":false,"given":"Josh","family":"Garton","sequence":"additional","affiliation":[{"name":"Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean E.","family":"Draayer","sequence":"additional","affiliation":[{"name":"Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9919-1959","authenticated-orcid":false,"given":"Insha","family":"Zahoor","sequence":"additional","affiliation":[{"name":"Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7123-829X","authenticated-orcid":false,"given":"Shailendra","family":"Giri","sequence":"additional","affiliation":[{"name":"Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6041-4588","authenticated-orcid":false,"given":"Robert C.","family":"Axtell","sequence":"additional","affiliation":[{"name":"Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Mao-Draayer","sequence":"additional","affiliation":[{"name":"Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1016\/S0140-6736(23)01126-1","article-title":"CAR T-cell therapy in autoimmune diseases","volume":"402","author":"Schett","year":"2023","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/ene.13819","article-title":"Multiple sclerosis\u2014A review","volume":"26","author":"Dobson","year":"2019","journal-title":"Eur. 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