作者: Martos-Folgado, Inmaculada ; Martin-Ventura, Jose L ; Martinez-Lopez, Diego ; Ferrarini, Alessia ; Wardemann, Hedda ; Bonzon-Kulichenko, Elena ; Vázquez, Jesús ; Gonzalez-Valdes, Ileana B ; Delgado, Pilar ; Roldán-Montero, Raquel ; Sanz-Bravo, Alejandro ; Mur, Sonia M ; Lorenzo, Cristina ; Ramiro, Almudena R ; Busse, Christian E

Cardiovascular disease (CVD) is the leading cause of mortality in the world, with most CVD-related deaths resulting from myocardial infarction or stroke. The main underlying cause of thrombosis and cardiovascular events is atherosclerosis, an inflammatory disease that can remain asymptomatic for long periods. There is an urgent need for therapeutic and diagnostic options in this area. Atherosclerotic plaques contain autoantibodies^1,2, and there is a connection between atherosclerosis and autoimmunity³. However, the immunogenic trigger and the effects of the autoantibody response during atherosclerosis are not well understood^3-5. Here we performed high-throughput single-cell analysis of the atherosclerosis-associated antibody repertoire. Antibody gene sequencing of more than 1,700 B cells from atherogenic Ldlr^-/- and control mice identified 56 antibodies expressed by in-vivo-expanded clones of B lymphocytes in the context of atherosclerosis. One-third of the expanded antibodies were reactive against atherosclerotic plaques, indicating that various antigens in the lesion can trigger antibody responses. Deep proteomics analysis identified ALDH4A1, a mitochondrial dehydrogenase involved in proline metabolism, as a target antigen of one of these autoantibodies, A12. ALDH4A1 distribution is altered during atherosclerosis, and circulating ALDH4A1 is increased in mice and humans with atherosclerosis, supporting the potential use of ALDH4A1 as a disease biomarker. Infusion of A12 antibodies into Ldlr^-/- mice delayed plaque formation and reduced circulating free cholesterol and LDL, suggesting that anti-ALDH4A1 antibodies can protect against atherosclerosis progression and might have therapeutic potential in CVD.

项与 Anti-TACA1 antibodies(Siamab Therapeutics/Boehringer Ingelheim) 相关的新闻（医药）

2023-07-14

·FierceBiotech

Roche lining up potential $7B Roivant licensing deal to join Merck in bowel disease race: WSJ

A deal with Roche would again shake up the rapidly evolving TL1A race. Is Roche ready to bet $7 billion to challenge Merck & Co. in the a red-hot bowel disease space? That is the assertion of The Wall Street Journal, which reports that the Swiss drug developer is in talks with Roivant Sciences about acquiring the rights to an ex-Pfizer candidate. Roivant only secured rights to the anti-TL1A antibody RVT-3101 in November. Pfizer took the candidate to the cusp of phase 2b data in ulcerative colitis, only to decide to get the cost of further development off its books. Roivant set up a new subsidiary, Telavant, to advance the asset. Pfizer owns 25% of Telavant and retains the rights to RVT-3101 outside of the U.S. and Japan. According to the WSJ, Roche is nearing a deal to buy Roivant’s rights to the molecule. Talks over the deal, which could be worth more than $7 billion, may still collapse or be hijacked by another potential buyer. But, if everything goes smoothly, Roche and Roivant could sign off on the agreement within days. A deal with Roche would again shake up the rapidly evolving TL1A race. Months after Roivant picked up rights to Pfizer’s candidate, Merck agreed to pay $10.8 billion to buy Prometheus Biosciences for a rival therapy. Merck reportedly held off competition from AbbVie and Bristol Myers Squibb for Prometheus, suggesting Roche is unlikely to be the only company interested in RVT-3101. The flurry of business development activity is underpinned by evidence that anti-TL1A antibodies could be the next big thing in blockbuster markets. TL1A modulates the location and severity of inflammation and fibrosis, and, as such, drug developers have identified the protein as the key to treating conditions including ulcerative colitis. Data drops on the two dueling anti-TL1A antibodies have added to excitement about the mechanism in recent months, with shares in Prometheus surging after it reported 26.5% of recipients of its anti-TL1A antibody went into clinical remission by Week 12 compared to 1.5% of their peers on placebo. Roivant quickly hit back with clinical data that it claimed show RVT-3101 is a best-in-class prospect. Having aced phase 2b, Roivant and Merck are now racing to deliver pivotal data in ulcerative colitis and expand into other indications. The list of diseases that could be treated by targeting TL1A includes a slew of blockbuster indications such as rheumatoid arthritis, atopic dermatitis and psoriasis.