First nano antibody drug approved for market

On September 3, 2018, EMA approved the nanoantibody drug caplaizumab for the treatment of adult acquired thrombocytopenic purpura (attP) Cablivi has become the first specific attP treatment drug, and also the first nano antibody drug on the market In addition, FDA has granted caplacizumab the priority review qualification, and the target review decision-making time is February 6, 2019 According to analysts, the peak sales of the drug may reach 400 million US dollars ▲ the development of cognition and treatment of TTP in the past hundred years Sanofi antibody drug layout Sanofi has a lot of layout in the field of biological medicine, but also full of frustrations Considering the expiry of the patent for insulin glargine, Sanofi tried to acquire the inhaled insulin of mankind, resulting in poor sales A US $4.2 billion agreement on long-term GLP-1 (FC coupling) was reached with South Korea and the US, which soon shrank significantly In the field of antibody, we have reached cooperation with regenerator for a long time Although PCSK9 antibody praluent, IL-4 / IL-13 antibody dupixent and IL-6R antibody kevzara have been successively launched, the biggest failure is to miss eylea, a heavy product Nevertheless, Sanofi still hopes to make a difference in the field of antibody In January 2018, Sanofi brought Ablynx, the leading nano antibody company, under its management for 3.9 billion euros Caplacizumab is one of the Ablynx product lines Ablynx has extensive cooperation with multinational pharmaceutical companies such as MSD, Novo Nordisk and bringer Ingelheim, and has authorized the rights and interests of China of one of its products, RANKL nano antibody alx-0141, to Yiteng pharmaceutical ▲ the development history of nano antibody in the research and development pipeline of Ablynx in 1993, scientists first found single chain antibody; in 2001, Ablynx was founded in Belgium; in 2007, the first nano antibody entered clinical research; in 2018, the first nano antibody, capracizumab, was approved to be listed in the EU In China, Corning Jerry took the lead in declaring kn035, a nano antibody targeting PD-L1, and then obtained FDA approval for clinical research ▲ the development of nano antibody: caplacizumab has the advantage of small molecular weight, but it also has the problem of short half-life For example, kn035, the PD-L1 antibody developed by corningeri, is fused with FC to prolong the half-life The nano antibody of Ablynx adopts different strategies to fuse the nano antibody drug into another anti albumin nano antibody, and the drug binds with albumin in the blood to prolong the half-life Caplacizumab, on the other hand, connects two nanoantibodies against VWF via a linker of 3 * alanine (AAA) The combination of capracizumab and vWF can prolong its half-life The half-life of capracizumab is 10-30h, which is equivalent to the reported VWF (some drugs combine with VWF, and the excessive drugs are quickly removed with glomerular filtration), which also proves its mechanism from one side ▲ the mechanism of action of capracizumab: capracizumab contains 259 amino acids, which are composed of two VHS with 128 amino acids connected by aaalinker The specific sequence is as follows: The significance of umab's approval Acquired thrombocytopenic purpura (attP) is due to the lack of ADAMTS13 activity, which leads to the formation of vWF platelet polymer, the formation of platelet linear ring, tissue ischemia and end organ damage ▲ the pathogenesis of attP was prior to capracizumab There was no specific therapy for attP, and only plasma exchange or immunosuppressant could be used to alleviate it In this case, there is still a high mortality rate of 10-20%, and it is easy to develop treatment tolerance and rapid progress after stopping plasma exchange The specific prevention and treatment of TTP is mainly to prevent the formation of platelet micro thrombus ADAMTS13, ADAMTS13 antibody and vWF are the main research targets Now VWF first brings breakthrough progress, and is approved to market after clinical verification ▲ the TTP treatment target, capracizumab, combined with the A1 domain of vWF, can prevent the formation of platelet string, which is the first specific therapy for attP ▲ the mechanism of action of capracizumab the approval of capracizumabo is mainly based on phase II clinical trial Titan and phase III clinical trial Hercules Intravenous injection was used for the first administration, and subcutaneous injection was used for the subsequent administration The injection frequency and dose were once a day, 10mg each time ▲ the primary end point of Hercules design scheme in phase III clinical trial was the time to restore normal platelet activity The combined outcome measures for attP related deaths, attP and / or major thromboembolic events were also reduced by 74% compared with placebo The mature expression and purification technology of Pichia pastoris was established by Ablynx, and the expression amount was more than 1G / L.