Current situation and trends of the development of bispecific antibody industry at home and abroad (above)

With the rapid development of antibody drug research and development technology, the new antibody drug type - bispecific antibodies also ushered in the research and development boomUp to now, more than 30 different technology platforms around the world can be used to design and develop bispecific antibodies, designed more than 60 bi-anti-molecular structures, 3 bi-specific antibodies have been approved for marketThis article focuses on the development course of double resistance, the representative dual anti-drug structure and technology platform at home and abroad, the next article will further introduce the current situation and trend of double resistance clinical research at home and abroad, bispecific antibody overviewbispecific antibodies (BsAb, referred to as bi-specific antibodies), which has two different antigen binding sites, can be combined with two target antigens or two different epitope sites, while playing antibody-oriented, in addition to the role of a special function, as shown in Figure 1Figure 1 Bispecific Antibody Action Schematic (for example)according to the structure of bi-resistance can be divided into IgG subtype (structure similar to ordinary antibodies) and non-IgG subtype (generally no Fc structure, volume is smaller than ordinary antibodies) two kinds, each category has a number of different structural forms, its structure represents composition and corresponding characteristics as shown in Figure 2More than 60 forms of double resistance can now be obtained through genetic engineering, and researchers can adjust the size, covalent, flexibility, half-life and inviva distribution of the structure based on product requirementscompared with ordinary antibodies,, double resistance has the advantages of high specificity, strong targeting, high yield, good stability, low dosage and fewer toxic side effects, which is of great significance in the clinical treatment of tumorsThe classification and characteristics of bispecific antibodies of different structuresii, double resistance development course
the development of double resistance through the initial period, breakthrough period and rapid development period three stages, forming a development path from concept to clinical trial and even clinical application, as shown in Figure 2Figure 3 Conceptual Innovation and Technology Innovation timeline for the development of bispecific antibodies
1The initial phase of bi-anti-development: from concept to clinical trialbi-specific antibody dual-target characteristics (refers to two different epitopes that can target two antigens or one antigen at the same time) give it a great therapeutic prospect As early as 1960, scientists proposed the concept of bispecific antibodies Between 1970 and 1980, with the invention of technologies such as hybrid tumors, scientists were able to produce bi-anti-molecules with different structures Over the next 30 years, the disantion molecules of different structures were constantly designed and gradually moved towardclinical trials 2 Double Anti-Development Breakthrough Period: Beyond the Era's First Bi-Specific Antibody In 2009, the European Union approved the first therapeutic bispecific antibody, Catumaxomab (Target CD3 and EpCAM), with a three-function bispecific antibody (Triomab) structure for the treatment of cancerous ascites In the early 2000s of catumaxomab clinical development, the concept of immunotherapy was not yet mature, and many people could not believe that tumor immunotherapy had better therapeutic results, which limited the clinical development of Catumaxomab to the understanding of the times At the same time, due to the cost of research and development, speed of consideration, the product in clinical development did not choose the treatment of celiac metastatic cancer, but chose the abdominal water subsidence, abdominal water subsidence of the adaptability of many doctors to position it as a significant side effects of auxiliary drugs, which also largely for the later Catumaxomab sales of poor ambush Figure 4 The world's first approved bispecific antibody Catumaxomab (Removab) drug map picture from the network in 2009, Catumaxomab was approved to go public, due to its ownership company Fessenius strategic transformation, the company did not set up a professional sales team for the product, did not develop a reasonable price and marketing plan for the innovative product, not enough to extend the efficacy of the drug to prolong the survival of patients as a major bright spot, which led directly to the commercial fiasco Catumaxomab had sales of just $1.66 million in 2009 and $3.32 million in 2010, 2011 and 2012, respectively, and poor sales figures led to Catumaxomab's temporary exit from the market in 2017 3 Rapid Phase of Dual Anti-Development: Rapid Approval accelerated dual-specific antibody market
in 2014, the FDA quickly approved the second bispecific antibody drug Blinatumomab (target CD3 and CD19), which is also the first approved target CD19 drug Blinatumomab is used to treat acute B lymphoblastic leukemia, and its better clinical results have rekindled the industry's interest and investment in bispecific antibodies Sales of the drug were $85 million in 2016 and $175 million in 2017, a significant increase over its predecessor, Catumaxomab in addition to cancer, inflammatory diseases have also been the focus of clinical development of bispecific antibodies In November 2017, the FDA quickly approved a third bispecific antibody, Emicizumab (targeting coagulation factor X and factor IXa), which became the first approved non-cancer indication of bispecific antibodies Currently, many teams are exploring the potential of bispecific antibodies to treat other diseases, such as diabetes, HIV infection, other viral and bacterial infections, Alzheimer's disease, osteoporosis, and so on three, domestic and foreign dual anti-research and development major companies and their technical platforms
different from the normal sense of antibody molecules, bispecific antibodies in the natural state does not exist, need to be achieved through recombinant DNA or cell fusion technology artificial preparation Therefore, the design of the molecular structure of double resistance is very important, that is, the technical platform of double resistance is the core of dual resistance technology more than 30 technology platforms currently in use worldwide, and according to clinical trials, the most widely used technology platforms are BiTE and Triomab In addition, the more clinically used and promising technology platforms include TandAb, DART, Nanobody and Crossmab these technical platforms can be broadly divided into three categories according to the mechanism of dual resistance to therapeutic action: (1) immune cell recruitment and activation: the identification of T-cell or NK cell surface receptors at the same time as a dual-target tumor cell surface antigen to induce immune response sedatives near tumor cells such as Triomab, BiTE (Blincyto), DART and TandAb (2) receptorcostimulation or inhibition: the use of double antagonistic 2 or more signaling ligands to avoid escape mechanisms to improve treatment effects such as DVD-Ig, DAF, 2-in1-IgG, Tv-IgGs and Crossmab (3) promotes protein complex formation: for example, Roche's Emicizumab can simultaneously bind to the clotting factor IXa and coagulation factor X in the clotting cascade enzyme-promoting reaction, bridged FIXa and FX to promote the production of FXa, producing a clotting reaction some domestic enterprises are also actively layout of dual-resistance business, representative technology platform has 5, including key energy long iTAB, Tianxing Pharmaceutical's dynamic precision antibody technology DPL, Youzhiyou Ybody, Corning Jerry's CRIB and ShoreMay bio's FIT-lg Among them, the FIT-lg platform of Shorelife is also used by Cinda Bio through a technology license, and its founder Wu Chenbing is also the inventor of the Abbott DVD-IgG technology platform Table 1 the relatively mature bispecific antibody technology platform IV, summary bispecific antibodies are a relatively new concept in the field of antibody drugs, is considered to treat tumors of the second generation of antibody therapy With the rapid development of antibody drug research and development technology, the new antibody drug type - bispecific antibodies also ushered in the research and development boom So far, more than 30 different technology platforms worldwide can be used to design and develop bispecific antibodies, designed more than 60 bi-anti-molecular structures, and 3 bi-specific antibodies have been approved for market In the experience from the concept to clinical trials, advanced design by the times, to now a number of dual resistance to obtain rapid approval, a number of enterprises at home and abroad are accelerating the development process of dual anti-drug, sustained enthusiasm will quickly promote the development of dual resistance industry at home and abroad References 1 Aran F, Maarten L, Janice M et Bispecific antibodies: a mechanistic review of the tha Nature Reviews Drug Discovery, 2019, 18 (6): 585-608 Nisonoff A , Wissler F C , Lipman L N Properties of The Major Component of a Peptic Digest of Rabbit Antibody Science, 1960, 132 (3441):1770-1771 Roland E Ulrich B Bispecificantibodies Drug Discovery Today, 2015, 20 (7): 838-847 Zhou Mengya Nearly 30 billion bispecific antibodies market, domestic layout enterprises less than 20 NoFMhfgAuWNZ_0bWtluKOw Bispecific Antibodies: Want to Say Love Your Mouth Hard to Open .