Over 60 new drugs have been approved for clinical use, and the outbreak of bispecific antibodies is imminent?
July 23, 2021
In recent years, global bispecific antibodies have been growing rapidly in the preclinical and clinical stages. Up to now, 4 dual-antibody drugs have been marketed worldwide, two of which have been approved in China. Yaozhi data shows that more than 60 types of bispecific antibodies have entered the clinical stage in China, involving more than 30 companies. From the perspective of clinical progress, there are more products in the early stage of clinical trials, and the faster progress of Kangfang Bio's AK104 and Kangning Jerry's KN046 have entered phase 3 clinical trials. In the past two years, domestic pharmaceutical companies have gradually accelerated their deployment in the field of dual antibodies through independent research and development through pipeline introduction and technology platform authorization. The number of new dual antibodies in clinical trials has been increasing year by year, which seems to be explosive.
Where is the advantage of the double antibody?
Bispecific Antibodies (BsAb) refers to antibodies that can bind two different antigens or different epitopes of one antigen at the same time. Bispecific antibodies do not exist naturally in nature and need to be artificially prepared through recombinant DNA technology or cell fusion technology. Dr. Zhuozhi Wang, Vice President of WuXi Biologics, said in the live broadcast that compared with monoclonal antibodies or two monoclonal antibodies, bispecific antibodies have some unique biological mechanisms, such as anti-angiogenesis, anti-tumor production, and anti-tumor immunity. , Regulate the tumor microenvironment, directly remove tumor cells, reduce inflammation, help the effect of cofactors, and help antibodies to enter different tissues (such as passing through the blood-brain barrier). Up to now, there are 4 dual-antibody drugs in the world, namely: Trion Pharma's Catuxomab (targeting CD3 and EpCAM, listed in 2009 and delisted in 2017), Amgen's Belintumomab ( Targeting CD3 and CD19, launched in 2014), Roche's Iimerizumab (targeted FIX and FX, launched in 2017), Johnson & Johnson's Rybrevant (targeted EGFR and cMet, launched in 2021). There are a total of two dual antibodies on the market in my country, namely: Roche's imitolizumab (December 2018) and Amgen/BeiGene's Belintumomab (December 2020).
Difficulties in double antibody development
Compared with monoclonal antibodies, double antibodies put forward higher requirements for the adaptability of target selection, which leads to the complexity of double antibody development far greater than that of monoclonal antibodies. Double antibodies can be divided into two major categories in terms of structure: full-length double antibodies (similar in structure to IgG monoclonal antibodies, with Fc region) and fragment double antibodies (composed of the Fab region of IgG monoclonal antibodies without Fc region), and those with Fc region The presence or absence directly affects the biological effect, half-life, R&D & production cost of the double antibody. Dr. Lu Guocai, general manager of Suzhou Huace Biotechnology, pointed out that "the difficulty in the production of dual antibodies is to avoid chain mismatch problems." Mismatch refers to the non-complementarity between the bases on one strand of DNA and the corresponding bases on the other strand. In the structure of the monoclonal antibody, since the two heavy chains and the two light chains have exactly the same amino acid composition, there is only one structure after the combination of the four chains. However, the four polypeptide chains of the double antibody, including two heavy chains and two light chains, have different structures, and 16 possible structural combinations can be randomly generated when combined. Since there is only one target product, this means that the remaining products of the mismatch are invalid products or even by-products, which makes it difficult to separate the target product, and the production process is complicated in the final industrialization, the production cost is high, and the product efficiency of the dual antibody is Low, high impurity protein. In order to solve this problem, the mainstream anti-biological technology companies all have their own anti-biological technology platforms. Among the domestic pharmaceutical companies, WuXi Biologics, Cinda Biologics, BeiGene, Anmei Biologics, Youzhiyou Biologics, Corning Jerry, Aisimai and other companies have established dual antibody technology platforms through independent establishment or technology platform authorization. .
Table 1 Bispecific antibody platform
However, the difficulties in the development of double antibodies are not the only ones. The development of double antibodies has high complexity and technical barriers, and new companies need to choose a suitable development path based on their own circumstances.
Dozens of double antibodies entered the clinic
Last year, WuXi Biologics published an article that counted the global selection of bispecific antibody target combinations (see the figure below). It can be seen from the figure that CD3 is the hottest target, and multiple targets can be combined. Other targets, such as CD47, HER2, etc., are also popular.
Schematic diagram of the selection of dual antibody target combinations in clinical and pre-clinical stages
Source: doi:10.1093/abt/tbaa003
The layout of our country is similar to that of other pharmaceutical companies in the world, with dual immune cell targets strengthening coordination and mediated immune cell killing mechanisms. However, there are many layouts in China based on PD-(L)1 dual immune cell target to strengthen the coordination mechanism, and more than half of the bispecific antibodies in the clinical development stage use PD-(L)1 as the target.
Table 2 Approved clinical status of domestic double antibodies
Data source: Yaozhi data
From the perspective of research and development progress, there are many products in the early clinical stage. Kangfang Bio's AK104 and Kangning Jerry's KN046 are progressing rapidly and have entered the third clinical phase. In terms of the number of research and development, Cinda Bio has 7 bispecific antibodies that have entered the clinic, and BeiGene and Baili Pharmaceutical have entered the clinical stage with a large number of dual antibody drugs.
summary
Multispecific drugs are an important part of innovative drug discovery and the future development trend. In addition to double antibodies, polyclonal products also have products in the research stage. It should be noted that the clinical value of drug development is the core. On July 2, 2021, the Food and Drug Administration issued the "Clinical Value-Oriented Anti-tumor Drug Clinical Research and Development Guidelines" for soliciting comments, stating that "the development of new drugs should provide patients with better treatment options as the highest goal." The unmet clinical needs are the key. Multispecific drugs have many advantages in theory, but whether they can be transformed into clinical advantages requires more scientific research to prove.
Reference materials:
Antibody Therapeutics, 2020, Vol. 3, No. 1 18–62. doi:10.1093/abt/tbaa003.
