Natural human-derived HBV antibodies or will replace hepatitis B immunoglobulin

Natural human-derived HBV antibodies or will replace hepatitis B immunoglobulin

June 29, 2018 Source: Medical Rubik's Cube Data

Hepatitis B, referred to as hepatitis B, is a disease caused by hepatitis B virus (HBV), which is mainly caused by the liver. It can infect others through blood, mother-infant vertical transmission, close contact and sexual transmission. It is one of the most common infectious diseases in the world, and it is also the most widespread and most harmful disease in China. Due to the lack of specific anti-hepatitis B treatment drugs, chronic hepatitis B caused by hepatitis B virus infection still poses a serious threat to human health. Only antiviral drugs and hepatitis B immunoglobulin (HBIg) can be used clinically, mainly for blocking mother-to-child transmission, transplant surgery, passive immunization of high-risk populations and prevention of transfusion infection.

However, since hepatitis B immunoglobulin is a blood product, its supply can only come from the human body, and there is scarcity of resources. China has long been in a state of specific immunoglobulin shortage, and plasma used for blood product production can only be controlled by blood products enterprises. Apheresis plasma station (referred to as "slurry station") collection. In the history of the blood products industry, there have been many serious accidents both at home and abroad. Therefore, this industry is strictly restricted by relevant policies and laws, and the industry barriers are high. The clinical use price of hepatitis B immunoglobulin is limited by relevant policies, resulting in many blood products enterprises in the case of high production, low profits, often due to price costs upside down, manufacturers have to stop the production of hepatitis B immunoglobulin, so often There is a phenomenon of "one needle is hard to find". Although the blood product extraction process is mature, the processes of major blood product manufacturers all over the world are similar, but due to different populations, different regions and even different production enterprises, hepatitis B immunoglobulin products from different batches are from ingredients to effective. The potency is very different and the quality is difficult to guarantee. In addition, because hepatitis B immunoglobulin is derived from volunteers or infected patients, it is a high-risk product. Due to the existence of “window period”, such products are at risk of transmitting infectious diseases such as AIDS, hepatitis B and hepatitis C.

The natural whole human hepatitis B virus neutralizing antibody means that the antibody is derived from a natural human antigen-specific B cell secreted monoclonal antibody capable of neutralizing the HBV virus in vitro and not artificially modified. The main technologies for the development of natural fully human antibodies include B cell immortalization technology, single B cell RT-PCR amplification of antibody genes and single B cell sequencing technology. These technologies are based on B cells isolated from humans. Finally, an antigen-specific antibody expressed by a single B cell is obtained. The natural whole-human monoclonal antibody technology not only has a sequence of 100% human, but also a mature antibody that has been selected and produced under the human immune tolerance environment, and has no side effects on the body, and is called a natural whole human antibody. The antibody drugs thus developed for use in human disease treatment minimize the possibility of immunogenicity.

Figure 1. Natural Whole Human Monoclonal Antibody Technology Platform (HitmAb@) Technology Roadmap

Zhuhai Tainuo Maibo Biotechnology Co., Ltd. has established a natural all-human monoclonal antibody technology platform (HitmAb@) (Figure 1). Six anti-hepatitis B viruses with high binding capacity (EC50<0.039μg/ml) capable of identifying hepatitis B virus surface antigen (HBsAg) were isolated from peripheral blood mononuclear cells (PBMC) of volunteers immunized with hepatitis B vaccine using this technology platform. Natural full-human monoclonal antibody.

Cell-neutralization test of six recombinant natural human-hepatitis B monoclonal antibodies, detection of viral DNA replication, hepatitis B virus surface antigen secretion, and hepatitis B virus core antigen secretion after infection. Monoclonal antibody against HBV virus infection HepG2-hNTCP The neutralizing effect of the cells identified four strains (MAb2, MAb3, MAb4 and MAb6) monoclonal antibodies with good virus neutralization (Table 1), among which MAb3 and MAb6 had the highest neutralizing potency (EC50<0.046 ug/ml). ).

Table 1. Neutralization effects of natural fully human anti-HBV monoclonal antibodies

The main advantages of natural whole human HBV neutralizing antibodies:

1. Low immunogenicity and good safety

Due to the natural whole human HBV neutralizing antibody, the sequence is 100% human sequence, and is a mature antibody selected and produced under the human immune tolerance environment, and is applied as a medicine to the human body, and has extremely low immunogenicity. At the starting line of its research and development, natural human-derived antibodies have greatly reduced the risk of research and development and investment, greatly improved the rate of drug formation, and have high safety in clinical applications.

2. Neutralization titer is high

Human immunoglobulin is a mixture of blood products, while natural whole human HBV neutralizing antibody is a single macromolecular product of recombinant gene with high neutralizing potency. The 50% virus neutralization titer (EC50) of MAb3 and MAb6 antibodies as mentioned herein reaches <0.046 μg/ml (very low concentration of antibody can effectively inhibit the virus), showing great drug-forming properties. potential.

3. Quality controllable

The natural whole-human HBV neutralizing antibody drug will be expressed by large-scale mammalian cells of GMP grade. It is a standardized bioengineering product that is produced under the control of strict quality system. All production processes are not dependent on animal products. It is completely production at the cellular level, so the process will completely eliminate batch-to-batch differences due to blood collection.

4. Low cost

Hepatitis B virus immunoglobulin is the blood of people who rely on blood collection and is expensive to produce. Recombinant natural full-human HBV neutralizing antibodies will operate entirely at the genetic and cellular levels, and once scaled up, the cost of production will be significantly lower than that of blood products. The cost of natural human-derived HBV neutralizing antibody is about 1/5-1/10 of that of traditional hepatitis B immunoglobulin. The price of each natural human-derived HBV neutralizing antibody is about 1/2 of that of traditional hepatitis B immunoglobulin. The neutralization titer of each natural human-derived HBV neutralizing antibody drug is at least 2-3 times that of the traditional hepatitis B immunoglobulin.

The mixture of natural all-human anti-HBV monoclonal antibody against polyclonal antibody against hepatitis B immunoglobulin derived from human serum is undoubtedly an iterative advancement. Once put on the market, it compares the traditional hepatitis B immune ball on the market. For protein products, it will produce a competitive advantage at the level of generation, and will gain advantages that are unmatched by traditional products in terms of safety, antiviral activity, production process standardization, and product cost. Natural human-derived HBV antibodies will likely completely replace hepatitis B immunoglobulin.

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