Single-domain antibody drug development

Posted by beauty33 on January 13th, 2020

Single domain antibody was first reported by a Belgian scientist in the journal Nature in 1993. He found there is a naturally light chain antibody free in the alpaca's peripheral blood. The antibody only contains variable region of heavy chain (VHH), CH2 and CH3 regions, and it’s not as easily adhered to each other as the artificially engineered single-chain antibody fragment (scFv). More importantly, the VHH structure cloned and expressed separately has structural stability equivalent to that of the original heavy chain antibody and binding activity to the antigen, which is the smallest unit known to antibody. VHH crystal is 2.5nm, 4nm long, and has a molecular weight of only 15KD. Therefore, they are also known as Nanobody (Nb).

In February 2019, the FDA approved Caplacizumab (a bivalent monospecific sdAb targeting von Willebrand factor) for the treatment of a rare disease, acquired thrombotic thrombocytopenic purpura (aTTP). Acquired thrombotic thrombocytopenic purpura is characterized by excessive blood clotting in small blood vessels. Caplacizumab is the first drug approved for the disease and the first to target von willebrand factor (vWF). The drug, vWF is a key protein in the blood coagulation cascade. At the same time, Caplacizumab is also the first single-domain antibody approved by the FDA. The approval of Caplacizumab is a landmark event in the field of single-domain antibodies, which has officially entered the stage of human disease treatment.

Single-domain antibodies are an emerging field of drug development. But the process is not smooth. Many single-domain antibodies developement in previous years, including GSK and BMS, did not go to market as successfully as the researchers envisioned. And thus significantly reduced their single-domain antibody R & D pipelines. However, with the successful listing of Caplacizumab, pharmaceutical companies and researchers have reached a new level of interest in single-domain antibodies, and their interest is increasing.

Traditional antibody molecules (mAb) are structurally composed of two identical heavy chains and two identical light chains, and this structure is very conserved in mammals. In 1993, Hamers-Casterman et al. from the Free University of Brussels discovered and reported the novel antibodies in camel blood. Unlike the molecular structure of traditional mammalian antibodies, this antibody lacks light chain, which also lacks the CH1 region of the heavy chain constant region, which is called a heavy chain antibody (HcAb). The single-domain antibody (sdAb) is a variable region of an antibody with only a heavy chain extracted from camel family sera.

Studies have shown that single-domain antibodies have many advantages over previous antibody drugs, for example:

1. Good permeability: single-domain antibodies have a strong penetrating ability, can enter dense tissues and bind to antigen surfaces that are not accessible by conventional antibodies, and excess unbound single-domain antibodies can be quickly removed;

2. Easy to express: Single domain antibodies are a class of antibodies with a relative molecular mass of 12-30 kDa, which are easy to assemble and easy to express in the cell;

3. High stability: Single domain antibody has high stability and strong heat resistance. In general, camel-derived VHH can maintain antigen-binding ability after being stored for several months in a low-temperature environment, and is not easily damaged by the acid-base environment and enzymes of the gastrointestinal tract;

4. High antigen-binding ability: single-domain antibodies have smaller molecular structures and extended CDR3 regions that can form exposed convex loop structures, allowing them to penetrate into the antigen's antigen sites that are not normally recognized by traditional antibodies;

5. Low immunogenicity: single-domain antibodies have a small molecular weight and only one domain. They do not contain the Fc segment of ordinary antibodies. Therefore, single-domain antibodies can avoid complement reactions caused by Fc segments.

Antibody drugs are a major area of ​​drug development, but from the perspective of antibody drug development, many of them didn’t go to market. Therefore, solving the breakthrough of antibody drugs from the suspension and preclinical stages to the clinical and marketing direction is a key point of current antibody drug research. The single-domain antibody drug simplifies the antibody drug structurally, and has a great potential to improve the success rate of antibody drug development. With the launch of the first single-domain antibody drug, Caplacizumab, and the continuous research on single-domain antibodies, single-domain antibodies will surely gain more and more recognition, bringing more possibilities for drug development.

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beauty33
Joined: July 10th, 2017
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