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The development history of bispecific antibodies!
The development history of bispecific antibodies! When it comes to antibodies, many people are not unfamiliar. The so-called antibody refers to the protective protein produced by the body due to the stimulation of antigen.
Antibody drugs refer to drugs prepared using antibody technology based on cell and genetic engineering technology, mostly represented by monoclonal antibodies. In recent years, it has become a therapeutic drug for various inflammations, malignant tumors and autoimmune diseases. As antibody drugs enter clinical treatment, people have gradually discovered that traditional single-targeted antibody drugs themselves have many limitations.
Bispecific antibody (BsAb) is a type of antibody with two different antigen binding arms, composed of two different light chains and heavy chains, which can bind two different antigens at the same time.
Bispecific antibodies have rapidly become a hot research project in the field of immunotherapy due to their unique structural specificity and significant clinical treatment effects, especially in the field of tumors.
Compared with traditional monoclonal antibodies, bispecific antibodies have the following advantages:
Can reduce the cost of drug development and clinical trials;
The therapeutic effect of bispecific antibodies is significantly better than the combined application of two or more monoclonal antibodies;
Compared with the combined application of multiple monoclonal antibodies, bispecific antibodies have less side effects.
With the advancement of research and technology, we have entered a new era of customized immunotherapy, and the demand for bispecific or multispecific immunoglobulins is increasing at a huge rate for the treatment of various diseases.
Next, I will briefly share with you the development history of bispecific antibodies.
In 1960, Nisonoff et al. linked two different antigen-binding fragments together through reoxidation, and proved that the product can recruit two different types of cells, and proposed the concept of bispecific antibodies for the first time.
In 1975, Kohler and Milstein successfully fused the splenic B lymphocytes of immunized mice with myeloma cells in the Molecular Biology Laboratory of the Medical Committee of the University of Cambridge, forming a B cell-myeloma hybrid. This cell hybrid can not only proliferate and survive indefinitely in vitro culture, but also secrete monoclonal antibodies against sheep red blood cells. On August 7 of the same year, Kohler and Milstein published a famous paper entitled (Continuous cultures off used cells secreting antibody of predefined specificity) in the British journal Nature, and formally proposed the concept of hybridoma. Later, for their contribution to immunology, they and Niels K. Jerne won the Nobel Prize in Physiology and Medicine in 1984.
In 1983, Milstein et al. used the fusion of two hybridoma cells to produce bispecific antibodies with an asymmetric structure for the first time, and proved the advantage of this method over chemical synthesis, that is, it avoids the latter in processing the antibody to melt the chain. When causing protein denaturation, the antibody is inactivated. However, in the random pairing of the heavy and light chains of the fusion hybridoma cells, a large number of non-functional antibodies are produced, which makes the yield of bispecific antibodies extremely low. This phenomenon is called the chain cross-linking problem (Chain- associationissue).
In 1985, Perez et al. first proposed a bispecific antibody that can specifically target T cell surface receptor T3 and target cell surface antigen. Studies have shown that the antibody can specifically connect to effector cells to kill the second antigen. The target cell bound by the binding site enhances antibody-dependent cytotoxicity.
In 1988, Huston et al. invented ScFvs (single-chain antibody fragment). ScFvs consist of a single-chain variable region composed of a heavy chain variable region (VH) and a light chain (VL) variable region. 15-20 amino acid links. Each subunit of ScFvs includes 3 hypercomplementarity determining regions (CDRs) that can bind to antigen. Since ScFvs is only about 25kDa, ScFvs is considered to be the smallest IgG unit with full antigen binding activity.
In 1993, Diabodies, a bispecific antibody without Fc segment, was reported for the first time. Diabodies have small molecules, strong tissue penetrating ability, and easy access to the focus of the disease. They play an important role in immunotherapy.
In 1995, Lindhofer et al. solved the problem of chain cross-linking. They found that the fusion of rat and mouse hybridomas can increase the correct rate of light chain and heavy chain pairing. This discovery significantly increased the yield of bispecific antibodies. , Provides the possibility of its mass production.
In 1996, Ridgway et al. solved the problem of chain cross-linking by using a spherical hole method on the CH3 domain of an antibody.
CH3 dimer interface (Source: Reference 1)
In 1999, Schuurman et al. reported that natural immunoglobulin G (IgG) (subclass 4) antibodies naturally exist in a bispecific form.
In 2007, the process of bispecific IgG4 Fab arm exchange in humans was discovered and elucidated. IgG4 Fab arm exchange is the exchange of a heavy chain and light chain pair (half molecule) of an IgG4 molecule with another IgG4 molecule.
IgG4 Fab Arm Exchange (Source: Literature 3)
In 2009, the world’s first bispecific antibody drug Catumaxomab (Catumaxomab) was approved in the European Union for the treatment of patients with EpCAM-positive malignant ascites. Catumaxomab is a trifunctional antibody with a molecular weight of 150kDa. It consists of a mouse IgG2a targeting tumor EpCAM and a rat IgG2b targeting CD3ε. It can also activate monocytes, macrophages, and stellate cells through Fcγ receptors. Cells and NK cells.
Although Catumaxomab is the first bispecific antibody approved for marketing, it also has very obvious limitations, which are mainly reflected in the complicated production process of Triomab antibody and the immunogenicity problem that heterologous antibodies are easier to produce.
In 2011, Wolfgang Schaefer et al. reported on immunoglobulin domain crossover as a general method for producing bispecific IgG antibodies. The article described a general method to correctly assemble two heavy chains and two light chains. The existing antibodies form human bivalent bispecific IgG antibodies without the use of artificial linkers.
In 2014, the world’s second bispecific antibody drug Blinatumomab (bonatumomab) was approved in the United States for the treatment of Fischer-negative precursor B-cell acute lymphoblastic leukemia.
Blinatumomab was developed by Micromet (later acquired by Amgen). It is a bispecific single-chain antibody BiTE prepared by DNA recombination technology. It uses a polypeptide chain to target tumor cells and T cell surface antigens. The variable regions of the antibody are connected, Blinatumomab selectively targets the B cell surface antigen CD19, and specifically binds to the T cell surface antigen CD3 to activate T cells.
In 2017, the world’s third bispecific antibody drug Emicizumab (FXIa x FX) was approved in the United States, becoming the first bispecific antibody drug in the field of hemophilia for routine use in hemophilia with factor VIII inhibitors Prevention, and was approved in the EU in 2018.
The approval of Emicizumab indicates that the treatment of hemophilia is no longer limited to traditional clotting factor replacement therapy, but is moving towards immunotherapy and gene therapy.
On May 21, 2021, the world’s fourth bispecific antibody drug Amivantamab (amivantamab-vmjw, Rybrevant) was approved by the FDA for accelerated marketing. Patients with small cell lung cancer (NSCLC). This is the first drug approved by the FDA for this type of mutation.
Amivantamab is a bispecific antibody that targets EGFR resistance mutations, MET mutations and amplifications. It can simultaneously bind to the extracellular structures of EGFR and c-Met, block the binding of ligands to EGFR and MET, and promote Body degradation can also trigger antibody-dependent cytotoxicity.
On the whole, there are still few bispecific antibody drugs that have been approved for marketing. Most drugs are in the preclinical development stage or clinical research stage. Opening up a new field of molecular medicine, we look forward to the launch of more and better dual-antibody drugs to benefit human health.
(source:internet, reference only)