In the development of antibody drugs, bispecific antibodies currently account for about 20%, about 68% of the drug candidates are concentrated in the tumor field, and 50% of the drugs in the tumor field have a common target molecule-CD3.

There are currently two products on the market, namely Catumaxomab launched in 2009 and Blinatumomab launched in 2014. As pioneers, the market performance of the two does not prominent. This may also be related to the "congenital deficiencies" of the two. Catatumaxomab, as a chimeric antibody for mice and rats, cannot be kept up to date with the current vision. Amgen’s Blinatumomab was first approved by the FDA for the treatment of Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia (B-cellALL). The poor market performance is mainly due to the small number of indications.

1. Mimetic function

1.1 Emicizumab

Emicizumab, developed by Roche for the treatment of hemophilia A, if approved, will be the first bispecific antibody in the non-tumor field. Emicizumab can simultaneously bind FIXa and FX, pulling the two proteins together to activate the downstream coagulation signaling pathway. Completely imitated the role of FVIII in the body. At present, FVIII is the main drug for the treatment of hemophilia, but after long-term use of drugs, about 30% of patients will produce antibody FVIII antibodies, and these patients urgently need new drugs. The emergence of Emicizumab can meet the needs of these patients.

1.2 RG-7992

Roche/Genentech's RG-7992 provides another method of using bispecific antibodies. First, scientists discovered that anti-FGFR1 (anti-fibroblast growth factor receptor 1) antibody stimulates the activity of brown adipose tissue, which can increase energy consumption and remove excess calorie energy in the treatment of type 2 diabetes. However, because FGFR1 is widely present in various tissues of the human body, a single anti-FGFR1 antibody has many off-target side effects, which can cause hypophosphatemia in mice. However, by making bispecific antibodies to bind anti-FGFR1 and KLB (co receptor β klotho) at the same time, they can all simulate FGF21 to promote the reduction of blood glucose and lipid in the body, improve insulin resistance, and protect islet β cells and other functions of regulating glucose and lipid metabolism. At present, this drug candidate has entered the first phase of clinical use in type 2 diabetes.

2. "Double-headed snake" bispecific antibody-MDG-010

Most bispecific antibodies are like a "two-headed snake", using two heads in the blood circulation to grab two different target molecules. For example, MDG-010, developed by MacroGenic on its own DART technology platform, can simultaneously bind CD32B and CD79B on the surface of B cells. When they are combined with each other, they will initiate a signal that inhibits the activity of B cells. It is expected that a similar or better clinical effect of rituximab targeting CD20 can be achieved during RA treatment. Since the goal is not to eliminate B cells, theoretically the side effects will be smaller. In June of this year, the company announced the first phase of clinical data, which provided strong support for the continued advancement of MDG-010. In addition, BIOCAD's BCD-121 can also "catch" IL-17 and TNF at the same time. It is not denied that this model will be a good drug, but there are also different opinions that it is not convenient to adjust the dosage of the drug according to the disease state in real time compared to the combination of the two drugs.

3. Exploration in the field of drug-resistant bacteria-MEDI-3902

AstraZeneca's MEDI-3902 provides another application method, which recognizes Pseudomonas aeruginosa by combining Ps aeruginosa surface polysaccharide-Psl and enriches on the surface of the bacteria. As we all know, Pseudomonas aeruginosa can secrete toxins through the spike to kill nearby immune cells. Therefore, another target of MEDI-3902 is PcrV against Pseudomonas aeruginosa type III toxin secretion system, which blocks the release of bacterial toxins by neutralizing PcrV.
Pseudomonas aeruginosa, which was cut off from the function of toxin release, became fish on the knife board. At this time, the Fc region of the antibody was combined with immune cells, especially macrophages, to remove the bacteria. At present, MEDI-3902 is mainly aimed at drug-resistant Pseudomonas aeruginosa. In an era when bacterial resistance has caused great concern and panic, whether MEDI-3902 can finally overcome drug-resistant Pseudomonas aeruginosa is worth looking forward to.

4. 'Trojan Horse' carrier

As antibody drugs have collapsed in Alzheimer's disease, many researchers have begun to reflect on whether it is difficult for antibodies to pass the blood-brain barrier, resulting in too few effective drugs in the brain and unable to function. In view of this idea, many companies have begun to target the use of antibodies for the delivery of drugs across the blood-brain barrier, namely: "Trojan horse" bispecific antibodies. The locked target is central nervous system diseases. For example: Genentech targets Alzheimer’s disease, and TfR-knock-in mice and monkeys have respectively confirmed that anti-TfR/BACE1 antibodies can effectively reduce the content of amyloid-β (Aβ) in the brain without adverse effects; Angiochem ANG4043 achieves the crossing of the blood-brain barrier by binding to LRP-1 receptors; developing the treatment of Hunter's syndrome in lysosomal storage diseases (LSDs), which is currently in Phase I clinical stage.

5. Enhance nanobody half-life

In addition to the above, Ablynx has also created a new application method. In order to increase the half-life of Nanobodies on the product line, the two arms of the bispecific antibody designed by Ablynx are used to connect albumin, so that the bispecific antibody enters the blood, it will first bind to the albumin in the blood and then find its own target. In this way, the half-life of the Nanobody drug is enhanced.

Summary

At present, bispecific antibodies have been recognized. In addition to being directly used in combination with tumor immunotherapy, their applications are becoming extensive, and a variety of novel ideas are constantly emerging. Although there are no products that have been successfully marketed in the field of oncology, the exploration of many scientists still brings great expectations.

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