Read a article about dual-specific antibodies.

Guide: As of September 2019, there are 120 kinds of double resistance in clinical research and development, and nearly 200 kinds of double resistance in preclinical research.
. Recently, the dual-specific antibody KN046 developed by Corning Jerry officially entered clinical Phase III trial, KN046 is the world's first PD-L1/CTLA-4 dual-specific antibody, has been carried out covering non-small cell lung cancer, triple-yin breast cancer, esophageal squamous cancer, pancreatic cancer and other more than 10 different stages of clinical trials, the results show better safety and effectiveness.
bispecific antibody (Bispecific Antibody, Bispecific) refers to an antibody molecule that can be combined with two different antigens or two different antigen cpotypses of the same antigen.
as of September 2019, there are 120 kinds of double resistance in clinical research and development, and nearly 200 kinds of double resistance in preclinical research.
(i) the difference between multi-resistance and mono-resistance can be described as a mixture of two kinds of single-resistance, with typical multi-resistance characteristics.
analysis of the difference between multi-resistance and mono-resistance, the preparation method and application path are the main differences between the two.
from the point of view of preparation, the preparation period of multi-resistance is short and the preparation price is lower.
monoantigen preparation method is more cumbersome, first by antigen treatment of B lymphocytes and myeloma cells through cell fusion method to get hybrid tumor cells, followed by HAT medium screening, ELISA testing ability price can get a positive clone strain, and finally cell culture or injection of cells into the abdominal cavity of animals (mice) culture with abdominal water, collection of clean / abdominal water purification after obtaining monoclonal antibodies.
and the preparation of multi-clone antibodies is relatively simple, just inject antigens directly into the animal body for immunity, after 3 to 4 immunizations, ELISA test its effectiveness pass, collect blood centrifugation to get clear, purification will be able to get multi-clone antibodies.
from the application point of view, multi-resistance can improve the sensitivity of detection.
monoclonal antibodies are highly specific and can be used to produce fully consistent antibodies once prepared, so their specificity can be fully and systematically verified.
if the antigen surface identified by monoantials is destroyed, the results of the experiment will be greatly affected.
and dual resistance is poor, even if the same antigen preparation double resistance, there will be differences between batches, so there are greater limitations in specificity, consistency.
the results of the experiment will not be affected because multiple antigens are identified, even if a few antigens are destroyed or the antigen composition changes.
, monoantigens can be selected if antibody specificity is required, with a large dosing or long-term use of consistent antibodies.
if the antibody specificity requirements are low, the number of identification tables is higher, the preparation cycle and cost is short, it is recommended to choose multiclonal antibodies.
given that the current development of the disease tends to be complicated, multi-drug can effectively supplement the deficiency of mono-drug single-table therapy. Table
Table 1 The difference between monoclonal antibodies and polyclonal antibodies (ii) The current role of dual antibodies consists of two main functioning elements: bridgeting two cell types (in-transbinding) and binding two molecules (in-cisbinding) of a cell.
In Bispecificantibodies: Amechanisticreviewofthepipeline, the authors counted 119 preclinical and 176 preclinical dual-anti-drugs, and divided the current mainstream therapeutic areas into three categories: anti-tumor, autoimmune and other diseases, most of which are anti-tumor products.
1. Anti-tumor double anti-tumor dual anti-tumor is currently the hottest field, in 119 clinical and 176 preclinical dual anti-drug projects, 99 clinical and 153 preclinical projects for the field of oncology.
its action is mainly by briddification cell method, such as one target selects T cell recruitment and resification through CD3, and another target selects tumor antigen.
number of dual-specific antibodies targeted at immune checkpoints (PD-1/PD-L1, CTLA-4, etc.) is also growing rapidly.
can be further subdivided into five categories according to physiological factors: (1) anti-angiogenesis: angiogenesis: angiogenesis: angiogenesis promotes tumor growth and promotes its deterioration, diffusion and metastasis.
two or more angiogenesic path paths, such as VEGF, VEGFR2, DLL4 and ANNGPT2, simultaneously, to enhance anti-angiogenesic effects.
(2) Anti-tumorogenesis: Targeting cancer-causing lithums is one of the most widely used anti-tumor methods.
most of these dual-resistance projects are HER2, HER3, EGFR, cMet, and LRP5/6.
(3) Enhancing Anti-Tumor Immunity: Tumor immunotherapy is designed to improve a patient's own anti-tumor immune response and has two mechanisms: "stepping on the accelerator" and "loose brake".
stepping on the accelerator enhances anti-tumor immunity by enhancing T-cell-assisted activation signals, common targets include 4-1BB, OX40, and loose braking mechanisms enhance anti-tumor immunity by blocking T-cell response suppression signals, common targets include CTLA-4 and PD1/PD-L1 antibody therapy.
(4) Regulating the tumor microenvironment: To escape immune system monitoring, tumors can inhibit the function and proliferation of immune cells in tumor microenvironments by expressing immunosuppressive molecules such as TGF beta, CD73, and recruiting immunosuppressive cells.
of these double-resistant and dual-functional proteins have been developed to overcome immunosuppressive effects in tumor microenvirons.
(5) Targeting tumor cell removal (Depletionoftargetcells): This type reflects the biological mechanisms that are currently mostly in the study of dual resistance, i.e., direct targeting tumor cells for removal through the mediated effect cells or through functions such as Fc-mediated ADCC, ADCP, and CDC.
2. Autoimmune disease double anti-autoimmune dual anti-currently has 10 clinical projects and 12 preclinical projects, most of which achieve better anti-inflammatory effects than monoantimmunes by simultaneously meso-meso-inflammatory factors.
are: IL-1 alphaxIL-1 beta, IL-17xIL-13, IL-4xIL-13 and BAFFxIL-17.
(iii) The global dual-anti-market development double-anti-global sales are small, but rapid growth, the current global approval of only three dual anti-injection varieties, namely, Catumaxomab, blinatumomab and emicizumab.
Table 2 is the world's first dual-specific antibody against CD3 and endothocyte adhesion molecules (EPCAM), with a malignant astrophic disease, approved by the EMA in 2009. Catumaxomab.
But the product was de-marketed in 2017 due to dismal sales of the drug, which sold $1.66 million, $3.32 million, $4.43 million and $4.54 million worldwide from 2009 to 2012, fell sharply to $2.7 million in 2013 and ceased sale in 2014.
is due to the drug's embarrassing adaptive disorder.
Because the drug's adaptation is malignant asperin, the common treatment for malignant asperin is simple intestion drain, and the high price of dual anti-drugs is not competitive in the face of the symptoms, it is easy to become an auxiliary drug.
In fact, Catumaxomab should declare celiac metastatic cancer as an allergy when filing a drug, but for budget, risk, and time reasons, the drug development team chose a conservative reporting strategy, which set the stage for a later promotional disadvantage.
1 2009-2013 Catoso monoantial sales (US$10,000) December 2019, Catoso monoantial submitted a clinical trial application at CDE.
also plans to conduct clinical trials for non-muscle immersive bladder cancer and local recurrence of colorectal cancer, both of which are expected to be approved for listing in China in 2023 and 2024, respectively.
2. Perintomo double-anti-lyndomab is a CD19/CD3 dual-specific antibody that selectively targets cd19 proteins on the surface of B-cell lymphocytes that bind to excessive proliferation in patients, or specifically binds CD3 proteins on the surface of T-cells.
2014, Perintomo Double Resistance was approved by the FDA for relapsed pregenuity B-cell acute lymphoblastic leukemia (ALL), the first drug to destroy leukemia cells through human T-cells.
acute lymphoblastic leukemia is a rapidly developing blood and bone marrow malignancies, which is a rare disease.
stage, in addition to chemotherapy, there is no widely recognized and accepted effective treatment for recurrence and difficult treatment of acute lymphoblastic leukemia.
patients diagnosed with relapsed and incurable acute lymphoblastic leukemia had poor prognosis and a medium survival of only about 3 to 5 months.
after the listing of the bilintomo double resistance, the adaptive disorder has been widening.
extended to children in September 2016; in February 2017, the adaptation was extended to Philadelphia chromosomal-positive recurrence or refractic precursor B-cell acute lymphoma leukemia; and in March 2018, fdate approval via FDA accelerated treatment for the first or second full remission of precursor B-cell acute lymphoma leukemia.
the growing number of adaptive disorders, the double sales of Perintomo are not optimistic.
as an orphan drug, high pricing is a common strategy for pharmaceutical companies in the face of small patient capacity.
two cycles cost $178,000 and are perhaps one of the most expensive drugs on the market.
230 million U.S. dollars in global sales in 2018, equivalent to about 1,300 patients worldwide, and $310 million in global sales in 2019, raising the number of drug use to 1,750.
2 2016-2019 Perintomo Double Anti-Global Sales October 2019, Perintomo Double Anti-China was declared listed and accepted in China and included in the priority approval process.
But unlike the model of foreign insurance companies to pay for, China has not yet had a good way of reimbursement for orphan drugs, sky-high orphan drugs difficult to enter the medical insurance directory, conventional commercial medical insurance and serious illness insurance coverage is also a cup of water.
taking into account that perintomo double resistance was increased from four months to 7.7 months, although the median total survival of the patients doubled in the trial.
from the point of view of cost and revenue, the future sales of Perintomo double resistance in China are not optimistic.
3. Emicizumab is the world's third approved dual-specific antibody to be approved for listing in November 2017 through FDA Priority Review for bleeding prevention therapy for type A haemophilia containing FACTOR VIII inhibitors.
A hemophilia is a common treatment method for clotting factor VIII alternative therapy, but after treatment for a period of time, the patient's blood may produce coagulation factor VIII inhibitors, the presence of inhibitors will lead to a reduction in the effectiveness of treatment, improve the risk of death of patients with type A haemophilia.
amesai single resistance can provide therapeutic protection for haemophilia patients who produce coagulation factor VIII inhibitors.
, however, due to the small number of patients with type A haemophilia with coagulation factor VIII inhibitors, only 5% of total haemophilia patients were showed, and sales growth of the drug was slow after its launch.
but with the approval of new adaptations and a longer half-life, sales of the Emmys have leapt.
, on the other hand, the prevention and treatment of type A haemophilia, which does not contain VIII factor inhibitors, was approved for sale in April 2018, greatly expanding the adaptive population.
the other hand, compared to recombinant coagulation factor VIII twice a week, The Emmys single resistance achieved Q2W or even Q4W dosing, greatly improving patient compliance.
2019, The Emmys will be worth $1.52 billion, up 500% year-on-year.
forecast that sales of the Emmys will reach $4 billion in 2022, according to CoreLogian.
3 Emmys Cymru 2018 and April 2019 sales in April 2018, Amesai Beads Single Resistance was approved by NMPA for the treatment of patients with type A haemophilia with coagulation factor VIII inhibitors.
But the Emmys, a dual-anti-drug drug, are also expensive, costing $484,000 in the first year and $448,000 a year in follow-up.
from the point of view of health care, Societe Generale believes that the Emmys are too expensive to enter the catalog.
(4) Domestic dual-resistance research and development at present, China's local pharmaceutical enterprises developed a number of dual-resistant varieties in the research has entered the clinical trial stage, including Hengrui Pharmaceutical SHR-1701, Wuhan Youzhiyou M802, Shore Mei BioEMB01, Xinda Bio IBI-318 and so on.
the best in the double resistance circuit, had to mention Kang Fang Bio and Corning Jerry, a pair of "Con" brothers.
1. Kangfang Bio-Kangfang Bio was founded in 2012 by a team of senior Dr. Hai Hui, led by a national expert, in Zhongshan, Guangdong Province, one of the national health bases, and was successfully listed on the Hong Kong Stock Exchange on April 24, 2020 (stock code 9926. HK).
company currently has more than 20 innovative drug product pipelines for treating major diseases such as tumors, autoimmune, inflammation, metabolic diseases, 12 of which are in clinical research.
company currently has two dual resistances, the AK104 and ak112, the former target PD-1/CTLA-4, after.