Recombinant monoclonal anti csf1r antibody to CSF-1R, CXIIG6, is a mouse monoclonal antibody intended for the prophylaxis and treatment of related disease.
Tuesday, September 3, 2019
Sunday, August 4, 2019
anti mouse cd3
The anti-CD3 monoclonal antibody specifically target CD3 and can induce downmodulationg of the TCR/CD3 complex in mouse CD4+ T cells without activating T cells. Thus, the specific antbody can be used for suppressing immune responses and inducing immunosupression.
Specifications
- Host
- Rat
- Specificity
- Mouse
- Clone
- Dow2
Target
- Alternative Names
- CD3; CD3 T-Cell Co-receptor;CD3D; CD3E; CD3G
- For lab research use only, not for diagnostic, therapeutic or any in vivo human use.
Thursday, July 11, 2019
cd14 mouse
This antibody is a mouse monoclonal antibody that binds specifically to CD14, and it can neutralize the bioactivity of CD14.
For lab research use only, not for diagnostic, therapeutic or any in vivo human use.
Friday, June 21, 2019
Principle of Humanization of Antibodies and Classification of Humanized Antibodies
The entry of non-human antibodies into the human body can cause serious body rejection, which in turn affects the safety and therapeutic effect of the antibody in clinical application. Therefore, it is necessary to humanize the antibody to minimize the heterogeneity of the antibody. And keep its specificity and affinity unchanged.
Each variable region of the antibody contains three amino acid sequence hypervariable regions, which are binding sites of the antigen and are complementary to the structure of the antigenic determinant, and are referred to as antibody complementarity determining regions (CDRs), amino acid sequences and spaces of the CDRs. Polymorphism in the structure is a factor determining the heterogeneity and affinity of antibodies. Other amino acids in the variable region serve as a backbone support moiety, called Framework Residue (FR), which is not in direct contact with the antigen. The amino acid sequence and spatial structure are relatively conservative, providing a skeleton for maintaining the typical three-dimensional structure of the antibody, indirectly affecting the antibody. The specificity and affinity of the antibody constant region and the antibody variable region FR are relatively conservative during the evolution process, and the species are specific to the species, which is the main factor causing the body to reject the reaction. Therefore, the basic principle of humanization antibody is to preserve the conserved sequence of the antibody as a human sequence, reduce the body rejection reaction, replace the antigen-binding region with the sequence of the antibody produced by the animal immunization, and maintain the specificity and affinity of the antibody.
Humanization of antibodies requires the use of genetic engineering methods. Therefore, humanized antibodies belong to genetically engineered antibodies, and humanised antibodies can be classified into chimeric antibodies, modified antibodies, and fully humanized antibodies depending on the degree of antibody sequence modification.
Modified antibody
The modified antibody is also called CDR grafting antibody, and the CDR grafting method is used for preliminary humanization of the antibody, that is, the 6 CDR regions of the non-human antibody are moved to the human skeleton, due to the human FR skeleton. The region will indirectly affect the specificity and affinity of the antibody. Based on the CDR grafting, the individual amino acid residues in the human FR framework region are further adjusted to further improve the specificity and affinity of the CDR-grafted antibody.
Full human antibody
The entire sequence of the fully human antibody antibody is a human sequence, which is realized by the antibody library technology. The main antibody library technology is a phage display and ribosome display technology.
Antibody Library Technology Basic Approach to Obtaining Fully Humanized Antibodies: Selecting a Variable Region Light Chain (or Heavy Chain) Gene of a Parent Mouse Monobody to Pair with a Variable Region Heavy Chain (or Light Chain) Gene Library of a Human Antibody The mouse-to-human hybrid antibody library is constructed, and the corresponding antigen is used to select a clone capable of producing a specific binding antibody, thereby obtaining an Fv fragment capable of binding to the parent mouse monoclonal antibody and having specific binding ability to the composition. Human heavy chain (or light chain) variable region gene, combined with another human antibody variable region light chain (or heavy chain), construct a human antibody library, and again use antigen screening to obtain specificity and mouse The human antibody with the same source parent antibody is identical.
Sunday, May 19, 2019
Common antibody drug development strategy
Monoclonal antibodies are the most shining and mature technology in the field of modern biomedicine. Whether it is tumor targeting drugs, immunological checkpoint blocking drugs, or the hot market CAR-T technology, it is based on monoclonal antibodies and their downstream basis. Above. In general, a humanized mouse monoclonal antibody represented by a murine monoclonal antibody, after demonstrating its pharmaceutical value, requires a series of engineering modifications to improve its pharmacokinetics in vivo. Common antibody engineering strategies include antibody humanization, antibody affinity maturation and FC modification, or reduced antibody aggregation.
Humanization of antibodies
Mouse monoclonal antibody is the first monoclonal antibody to enter the clinic, but early clinical application found that because mouse monoclonal antibody is a heterologous protein, it will gradually cause HAMA response in clinical use, and the infused mouse monoclonal antibody will gradually be Neutralizing antibodies were neutralized, so that the murine monoclonal antibody was ineffective after infusion. Grafting the CDR regions of the murine monoclonal antibody humanization into the FRAME WORK region of the human antibody by antibody engineering techniques can effectively reduce the HAMA response induced by the antibody in clinical use. This approach is more advantageous than human-chimeric chimeric antibodies in terms of humanization. In fact, the most widely used antibody drugs in clinical practice are humanized mab or human and mouse chimeric antibodies.
With the development of bioinformatics, antibody humanization technology has been rapidly updated, and it is usually possible to recognize that some of the CDRs of the antibody antigen-binding region are grafted into the framework region of human antibodies, and some also have mouse anti-CDR regions and framework regions. The surface residues are replaced to be closer in sequence to human antibodies; in addition, the key amino acid sequence of the antibody antigen recognition region is replaced by the antibody antigen recognition region of the human antibody. In addition, different strategies have been proposed, such as CDR compensation, positioning reservation, and template replacement.
At the same time, full-human antibodies obtained by phage display library technology, or fully human antibodies expressed by humanized mice have gradually become an important direction in the field of antibody research and development, but different strategies have certain advantages and disadvantages in evaluating patients. The risk-return rate should always be considered when considering this issue.
Different companies have roughly similar technical pathways in the field of antibody humanization, but how to obtain the most humanized monoclonal antibodies while maintaining their high affinity for target proteins, for each company's technicians It is a big test. The technical team of Elken Bio has accumulated considerable experience in the field of antibody humanization. Based on years of experience in antibody drug research and development, it has provided antibody humanization services for many pharmaceutical companies. Some antibodies have entered the clinical trial stage. .
In vitro affinity maturation
Usually, the murine monoclonal antibody has a good affinity for the target antigen, but the affinity of the antibody obtained by humanization or by the phage display library technology to the target antigen may be unsatisfactory, which is not conducive to reducing the clinical use of the therapeutic antibody. The amount and toxic side effects, at this time the affinity maturation of the antibody, will contribute to future clinical use. The theoretical basis for antibody affinity maturation in vitro is the process of mimicking the affinity of antibodies in vivo. High-affinity antibodies can be screened by constructing a random mutagenesis library that mimics high-frequency mutations in B cells in vivo. In fact, in the course of monoclonal screening, affinity-maturation of any one of the antibodies results in an antibody with improved affinity.
Fc modification enhances effector function and half-life
FC receptors play an important role in the process of cellular immunity, and the modification of the FC region can produce profound effects on monoclonal antibodies with specific pharmacological effects. Monoclonal antibodies can mediate immune responses via Fcγ receptor binding (FcγR). The binding of different types of FcγR to IgG enhances/inhibits the immune response, and therefore preferentially enhances binding to FcγRIII while reducing binding to FcγRIIB to enhance clinical efficacy. At the same time, the half-life of the antibody can be prolonged by modification of the Fc. Since the binding of the antibody to FcRn is a pH-sensitive form, the antibody enters the cell by pinocytosis, in the endosome of acidic pH, the antibody binds to FcRn, and the FcRn mediates the antibody back to the extracellular, in extracellular neutral pH conditions. Next, dissociate from FcRn. In this way, FcRn avoids the fate of other proteins in the blood to be degraded by lysosomes into the cells through the pinocytosis, thereby achieving long-term effects, and the half-life is as long as several weeks (IgG1, IgG2, IgG4 half-life three weeks, IgG3 is 9 days). A number of pharmaceutical companies have attempted to modify antibodies to specifically increase the affinity for FcRn under low pH conditions for further long-acting effects. Although Fc modifications to enhanced cycle time may affect the effector function of Fc, studies have shown that mutations in different AAs of bevacizumab and cetuximab lead to more potent antitumor activity in mouse cancer models, Thus a strategy to increase the half-life of therapeutic antibodies was verified. Since then, a large number of favorable mutations have been reported. Unfortunately, the results of animal models are not always related to humans. However, an increase in affinity with FcRn by a factor of 5-10 usually results in a 2-4 fold increase in half-life.
The binding of the antibody to FcRn is a pH-sensitive form, and the antibody enters the cell by pinocytosis. In the acidic pH endosome, the antibody binds to FcRn, and the FcRn mediates the antibody back to the extracellular, under extracellular neutral pH conditions. , dissociation from FcRn
Improve stability and reduce polymerizability
Since the production of therapeutic antibodies is free from the physiological environment of the body, its thermal stability and stability of the colloids are limited, which in turn causes certain problems in the production and preservation of the drug. By technical means, improving the physical and chemical properties of the antibody helps to improve the overall efficacy and productivity of the antibody. By altering the antibody framework structure, the antigen binding domain of the antibody helps to reduce the polymerization of the antibody. It is usually possible to reduce the polymerization of the antibody by: 1. by changing the antibody dosage form; 2 by changing the framework and CDR regions, 3; adding additional disulfide bonds to the CH2-CH3 region; 4, changing the Fab The disulfide bond structure of the region; 5 increases the fusion tag with dots. In fact, with the development of computer simulation technology, the polymerization of antibodies can be offset by different designs and in vitro screening methods, and the chemical degradation rate and serum clearance rate of antibodies can be predicted.
An Overview of Major Histocompatibility Complex(MHC)
The major histocompatibility complex is a collective term for a group of genes encoding the major histocompatibility antigens of animals. The human MHC is located on the short arm of human chromosome 6, and the mouse MHC is located on chromosome 17 of the mouse. The length of the MHC is approximately 4 x 10^6 bp. The human MHC is also called the HLA complex. The MHC of mice is called the H-2 gene. Due to the polygenic nature of MHC, it can be divided into MHC class I, MHC class II, and MHC class III genes, which encode MHC class I molecules, MHC class II molecules, and MHC III, depending on the structure, tissue distribution, and functional differences of the coding molecules. Class of molecules. The human MHC product is commonly referred to as HLA, the human leukocyte antigen.
MHC molecule
1. Types of MHC molecules
Different MHC-encoded products have different functions.
MHC class I (MHC I): Located on the surface of a general cell, it can provide some conditions in general cells. For example, if the cell is infected with a virus, the amino acid peptide of the outer membrane fragment of the virus is prompted to pass through the MHC to the outside of the cell. Can be identified by killer CD8+ T cells for culling.
MHC class II: only located on antigen-presenting cells (APC), such as macrophages. This kind of supply is external to the cell. If there is bacterial invasion in the tissue, the macrophage will be swallowed, and the bacterial fragments will be prompted by the MHC to help the T cells to initiate the immune response.
MHC class III: mainly encodes complement components, tumor necrosis factor, heat shock protein 70 and 21 hydroxylase genes.
2. Physiological significance of MHC molecules
MHC antigens were originally discovered as transplant antigens and are the major antigenic systems responsible for transplant rejection. This antigen is incompatible, which can cause the immune response of the receptor and reject the transplanted donor tissue. After the 1970s, MHC molecules also proved to have important immunophysiological functions.
MHC molecules are involved in antigen recognition during the immune response. In the 1970s, RM Zinkner Zeer and other mice found that killer T cells can kill the target cells infected with the same cells when killing the target cells infected with the virus, but have no killing effect on the infected target cells of different lines. The phenomenon is genetically restricted. It was subsequently confirmed that the killer T cells must be consistent with the MHC of the target cells to have a killing effect, so this phenomenon is also called MHC restriction.
This reveals the role of MHC in T cell recognition of heterologous antigens. Further studies have shown that T4 T cells are restricted by MHC class II molecules when recognizing heterologous antigens, while T8 T cells are restricted by MHC class I molecules when recognizing xenoantigens. This restrictive mechanism is that T cells, through their antigen recognition receptors, can simultaneously recognize new complex antigenic determinants formed by heterologous antigenic determinants and their own MHC molecules.
It has also been found that non-T cells such as peripheral blood B cells and monocytes can induce proliferative responses in certain autoreactive T cells in vitro, which is called self-mixed lymphocyte reaction (AMLR) and proves that this is a non- Caused by MHC class II antigens on T cells. Such autoreactive T cells may have an effect of enhancing or inhibiting immune function in vivo, thereby maintaining the immune stability of the body, and thus MHC molecules are also involved in immunomodulatory effects.
Studies have shown that MHC molecules also play an important role in the differentiation and maturation process of T cells in the thymus. In vitro studies have found that the removal of MHC class II antigen-positive stromal cells in the thymus inhibits the development of T4T cells, and the addition of monoclonal antibodies against MHC class II antigens in thymic culture cells can also prevent the development of T4 T cells. It is currently believed that MHC molecules play an important role in the formation of T cell self-tolerance and the production of T cell pools.
MHC gene
The understanding of the discovery, gene composition and function of MHC is based on mouse experiments. Therefore, it has been determined since the 1930s that the mouse MHC is located on chromosome 17, called the H2 complex. The H2 complex is composed of K region, I region, S region and D region, wherein the I region is further divided into two sub-regions, IA and IE, and the gene-encoded product is called the I region-associated antigen.
In 1958, Dausset et al found that there were different specific leukocyte antibodies in the serum of patients who received blood transfusions, multi-partum women and volunteers immunized with the same kind of leukocytes. These antibodies were used to identify many different specific white blood cell antigens. Human leukocyte antigen. Through genetic analysis of families and populations, it was found that human MHC is located on chromosome 6, called HLA complex.
All vertebrates have their own MHC. In addition to human HLA and mouse H2, the MHC of rhesus monkeys, chimpanzees, dogs, rabbits, guinea pigs, rats and chickens are called RhLA, ChLA, DLA, RLA, GpLA, AgBI (H-1I) and B.
In 1980, the Nobel Prize in Physiology or Medicine was awarded to Baruj Benacerraf, George D.Snell and Jean Dausset (three people). The study laid the foundation for the establishment of transplant immunology. Benaselav was an American medical scientist and immunologist who discovered immune response genes in MHC Tetramer when studying organ transplant rejection. Ir), pointing out that the immune phenomenon is controlled by this gene, and the immunology is pushed to the climax on the basis of genetics.
Snell is an American immunologist who proposed through tissue transplantation experiments in mice: The transplantability of tissues between different individuals is determined by specific antigens on the cell surface, ie histocompatibility antigen (also known as H antigen). , controlled by the H gene. This gene is present in a limited area of a chromosome called the major histocompatibility complex (MHC). Dosser, a French immunologist, discovered the human leukocyte antigen (HLA) and the HLA gene that determines these antigens, the H gene equivalent to mice; it also confirmed that humans and many other animals have MHC.
(1) Polygenicity: A gene complex consists of a plurality of closely adjacent gene loci whose encoded products have the same or similar functions.
For example: mouse H-2: chromosome 17: short arm of chromosome 6 (6P21.31), full length 3600-4000 kb, 224 gene loci (128 functional genes, 96 pseudogenes).
(2) Polymorphism: There are two or more alleles in the same HLA gene locus in the population.
The significance of MHC polymorphism:
1. Expanding the population's presentation of antigenic peptides is conducive to maintaining the survival and continuation of the population.
(The polymorphism of HLA products is mainly manifested in the difference in composition and sequence of amino acid residues in the antigen-binding groove)
2. It is not conducive to the choice of donors in organ transplantation.
It has been shown that MHC not only controls allograft rejection, but more importantly, it is closely related to the immune response, immune regulation and the production of certain pathological states. Thus, the complete concept of MHC refers to a group of closely linked genes that encode major histocompatibility antigens on a chromosome of a vertebrate, control mutual recognition between cells, and regulate immune responses.
Combination of TLR7 Agonists and Neutralizing Antibodies Can Kill Latent HIV Virus Libraries
Given that more than 35 million people worldwide are infected with HIV and nearly 2 million new cases of HIV infection each year, the virus remains a major global epidemic. Existing antiretroviral drugs (ART) do not cure HIV infection because the virus can enter a dormant state and persist in the presence of immune cells. These infected immune cells (called latent virus banks) -- despite the use of ART drugs, remain in a latent state -- can be active again at any time.
Dr. Dan H. Barouch, director of the Virology and Vaccine Research Center at the Beth Israel Deaconess Medical Center, said, "This latent virus library is a key barrier to the development of a cure for HIV-1 infection. There is a hypothesis that activation of these latent viral pool cells may Make them more vulnerable to damage."
In a new study, Barouch and colleagues demonstrated that the combination of a broadly neutralizing agonistic antibody (bNAb) targeting HIV and a Toll-like receptor 7 (TLR7) agonist that stimulates the innate immune system can delay HIV cessation. Monkeys taking ART drugs rebounded. These findings suggest that this two-pronged approach represents a potential strategy for targeting this virus pool. The results of the study were published online October 3, 2018 in the journal Nature, entitled "Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys".
Barouch and colleagues studied 44 rhesus monkeys infected with HIV-like virus (SHIV) and started treatment with ART for two and a half years after infection. After 96 weeks, these rhesus monkeys were divided into four groups. One group, the control group, did not receive any further study treatment. The other two groups were given only TLR7 antibody agonists or only bNAb antibodies. The fourth group was given both a TLR7 agonist and a bNAb antibody. All rhesus monkeys continued to receive ART medication until the 130th week of stopping the treatment, at which time the researchers began monitoring whether the rhesus monkeys showed signs of a rebound in SHIV.
As expected, in the control group, all rhesus monkeys rapidly rebounded with SHIV and they had a relatively high viral load peak, while in rhesus monkeys given only this TLR7 agonist, almost all The same is true for rhesus monkeys. However, among the rhesus monkeys receiving this combination therapy, 5 of the 11 rhesus monkeys did not rebound from the SHIV virus within 6 months. In addition, another 6 rhesus monkeys with SHIV virus rebound showed lower viral load peaks than rhesus monkeys in the control group. Rhesus monkeys given only bNAb antibodies showed detectable SHIV virus rebound, but this virus rebound was delayed.
"The combination of bNAb antibody and TLR7 agonist has led to the best killing of immune cells infected with SHIV," Barouch said. In summary, our data show that this combination therapy stimulates the innate immune system and allows infected cells to become more A mechanism that is easy to remove. T
Oncology Drug Development Brings Momentum to the Development of Humanized Mouse Drug Evaluation Model
For companies and researchers, clinical research requires high costs. Once the trial fails, it not only faces the stranding of drug research, but also loses a lot of money. For cancer patients, the clinical trials of taking some new drugs are often their last hope. If the test fails, it will bring a huge blow to patients and their families.
Promissing preclinical research challenges
The problems faced by major new drug research and development institutions include the clinical efficacy of new drugs, the risk of time cost and the benefits. In modern drug development, from preclinical research to clinical research, and then to CFDA/FDA approval, the time is long, the cost is huge, and the probability of failure is quite high. Everything in the new drug development process always needs to face difficulties, and every link is crucial.
The R&D process requires many steps, such as drug design and screening, chemical synthesis and transformation, pharmaceutics and pharmacokinetic studies, processes and preparations, quality testing and control, safety and clinical evaluation, market feedback, and so on.
According to the different content of the work, the research and development of new drugs can be divided into four stages: discovery and screening, preclinical research, clinical research, new drug declaration and follow-up work. First, discovery and screening include basic and applied research (including drug preparation and primary screening) to identify and screen drug sources. Subsequent clinical studies include Phase I (Preliminary Clinical Pharmacology, Human Safety Studies), Phase II (Preliminary Evaluation of Treatment, Safety Studies), Phase III Clinical Trials and Preparations (Expanded Clinical Trials, Special Clinical Trials) , supplement clinical trials, adverse reactions observed). The final declaration and follow-up of new drugs includes new drug declarations and additional work required by the CFDA (National Food and Drug Administration) to review new drug declarations.
For companies and researchers, clinical research requires high costs. Once the trial fails, it not only faces the stranding of drug research, but also loses a lot of money. For cancer patients, the clinical trials of participating in some new drugs are often theirs. After a glimmer of hope, if the test fails, it will bring even greater blows to patients and their families.
Preclinical research has become a challenge in drug development. Preclinical research refers to chemical synthesis or natural product purification studies, drug analysis studies, pharmacodynamics, pharmacokinetics, toxicology, and pharmaceuticals. Learning research. Every year, a large number of new drugs are eliminated in the phase I clinical process. After all, animal experiments and human experiments are very different.
Whether it is animal or human drugs, the research and development of drugs will follow the method of using animal models to study diseases, and the use of animal experiments to verify the safety and effectiveness of new drugs. What kind of drugs can enter clinical trials is a headache for many researchers. For tumor immunity (CAR-T/Checkpoint), because its mode of action is to mobilize autoimmune to kill, it has a different effect from the past drug-targeted drug killing. Therefore, there is a need for a model to simulate the immune environment in the human body in the preclinical stage. If you have a good pre-clinical evaluation system, you can provide very valuable and meaningful experimental data for reference, such as the use of humanized mice models for new drug evaluation.
A valuable tool - a humanized mouse model
Because of the significant differences between human physiology and animal physiology, experimental results obtained using animal models sometimes cannot be applied to the human body. The human derived xenograft (PDX) mouse model enables the assessment of the safety and efficacy of new human-related drugs in animals, simulating human clinical trials.
In view of the particularity of tumor immunotherapy, Edmo independently developed a mouse model-HSC mouse suitable for tumor immunotherapy evaluation. This model realizes the remodeling of the immune system in mice by transplanting human hematopoietic stem cells. On the basis of this, transplanting human tumor tissue and obtaining a tumor-immunized double-sourced mouse model can not only help pharmaceutical companies improve the drug clinical trial pass rate. To help patients find a suitable treatment plan, it also provides a powerful tool for pre-clinical evaluation of human immune system and cellular immunotherapy.
Dr. Peng Siying, CEO and founder of Beijing Aidemo Biotechnology Co., Ltd., said that humanized immune reconstituted mice can be a powerful tool for promoting the development of new drugs, effectively shortening the clinical trial cycle of new drugs, greatly reducing the cost and risk of clinical trials, and thus accelerating The birth of domestic innovative drugs and new therapies.
In 2011, the global anti-cancer drug market was about $83 billion. In the past five years, the global anti-cancer drug market has grown at a compound annual growth rate of 7.6%, which is significantly higher than the 4.3% average growth rate of the global drug market. China's anti-tumor drug market is about 80 billion yuan, with an average annual growth rate of about 20%. In 2012, anti-tumor and immune drugs exceeded the 16.46% market share with 18.2% market share, making it a large domestic prescription drug category.
The huge demand for new drug development has also brought a huge market for humanized mouse drug evaluation models. According to Amy's research data, 70 new drugs for treating more than 20 tumor diseases have been published in the past five years. At present, there are more than 586 kinds of tumors in research, which has increased by 63% in the past 10 years, of which 87% are targeted drugs.
Advances in science and technology have led to the development of medicine. In the face of disease patients, there are more choices, new oncology drugs continue to appear, and Emers data shows that there are more than 586 kinds of tumors in research, and the growth rate has increased by 63% in the past 10 years. Drugs accounted for 87%. The late stage of oncology therapy includes 270 biological therapies, including 16 gene therapies, 86 new monoclonal antibodies and 15 biomolecules of listed monoclonal antibodies; late development products also include 74 for multiple tumors.
China's industrial research network released the 2016-2022 China anti-cancer drug industry research analysis and development trend forecast report that China, India, Brazil and Russia "BRIC" will become the global fast-growing anti-cancer drug market. In China, due to the rapid increase in the incidence of cancer, the anti-tumor drug market has broad prospects for development. At the same time, due to the limitations of current drug efficacy, the new anti-cancer drug market needs to be vigorously developed, and anti-cancer drug development has become a major factor in the pharmaceutical industry. Popular.
The development of oncology drugs will also bring more impetus to the development of humanized mice antibody production evaluation models.
Friday, May 17, 2019
Recent Advances in PARP Inhibitor Bispecific Antibody Hotspots
In the AACR inventory on April 3, WuXi PharmaTech's WeChat team will share the latest developments in three hotspot research areas, namely “unlimited cancer” targeted drug development, PARP inhibitors, and bispecificity. antibody.
In 2018, Loxo Oncology's "unlimited cancer" targeted therapy Vitrakvi received FDA approval, becoming the first cancer-free, targeted therapy for patients with NTRK gene fusion variant solid tumors. Loxo has begun to develop a new generation of TRK inhibitors before Vitrakvi was approved. Although Vitrakvi acts as a TRK inhibitor, it achieves a 75% response rate in patients with solid tumors, but over time, tumors acquire genetic mutations that are resistant to TRK inhibitors, so development can be effective against these tumors. A new generation of inhibitors is an urgent task.
On April 2, Bayer announced the results of an early clinical trial of the new generation of TRK inhibitor LOXO-195 developed by Loxo. Bayer acquired the exclusive R&D rights of LOXO-195 after Loxo's acquisition by Lilly. LOXO-195 is capable of inhibiting the activity of TRK proteins that have developed resistance to existing TRK inhibitors. The results of the trial showed that LOXO-195 achieved an objective response rate (ORR) of 45% in 20 patients with solid tumors who had received a TRK inhibitor and were resistant to it. Although this study is still in its early clinical stage, it suggests that LOXO-195 may help address the unmet medical needs of patients with solid tumors that are resistant to existing TRK inhibitors.
PARP inhibitors are a class of drugs that treat tumors that are defective in BRCA gene mutations or homologous recombinant antibody DNA repair mechanisms by a "synthesis-killing" mechanism. They have shown excellent efficacy in the treatment of ovarian and breast cancer. Recent studies have shown that these drugs can also be used in cancer types other than breast cancer. In February 2019, Lystraza developed by AstraZeneca and Merck (MSD) as a maintenance therapy reached the primary end point in phase 3 clinical trials for the treatment of pancreatic cancer. At the AACR conference on April 3, Clovis's PARP inhibitor Rubraca also obtained positive data in Phase 2 clinical trials for the treatment of pancreatic cancer.
In a one-arm phase 2 clinical trial enrolling 42 patients with advanced pancreatic cancer, Rubaraca served as a first-line maintenance therapy for patients who had received platinum-based chemotherapy and had no progression of disease over the past four months. These patients carry mutations in the pathogenic germline or somatic BRCA1, BRCA2 or PALB2 genes.
Interim data analysis showed a median progression-free survival (PFS) of 9.1 months in 19 patients who were able to be evaluated. Of these 19 patients, one patient achieved complete remission and six patients achieved partial remission. These patients carried germline BRCA2 gene mutations (n=4), germline PALB2 gene mutations (n=2), and somatic BRCA2 gene mutations (n=1).
These preliminary data, combined with Phase 3 data from Lynparza, suggest that PARP inhibitors may provide a new treatment modality for advanced pancreatic cancer. Approximately 5-8% of patients with pancreatic cancer carry a BRCA1, BRCA2 or PALB2 pathogenic mutation.
Epitope specific Antibody and multispecific antibodies are becoming a new model of cancer treatment. At the AACR conference, Inovio announced preclinical data on the company's innovative DNA-encoded bispecific T cell adapter (dBiTE). One end of the bispecific TCR adapter (BiTE) can bind to the specific antigen on the surface of the tumor, while the other end can bind to the CD3 receptor on the surface of the T cell, and recruit T cells around the tumor to kill the tumor cells. effect.
One of the challenges faced by BiTE-type proteins is that the stability of these proteins is not high, leading to the need for patients to receive frequent treatment. Inovio's innovative strategy is to introduce DNA encoding the BiTE protein into human cells, making the somatic cells a "factory" for the production of BiTE, thus continuing to provide BiTE proteins.
Preclinical studies published in the AACR show that the DOBI-targeted dBiTE developed by Inovio maintains high levels of BiTE protein expression in mice for 4 months after one treatment in a mouse model of breast and ovarian cancer. Moreover, dBiTE targeting HER2 is effective in stimulating the cytotoxicity of T cells to HER2-expressing tumor cells, resulting in near complete tumor clearance.
Reveal the Secrets of Human Antibodies, Pushing the Frontiers of Vaccine Science
Researchers at the Vanderbilt University Medical Center (VUMC) and the San Diego Supercomputer Center used advanced genetic sequencing and computational techniques to achieve the first step in how the human immune system responds to infections.
Their findings, published this week in Nature, can help develop "reasonable vaccine design" and improve the detection, treatment and prevention of autoimmune diseases, infectious diseases and cancer.
“Because of recent technological advances, we now have an unprecedented opportunity to use the power of the human immune system to fundamentally change human health,” said Wayne Koff, CEO of the Human Vaccine Program, which is responsible for research. Press Releases.
The focus of this study is on the production of white blood cells called antibodies, called B cells. These cells carry a Y-shaped receptor that, like a microscopic antenna, can detect a wide range of bacteria and other foreign invaders.
They do this by randomly selecting and joining a unique nucleotide sequence (DNA building block) called the receptor "clonal". In this way, a small number of genes can produce incredible receptor diversity, allowing the immune system to recognize almost any new pathogen.
It is daunting to understand exactly how this process works. "Before the current era, people thought that it would be impossible to do such a project because the immune system is so large in theory," said Dr. James Crowe, senior director of the Vanderbilt Vaccine Center.
"This new paper shows that a large part can be defined," Crow said. "Because the size of each person's B cell receptor library is unexpectedly small."
The researchers isolated white blood cells from three adults and cloned and sequenced up to 40 billion B cells to determine their clonotype. They also sequenced t cell receptor from cord blood from three infants. This sequencing depth has never been achieved before.
They found that the frequency of shared clonotypes was very high. "The overlap of antibody sequences between individuals is unexpectedly high," Crow explained. "It shows some of the same antibody sequences between adults and infants even at birth."
Understanding this commonality is key to identifying antibodies that can be used as vaccines and therapeutic antibodies targets, and these vaccines and treatments are more prevalent in the population.
The Human Vaccine Program is a non-profit, public-private partnership of academic research centers, industry, non-profit organizations, and government agencies dedicated to research and advancement of next-generation vaccines and immunotherapies. The study is part of the Human Immunization Program and aims to decode the genetic basis of the immune system.
As part of a unique alliance created by the Human Vaccine Project, the San Diego Supercomputing Center uses its considerable computing power to process terabytes of data. The core principle of the project is the merger of biomedical and advanced computing.
“The Human Vaccine Program allows us to research problems on a larger scale than is usually possible with a single laboratory, and to bring together groups that may not normally collaborate,” said Dr. Robert Sinkovits, who leads San Francisco’s scientific applications. Diego Supercomputer Center.
Collaborative work is currently underway to expand the study to sequence other areas of the immune system, from older people and B cells from around the world, and apply artificial intelligence-driven algorithms to further mine data sets for insight.
Researchers hope that continued trials of the immune system will eventually lead to the development of safer, highly targeted vaccines and immunotherapies that can work in the population.
"Resolving the human immune system is critical to addressing the global challenges of infectious and non-communicable diseases, from cancer to Alzheimer's disease to pandemic influenza," Cove said. "This study marks a key step in understanding how the human immune system works. The integration of genomics and immunosurveillance technology with machine learning and artificial intelligence has laid the foundation for the development of the next generation of healthy products."
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