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    Home > Medical News > Medical World News > R & D strategy and early R & D pipeline of Genentech

    R & D strategy and early R & D pipeline of Genentech

    • Last Update: 2020-02-20
    • Source: Internet
    • Author: User
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    Recently, Genentech, Roche's subsidiary, held an early drug development investor event Roche has obtained 31 FDA approved breakthrough therapies in the past seven years, which are inseparable from the innovation of research and early development department (gred) of Genentech Nearly 70% of the drug molecules developed by Tech / Roche are "first in class" molecules Today, gene Tech's early research and development activities focus on the more difficult targets in the human genome Using a variety of different technology platforms to attack these targets, which are usually considered as "impossible to make medicine" In today's article, the content team of Wuxi apptec will share with readers the key projects in the early R & D pipeline of Genetech Source: reference [1] Genentech's early oncology research and development pipeline uses a variety of technology platforms, from traditional small molecule drugs to bispecific antibodies, personalized mRNA tumor vaccines, personalized T-cell therapy, to develop innovative therapies for the benefit of patients In terms of small molecule candidate drugs, the executives of Genentech company focused on the research and development information of PI3K inhibitor and SerD In cancer patients, PI3K / Akt signal pathway is often abnormal According to Genentech's estimation, 17% of the 14 million cancer patients diagnosed every year in the world carry pi3kca gene mutation, so targeting this signal pathway can significantly affect the treatment of many cancer patients Source: reference [1] Gdc-0077 developed by Genentech is a PI3K α specific inhibitor It is more selective for PI3K α, and can lead to the degradation of mutant PI3K α, resulting in stronger and more lasting inhibition effect ▲ introduction to gdc-0077 (picture source: reference [1]) Gdc-0077 showed a promising activity in a phase 2 clinical trial with CDK4 / 6 inhibitor (CDK4 / 6I) and endocrinotherapy (ET) in patients with HR positive and HER2 negative metastatic breast cancer The combined therapy achieved a total remission rate (ORR) of 52% At present, it is used to treat HR positive and HER2 negative breast cancer patients in phase 3 clinical trials Source: reference [1] Estrogen receptor (ER) inhibitors are commonly used to treat HR positive breast cancer patients However, the existing inhibitors can not completely inhibit the function of estrogen receptor, so that some ER positive tumor cells can continue to proliferate Gdc-9545 developed by Genentech is a selective estrogen receptor degradation agent It can not activate the transcription of target gene and the degradation of ER protein through the combination of ER and gdc-9545, thus blocking Er mediated signal pathway more thoroughly ▲ introduction to gdc-9545 (picture source: reference [1]) In the first phase of clinical trials, it showed promising anticancer activity in patients with ESR1 mutation or resistance to CDK4 / 6 inhibitors and fulvestrant This selective estrogen receptor degradation agent will enter the phase 3 clinical development stage Source: reference [1] Genentech's immune cell bispecific antibody technology platform provides the company with a variety of preclinical and clinical candidate therapies One end of the bispecific antibody mosunetuzumab targeting CD20 and CD3 can bind to CD20 antigen on the surface of B cells, and the other end can bind to CD3 receptor on the surface of T cells, which can collect T cells to the vicinity of tumor cells, activate T cells to kill tumor cells ▲ about mosunetuzumab (picture source: reference [1]) In clinical trials for patients with aggressive non-Hodgkin's lymphoma (NHL), mosunetuzumab achieved 46% Orr and 19.4% CR It is worth mentioning that 70.8% of the patients with complete remission have been maintained for a long time, and the longest duration has reached 16 months Source: reference [1] According to Genentech, cancer immunotherapy is the fastest growing part of oncology It is expected that in 2025, cancer immunotherapy will account for 32% of oncology market share According to Genentech, the development of cancer immunotherapy can be divided into four waves We have seen the first wave and the second wave of drug development progress, respectively, to establish the efficacy of single drug immunotherapy for major cancer types, and to form combination therapy with existing therapies The third wave of cancer immunotherapy will be the development of a new generation of cancer immunotherapy, and the fourth wave will be the development of individualized cancer immunotherapy with specificity for new antigens Genentech is also actively developing the 3rd and 4th wave of cancer immunotherapy Source: reference [1] We have known that different types of tumors respond differently to immunotherapy, so they are called "hot" tumors and "cold" tumors According to different tumor phenotypes, the strategies of promoting anti-tumor immune response are different ▲ for tumor phenotype, different strategies can be adopted to promote anti-cancer immune response (picture source: reference [1]) For example, one of the targets found by gene tech is an immune checkpoint protein called tigit Tigit is expressed in a variety of immune cells, including CD8 positive T cells, CD4 positive T cells and natural killer cells (NK cells) It is a specific negative regulator of CD226 costimulatory receptor ▲ introduction to tigit (picture source: reference [1]) The expression of tigit is closely related to T cell depletion When tigit inhibitors are combined with anti-PD-L1 therapy (such as tecentriq), it is possible to amplify important T cell subsets called stem like memory cells and prevent or reverse T cell depletion Source: reference [1] This combination has shown good antitumor activity in animal experiments Tecentriq and tigit inhibitors have been used in phase 1b and phase 2 clinical trials The test data is expected to be released in the first half of this year IL-15 β γ / il-15r α developed by Genentech is a cytokine with similar function to IL-2 Compared with IL-2, it can promote the formation of t-memory cells, and will not lead to the expansion of Treg cells with immunosuppressive function It can be combined with tigit inhibitor and tecentriq to promote the expansion of CD8 positive T cells and natural killer cells ▲ introduction to IL-15 β γ / il-15r α (picture source: reference [1]) Because tumor cells accumulate a large number of mutations, they will produce antigens that are not expressed in healthy cells Previous studies have shown that these new antigens can be recognized by T cells, and the input of new antigen-specific T cells can lead to tumor volume reduction Genentech believes that individualized new antigen-specific therapy (inest) will be the development direction of immunotherapy in the future In this aspect, gene tech mainly focuses on two directions: individualized new antigen-specific mRNA vaccine and new antigen-specific cell therapy In cooperation with bintech, Genentech has developed a fully personalized tumor vaccine with new antigen mRNA In clinical trials to treat melanoma patients, the tumor vaccine stimulated a strong T-cell immune response in all patients The clinical trial data of this vaccine combined with tecentriq is expected to be released at this year's AACR annual meeting Source: reference [1] Tumor vaccines based on new antigens still rely on the natural immune response of patients' T cells to new antigens to amplify tumor killing T cells However, T cell therapy based on new antigens breaks through the limitation of natural expansion of T cells in vivo In this therapy, when we get T cells from patients, we find the new antigens in patients' tumors, and then screen the T cell receptor (TCR) to recognize these new antigens, and use genetic engineering to express TCR targeting these new antigens on T cells, and then transfer the expanded T cells back to patients' bodies to kill tumor cells with higher specificity Source: reference [1] Genentech's non oncology research and development pipeline covers neuroscience, ophthalmology, immunology, infectious diseases and other fields In immunology, inflammatory bowel disease (IBD) is one of the focus of research and development IBD is a serious disability complex disease including Crohn's disease (CD) and ulcerative colitis (UC) UC lesions are located in the innermost layer of the large intestine, with a continuous and diffuse distribution Patients will have diarrhea, bloody stool, abdominal pain, fatigue, high fever and other symptoms, which seriously affect the life of patients and may lead to fatal complications CD may affect any digestive tract area from mouth to anus, but it is often found at the end of small intestine and the beginning of colon The treatment of this kind of complex disease needs many kinds of treatment At present, Genentech's R & D pipeline also has several in-depth therapies to treat IBD from different perspectives Multiple methods of gene therapy for inflammatory bowel disease (picture source: reference [1]) Among them, etrolizumab is a humanized monoclonal antibody targeting β 7 subunit of α 4 β 7 and α e β 7 integrin at the same time Etholizumab can specifically antagonize the binding of integrin α 4 β 7 to MAdCAM-1 At the same time, it can also block the interaction between α e β 7 and E-cadherin ▲ introduction to etrolizumab (picture source: reference [1]) The third phase clinical development project of etrolizumab includes up to eight third phase clinical trials In the Bergamot clinical study for patients with Crohn's disease, 70% of the patients in the first cohort were intolerant or resistant to TNF therapy The preliminary results showed that after 6 weeks of treatment, the treatment of etolizumab can make patients enter into the symptom relief period, and the effect can last for 14 weeks The study will continue to register patients and is expected to release trial data in 2021 ▲ phase 3 clinical development project of etrolizumab (picture source: reference [1]) Another in-depth treatment for IBD is a non immunosuppressive therapy Non clinical studies have shown that IL22 FC protein has multiple functions: it can stimulate tissue regeneration by increasing epithelial cell proliferation; enhance mucus production to strengthen intestinal barrier; and it can regulate intestinal flora disorders In phase 1 clinical trials, this in-situ therapy has demonstrated acceptable safety and dose-dependent drug activity in healthy volunteers and patients with ulcerative colitis Currently, it is tested in phase 2 clinical trials ▲ introduction to IL22 FC (picture source: reference [1]) Alzheimer's disease (AD) is the largest neurodegenerative disease in the elderly, and it is also a major challenge difficult to overcome in the medical field In the treatment of Alzheimer's disease, Genentech is not only developing antibodies targeting amyloid protein, but also developing antibody therapy targeting tau protein Tau protein is the main component of neurofibrillary tangles in the brain of AD patients Its abundance in the brain is related to the disease progression and cognitive decline of AD Semolinemab is an anti tau protein antibody, which can help clear the deposition of tau protein in the brain In phase 1 clinical trials, it has shown good tolerance and pharmacokinetic / pharmacodynamic characteristics Currently, it is tested in phase 2 clinical trials ▲ results of semolinemab1 phase clinical trial (picture source: reference [1])
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