Adenosine-inhibited tumor immuno-micro-environmental regulatory drugs (III): CD39 inhibitors

TextsTo the eastwith the progress of research on PD-1/PD-L1 and CTL-4 in the field of tumor immunotherapy, immunotherapy has become one of the main directions to combat cancerHowever, existing cancer immunotherapy methods are inefficient, inefficient or inactive to many "cold" tumors, and in recent years scientists have been digging deep into the resistance behind tumor immunotherapyThe study found that one of the main reasons for the poor response of tumor immunotherapy is the presence of immuno-suppressing cells in the tumor microenvironment, which causes tumor cells to escape the destruction of immune cellsadenosine is one of the important substances that produce tumor immunosuppression in the tumor microenvironment, which inhibits the immune activity of immune cells by binding to A2a receptorsIn the process of adenosine production, there are two important key links: 1When the body has tissue disorders (e.ginflammation, malignant tumors, etc.), atap in the cell is released in large quantities outside the cell, these ATP will be external nucleotide hydrolysis CD39 hydrolysis into ADP and AMP; 2AMP then in cd73 synergy down the phosphoric acid to produce immunosuppressed adenosineCD39 is the speed-limiting enzyme of the above process, that is, if it inhibits its physiological function, it can fundamentally inhibit the production of immunosuppressive adenosine, thus destroying the tumor immune escape mechanismBased on the above mechanism, the researchers developed CD39 inhibitors, the current global clinical phase of the relevant drugs including IPH5201, TTX-030, SRF617 and so on, in general, the research drugs for this target are currently few, and its clinical progress is in phase IIPH5201 was developed by Innate Pharma, which in October 2018 signed a joint development agreement with AstraZeneca to further develop and co-commercialize IPH5201Based on this collaboration, the two companies conducted a clinical study in which their clinical use strategies were IPH5201 monodrug, joint Durvalumab, joint Durvalumab and Oleclumabthis clinical study is based on pre-clinical data on IPH5201 presented at the 2019 Cancer Immunotherapy Society (SITC) Conference, which shows that IPH5201 combined PD-L1 monotonicas show stronger anti-tumor activity compared to PD-L1 monoantiticsAccording to an article published by InnatePharma in Cell Reports, the researchers also found that Oshalip and IPH5201 were linked to improved survival in mice and effectively inhibited tumor growthTable 1 IPH5201 related clinical trials TTX-030 was developed by Tizona Therapeutics, and in January 2019 AbbVie and Tizona Therapeutics jointly announced a global strategic cooperation agreement to jointly develop and promote target TTX-030 Currently, there are two clinical trials related to TTX-030, mainly for solid tumors, lymphomas, the main clinical use strategies are TTX-030 single drug, joint Pembrolizumab, joint Docetaxel, joint Gemcitabine and nab-Paclitaxel, joint Dudiglimaab and so on In a paper published by Cancer Discovery at the end of 2019, Tizona used CD39 antibodies in mice and humans to demonstrate that antibodies inhibit EDP metabolism in CD39 in in vivo and external trials A series of mouse and humanized tumor models were then used to show that targeted CD39 signals played a significant inhibitory role in tumor growth, some of which included the enhancement of extracellular ATP and inflammatory-mediated tumor immunity, and subsequent clinical trials were initiated The study provides new ideas for further exploration of tumor immuno-monotherapy or combination-targeted therapy Table 2 TTX-030-related clinical trials SRF617 was developed by Surface Oncology as a monoantinodrug There is currently a clinical trial related to solid tumor SRF617, and the clinical use strategy is SRF617 single drug Recently, Surface Oncology has partnered with MsD to evaluate the safety and efficacy of SRF617 and Mercadon's heavy PD-1 inhibitor Keytruda for patients with solid tumors This combination of therapies will be part of the first Phase 1/1b clinical study of SRF617, focusing on cancer patients who are resistant to gastric cancer and checkpoint inhibitors In preclinical studies, Surface Oncology found that when given SRF617 3mg/Kg, 10mg/Kg, 30mg/Kg dose, and isotype control in tumor model mice, SRF617 relative to isotype control in multiple dose groups significantly reduced tumor growth volume (p 0.0001) as the study time increased Table 3 SRF617 related clinical trials the tumor immune microenvironment CD39-CD73-A2aR pathway as the current cutting-edge drug target path, there are many innovative drug companies in the international community for this area of exploration, and developed more than one product, including the representative companies are Corvus Pharmaceuticals, Arcusscience, Surface, Innate Pharma, etc , and in the domestic hengrui Pharmaceuticals, Keystone Pharmaceuticals, Tianyi biological layout is also in the field Corvus Pharmaceuticals is a clinical biopharmaceutical company focused on the development and commercialization of tumor immunity CPI-444 (aka Ciforadenant, A2aR antagonists), CPI-006 (CD73 inhibitor), CPI-818 (ITK inhibitor), CPI-182 (CXCR2 antibody), CPI-935 (A2bR antagonists) have been developed Arcus Biosciences is also a biotech company dedicated to the development of cancer drugs AB928 (A2aR antagonists), AB680 (CD73 inhibitors), AB154 (TIGIT monoantisay), Zimberelimab (PD-1 monotag) have been developed Surface Oncology is a biopharmaceutical company that develops new immunotherapy for immunosuppressive tumor microenvironments NZV930 (aka SRF373, CD73 inhibitors), SRF617 (CD39 inhibitors), SRF388 (IL-27 inhibitors), SRF813 (CD112R inhibitors) have been developed Innate Pharma, a commercial-phase biotechnology company focused on cancer therapy, is dedicated to developing therapeutic antibodies that fight cancer through the immune system to improve patient treatment and clinical outcomes IPH5301 (CD73 inhibitors), IPH5201 (CD39 inhibitors), IPH5401 (C5aR inhibitors), Monalizumab (NKG2A monoid), IPH4102 (KIR3DL2 antibodies), etc have been developed Hengrui Pharmaceuticals is known as the domestic "research and development of a brother", its rich research and development pipeline has been praised by the industry, but at present, its products are mostly me-too drugs, although with its dominant local sales team of these me-too drugs can also achieve good sales, but with the implementation of policies such as tape procurement, the market prospects of me-too drugs have gradually darkened Facing the market, policy-driven innovation situation, Hengrui Pharmaceuticals is also deepening its own innovation capabilities, tracking emerging targets continue to add to its own research and development pipeline, in this stage, also born such as SHR5126 (A2aR antagonists) and other results Unlike some innovative pharmaceutical companies with limited research and development pipeline products, it is difficult to form complementary advantages between products, SHR5126 (A2aR antagonists) can be combined with Hengrui Pharmaceuticals' own Carriju monotagate (PD-1 monotag) and SJR-1316 (PD-L1 mono-reactor) to maximize the potential of the development of products Keystone Pharmaceuticals is a biopharmaceutical company focused on the development and commercialization of innovative oncology immunotherapy and precision therapy drugs, which has established a rich product pipeline of 15 tumor candidate drugs with the combination therapy of tumor immunotherapy as its core CS3005 (A2aR antagonist) is one of the drugs in the research, and was approved for phase 1 clinical trial in Australia in December last year Recently, CS3005 tablets have also been granted two clinical lycived licenses in China for the treatment of a variety of advanced solid tumors in combination with other drugs such as anti-PD-1 monotoids, protease inhibitors, etc CS3005 can also be combined with products such as CS1001 (PD-L1 mono-d), CS1003 (PD-1 mono-resist) and CS1002 (CTLA-4 mono-resistance) in the Cornerstone Pharmaceutical research and development pipeline to expand the market potential of these products , Tianyi Bio, an innovative biopharmaceutical company focused on tumor immunity and autoimmune biology, has also developed a number of products for these two areas of Tianyi biology, of which TJ004309 (CD73 monogenita-- is one of them Although Tianyi bioself does not have immunocheckpoint inhibitors to be used in conjunction with TJ004309, it has partnered with Junshi Bio to conduct Phase I/II clinical trials for solid tumors in conjunction with its Trepri monotogenic (PD-1 monotogenic) program it is not difficult to find that the development of CD39 inhibitors in the world is still at a relatively early stage, compared with the development of A2aR antagonists and CD73 inhibitors in the tumor immunoenvironment CD39-CD73-A2aR pathway, CD39 inhibitors have many places to explore the same, for the CD39-CD73-A2aR path of the three targets, many innovative companies focusing on this area have developed a number of products, but so far no products have been marketed to verify the clinical effect of this pathway It can be said that this path is a road of challenges that both dangerous and opportunity coexist, and more companies are still waiting to challenge and explore Title: New Immunocheckpoint Inhibitor - Adenosine Inhibitory Tumor Immuno-Micro-Environmental Conditioning Drug (III): CD39 Inhibitor