Adenosine inhibitors immuno-micro-environment-regulating drugs for tumors (I) : A2aR antagonists.

In recent years, with the listing of a large number of immunocheckpoint inhibitors such as PD-1, PD-L1 and CTLA4 monotophobic, people's understanding of tumor immunotherapy has become more and more adequate, and many tumor patients have gained benefits that were previously impossible through chemotherapy or targeted therapy.
, however, many patients are not able to benefit from immunotherapy because they are poorly responding or resistant to immunocheckpoint inhibitors targeted at PD-(L) 1 or CTLA4 pathways.
new challenge sourcing how to improve their response to immunotherapy for this segment of patients, and it's also a new opportunity for businesses.
CD39-CD73-A2aR pathway, how do you improve the immune response of the patients involved? Researchers have made a lot of attempts and achieved a lot of results, including the development of a new immunocheckpoint inhibitor, adenosine inhibitor immuno-microenvironment regulation drugs, is one of these results.
Figure 1. CD39-CD73-A2aR pathway, derived from reference materials, adenosine inhibitory tumor immuno-environmental regulatory drugs are mainly based on CD39-CD73-A2aR pathway development.
in this pathway, adenosine runs through the entire process and is also responsible for poor immune responses in immune cells.
adenosine is an immunosuppressive metabolite that inhibits the immune response of immune cells by binding to the G-protein conjugate dadeno receptor A2a (A2aR) expressed on immune cells, and the result of this inhibition process in the tumor microenvironment is reflected in the immune escape of tumor cells, which prevents tumor cells from being killed by immune cells. At the same time
, the environment of hypoxia, low PH, high cell renewal, high CD39 and CD73 expression in the tumor microenvironment are all important factors in the high level of adenosine.
cd39 and CD73 are expressed by regulatory Tcells (Treg) as key enzymes for catalyzing adenosine, which can be used to coly hydrolyze the presence of adenosine (adenosine triphosphate, ATP) produced by colysing hydrolysis tissuedue to hypoxia, inflammatory reactions, etc., and then raise the level of adenosine in the tumor microenvironment, and ultimately enhance the immunoflight of tumor cells caused by the above-mentioned pathway.
adenosine-suppressive tumor immuno-environmental regulatory drugs is not difficult to find, in cd39-CD73-A2aR pathway, there are three targets can inhibit tumor cells to obtain immune escape, and the use of PD-(L)1 or CTLA4 monoimmune pathways of immunology inhibitors can enhance the immune response.
Figure 2. Potential targets of the tumor immuno-microenvironment, derived from reference s3 (1) directly inhibit the binding of adenosine to A2aR expressed on immune cells, which is the most direct strategy; (2) inhibittheon of the role of CD39, and thus inhibit the production of adenosine, which is the most fundamental strategy;
all three targets are to achieve the killing of tumor cells by inhibiting the physiological function of adenosine in the tumor immune microenvironment.
based on these three targets, the researchers developed A2aR antagonists, CD39 inhibitors, and CD73 inhibitors.
this article only covers A2aR antagonists, CD39 inhibitors and CD73 inhibitors.
1 A2aR antagonists The in vitro activity of A2aR antagonists has been shown in preclinical studies, and A2aR antagonists can exhibit good antitumor activity either in combination with other immunotherapy drugs.
on the basis of this study, A2aR antagonists have AZD4635, CPI-444, AB928, PBF-509, CS3005, SHR5126, etc. in the clinical stage or clinical application stage.
2 AZD4635 AZD4635 was developed by AstraZeneca and currently has prostate cancer and NSCLC and other indications entering Phase II clinical, its clinical use strategy includes single drug, with PD-L1 monoantiphoresis, and CD73 monoantine.
Figure 3. AZD4635 Chemical Structure Currently, THE NCT02740985 test of AZD4635 has data published.
the study was for patients with solid tumors, and medication options included AZD4635 monodrug or combination Durvalumab (PD-L1 monoab). a total of 38 patients with advanced solid tumors were included in the study
, of whom 15 were treated with AZD4635 and the rest were treated with AZD4635 in combination with Durvalumab.
study found that the maximum tolerable dose of AZD4635 MTD was 100 mg qd in single-drug therapy and combination drug.
common adverse events associated with research drugs (defined as incidence of 15%) are level 1-2 of nausea, fatigue, vomiting, and dizziness.
in eight metastatic deified prostate cancer (mCRPC) patients who were assessed according to RECIST, one case of AZD4635 monodrug therapy reached partial remission (PR), while one patient in combination drug therapy was completely remission (CR) and one case partially remission (PR).
, one of the four patients who could not assess their tumor lesions observed a sustained PSA reduction of 99% in AZD4635 monodrug therapy (PSA, prostate-specific antigen, a marker for prostate cancer tumors).
and in other patients with head and neck cancer, bladder cancer, stomach cancer and sarcoma, patients who had been treated for more than 6 months achieved disease stabilization (SD).
Table 1. AZD4635 related clinical trials 3 CPI-444 CPI-444 developed by Corvus and Roche, currently nSCLC indications into Phase II clinical indications have NSCLC, its clinical use strategy includes single drug, with PD-L1 mono-resistance, with CD73 mono-resistance, and CD38 mono-resistance combination.
Figure 4. The latest clinical advances on CPI-444 on CPI-444 were published in Cancer Discovery in January 2020.
the article mainly analyzed 68 patients with renal cell carcinoma included in the NCT026558222 study, of which 33 patients were treated with CPI-444 monodrug, while the remaining 35 patients received CPI-444 combined Atezolizumab (PD-L1 monoantine) treatment for 5 (1-21.7) months.
all patients were treated with tyrosine kinase inhibitors or PD-(L)1 antibodies prior to entering the study and progressed, with more than 72% of patients being resistant or refractive to PD-(L) 1 antibodies.
results showed that in one patient treated with CPI-444 single drug, 17% of patients reached SD and lasted at least 6 months, median PFS was 4.1 months;
Figure 5. The results of the CPI-444NCT02655822 study, derived from reference materials, corvus also presented the latest data on the treatment of CPI-444 mCRPC at the 2020 ASCO GU Conference.
the report reported 35 mCRPC patients, 11 of whom were treated with CPI-444 monodrug, and the remaining 24 patients receiving CPI-444 combined Atezolizumab (PD-L1 monoantib), with visceral metastasis occurring at the baseline.
one patient's PR (the patient's PSA dropped from 98 to less than 1) in the median follow-up time of more than 3.2 months, seven patients with SD spent more than 6 months, and five patients who still did not reach SD.
Table 2. CPI-444-related clinical trials 4 AB928 AB928 were first developed by Arcus Bioscience.
currently entering stage II clinical indications are rectal cancer and NSCLC, its clinical use strategies include joint PD-1 monoyb, combined mFOLFOX6 chemotherapy, combined polyethyl glycol lipid amycin chemotherapy and so on.
Figure 6. AB928 Chemical Structure According to data released by Arcus at the 2019 ASCO Conference, a total of nine patients were included in ab928 combined polyethyl glycol lipid amycin, AB928 joint mFOLFOX6 chemotherapy and AB928 combined Zimberelimab (PD-1 monotag).
overall, patients were tolerant of AB928's combination therapy, and as of the time the data were reported, only two subjects had been pictured and evaluated to show their SD.
Table 3. AB928-related clinical trials 5 PBF-509 PBF-509 developed by Novartis, currently entering Phase II clinical indications with NSCLC, clinical research strategy for joint PD-1 monotophox.
Figure 7. PBF-509 Chemical Structure Table 4. PBF-509-related clinical trial 6 CS3005 CS3005 was developed by Keystone Pharmaceuticals and is currently conducting an exhibition clinical trial in Australia to assess the safety, tolerance, pharmacokinetics and initial antitumor activity of CS3005 in patients with advanced solid tumors.
Table 5. CS3005 Related Clinical Trials 7 SHR5126 SHR5126 was developed by Hengrui Pharmaceuticals and approved by CDE in February 2020 to obtain a notice of clinical trials for the treatment of patients with solid tumors.
in addition to the domestic, Baiji Shenzhou, re-polar medicine has also developed A2aR antagonists, have relevant patents open.
conclusion is not difficult to find that the current research on A2aR antagonists is still in a relatively preliminary stage, in the research enterprises to use it is also mostly with its own PD-(L) 1 monotonica, CD73 monotonica and CD39 monotonica, as an supplement to autoimmune checkpoint inhibitors.
as far as it stands, the development of A2aR antagonists has the following advantages: (1) the current market competition in this field is small, which also means greater opportunities; Even me-better;3 in today's market PD-1 mono-i-ret, PD-L1 mono-resistance so many cases, there are related products of enterprises can develop A2aR antagonists as a useful supplement to existing products, but no PD-(L) 1 mono-resistance and other products of enterprises in the external also have a broad space for cooperation.
Source Source: OncohemaKey , Robert D. Leone et et al. Targeting for Cancer Immunotherapy. J Immuno Cancer.2018; 6 (1):57. Corvus Pharmaceuticals official website s4) ClinicalTrials.gov s. 5) Abstract CT026: Evidence of immune in the first-first-in-human Phase Ia dose study of the adenosine 2a o'ratsine 2a o'ratonist, AZD4635, in patients with the snod. AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA ( 6) Fong L et al. Adenosine 2A A Borre Blockade as an Immunotherapy for Treatment-Refracto Renal Cell Cancer. CancerDiscov. 2020 Jan;10 (1): 40-53. Corvus Pharmaceuticals Presents Updated Clinical Data from its Phase 1b/2 Clinical Trial of Ciforadenant at the 2020 American Society of Clinical Oncology's Genitourinary Cancer. AB928, a novel dual adenosine eth ataggonist, combined with yr ab122 (anti-PD-1) in patients (pts) advanced with the field: preliminary results from on phaseson I. Title: New immunocheckpoint inhibitor - adenosine-suppressive tumor immuno-environmental regulatory drug (i): A2aR antagonists.