TargetING CD47: Can small molecules be a heavy burden?

CD47, also known as an integrated protein, is a widely expressed trans-membrane glycoprotein.
tumor cells can express CD47 and bind to the signal-regulating protein α (SIRPa) on the surface of macrophages, sending a "Do not eat me" signal to macrophages to escape attack by the body's immune system.
this, blocking the CD47/SIRP alpha signal is expected to restore the phagocytosphagy of tumor cells.
CD47 has been booming for nearly two years and is already one of the hottest potential tracks in the I-O field.
Source: It is well known that tumor cells can escape T cell surveillance and attack by expressing PD-L1 binding to PD1 on the surface of T cells, thus escaping the surveillance and attack of T cells;
the effect of the target, cd47 just like PD-L1, SIRPa just like PD-1, the similarities between the two are self-evident, which may be one of the reasons why the CD47 track is known as the next "PD-1."
source: To date, CD47 has been found to have been expressed in a variety of hematomas and solid tumor cells, including myeloma, non-Hodgkin's lymphoma, non-small cell lung cancer, acute lymphoblastic leukemia, breast cancer, head and neck squamous cell carcinoma, acute myeloid leukemia, etc.
not be heart-tinging when a wide range of adaptations also foreshadows huge market potential? Brambles: CD47 enthusiasm rekindled CD47 did not become hot as soon as it was discovered, in fact, also walked through the dark moment.
since 1980s, when it was first identified as a tumor antigen for human ovarian cancer, CD47 has been found to be over-expressed in a variety of tumors, and its expression level is associated with the prognosticity of the tumor.
in 1994, Lindberg and Mawby isolated and represented the CD47 protein, especially Mawby's separation process, which now seems to give us more inspiration.
literature shows that Mawby and others used monoclonal antibody BRIC-125 to isolate CD47 glycoprotein from human red blood cells through immunoprecipitation, further enzymatic deglysing showed that CD47 contained N-connected oligosaccharides, and the analysis of protein hydrolytic fragments obtained the amino acid sequence of CD47.
also revealed six potential N-glycosylation points of CD47, five of which were in the IG super-family domain, three of which carried N-polysaccharides in red blood cells.
same time, immunocellular chemical staining of human tissue also showed that CD47 was widely distributed in multiple parts of interstage and endoskin cells.
follow-up clinical studies have exposed this potential.
the end of 2017, Arch Oncology announced the termination of a solid tumor clinical trial in Europe for its CD47 monoantigen Ti-061 due to serious side effects;
these failed studies have also affected the stock prices of companies that lay out CD47 projects such as Forty Seven and Trillium, leading the industry to rethink and even look down on CD47.
: twitter.com The serious clinical side effects of the first generation of CD47 drugs are mainly adverse blood reactions, including a decrease in the number of red blood cells and plateplates.
Thankfully, the company represented by Forty Seven and Trillium did not completely abandon the design and development of the second generation CD47 product in the face of the first generation of drug molecular safety problems, but instead solved the toxic side effects of CD47 antibodies by envisioning a variety of solutions, including designing new antibody fusion proteins, reducing the binding of CD47 to the surface of blood cells, high selection of tumor cell CD47 and activation therapy at start-up doses.
thanks to Forty Seven for the CD47's ability to return to view and get attention.
ASCO 2018 conference, Forty Seven published clinical data on Hu5F9-G4 (magrolimab) combined with Lytoxides in non-Hodgkin's lymphoma, and published the results in the New England Journal of Medicine in November of the same year, the first time clinical data on CD47 antibodies has been published in a top medical journal.
This clinical study focused on evaluating the safety and stability of intravenous magolimab initial doses of 1 mg/kg (pre-exciting dose, priming dose) and weekly maintenance doses (10-30 mg/kg) combined with lysitsi monoantigens and determining phase II study doses.
results showed that of the 22 patients (15 DLBCL, 7 filaving lymphoma), the treatment-related adverse events were mainly level 1 or 2, the most common being anemia and infusion-related reactions.
initial and maintenance dose therapy of magolimab can reduce anaemia (expected targeting effect), dose-restrictive side effects are rare.
at the recommended Phase II dose (30 mg/kg), magrolimab has a approximately 100% share of CD47 receptors in circulating white and red blood cells.
50 per cent of patients showed objective remission, with complete remission (CR) reaching 14 per cent.
2019, Forty Seven presented data on patients with Magolimab combined azasides for primary treatment of high-risk bone marrow growth abnormal syndrome and acute myeloid leukemia that is not suitable for chemotherapy, with ORRs of 92% and 64%, respectively, and CR (CR/CRi) of more than 50%.
adverse events associated with common treatments were anemia (37 per cent), neutral granulocyte reduction (26 per cent) and plateiac reduction (26 per cent).
forty Seven's ongoing clinical results have injected a dose of strong heart needle into the market, allowing CD47 to heat up again.
in early 2020, Gilead paid $4.9 billion for Forty Seven, turning the target from cold to hot and cold, and making a good start to the CD47's performance in 2020.
the FDA in 2020 also granted Magrolimab a breakthrough therapy (BTD) for the newly diagnosed bone marrow growth syndrome.
throughout 2020, CD47-related project transactions and corporate finance, listing news flash screen: March 3: Gilead's $4.9 billion acquisition of Forty Seven; July 1: Saisheng Pharmaceuticals' $120 million acquisition of CenterRx's small molecule immunotherapy RRx-001 for CD47-SIRP alpha; July 17: ALX Oncology available for approximately $290 million in financing and listing; September 4: Tiantian Bio and AbbVie reach a $2.9 billion global strategic partnership on CD47 single-resistance TJC4; September 8: CD47 Star Company Trillium receives $25 million investment from Pfizer, up 40%; October 13: SurfaceOncology receives GSK takeover offer; Willow Dark Flower: CD47 Battle Forty Seven adopts innovative pilot scheme The pre-exciting dose was given to give positive clinical results to the treatment of anti-CD47.
Forty Seven could not have been the only winner on the CD47 development path.
according to The Rubik's Cube NextPharm, there are 72 projects involving CD47 signaling paths worldwide and 45 preclinical projects, including 24 in China.
can say that the Chinese enterprise's super fast follow ability makes the CD47's competitive heat already has the taste of PD-1/PD-L1.
most of the cd47 programs worldwide are currently in early clinical stages, Magrolimab's pre-exciting dose strategy is not appropriate for every product, not to mention Forty Seven's patented layout of the strategy, and companies such as Trillium avoid killing red blood cells And the use of antibody design strategy to reduce the ability of CD47 drugs and red blood cell binding, its clinical real effect is still to be followed up to verify, so the CD47 track is still in a state of war, each player is in a rush to progress, accounting for the mountain, there is not yet a drug unified situation.
will present the development progress of several representative CD47 projects outside Magrolimab in a table, in conjunction with the INFORMATION of the SITC2020 and ASH2020 conferences.
overall, some recent cd47-targeted products have shown promising clinical activity in both solid and hematoma clinical studies, but the side effects of the target should not be taken lightly.
, whether it's innovative clinical research programs or targeted antibody designs, anemia or trans-anemia still occurs.
effective control of this side effect has been achieved, whether antibody drugs can achieve an effective balance between efficacy and safety and realize the clinical value of CD47 has yet to be further clinically verified.
path through: small molecule regulation CD47 just as small molecules are also PD-1/PD-L1 track gradually heating up the development direction, the industry in the search for a balance between cd47 drug efficacy and safety, the small molecule CD47 regulatory drug as a positive attempt.
so far, the fastest progress in small molecule PD-1/L1 drug research has reached Clinical Phase II, while the fastest progress in small molecule CD47 drugs has reached Phase III.
newly published literature in November 2020 shows that several small molecule candidate drugs targeting cd47 path paths are in preclinical or clinical development (see table below).
target CD47 in the study of small molecule drugs Source: References to the mechanism of action of these small molecules are mainly divided into two categories, one is directly combined with CD47, which in turn blocks CD47/SIRPa signals, such as NC0GC0138783, pep-20, D4-2, etc. The other category is to reduce the expression of CD47/SIRPa signal by affecting transcription, translation or post-translation modification, such as RRX-001 by inhibiting the expression of cancer gene at transcription and translation level, PQ912 by inhibiting protein biosynthetic modification, inhibiting protein maturation and making CD47 difficult to play a regulatory function.
Source: References: Small molecule CD47/SIRPa inhibitors may theoretically have an advantage in side effect control due to their short half-life and flexible drug exposure.
However, whether small molecule CD47/SIRPa inhibitors can achieve high selectivity, that is, CD47 targeting the tumor surface instead of red blood cell surface CD47, to avoid the same blood toxicity of antibody drugs, this is also a matter of deep thought and concern.
the vast majority of small molecule CD47 regulators are in the preclinical stage, RRX-001 is currently the only drug entering the clinic and obtaining Phase III clinical data, this paper will only make a brief introduction to the drug.
RRx-001 is a magical little molecule, formerly a "synthetic intermediate" of explosives or rocket fuel, mainly used in the aerospace industry.
who brought RRx-001 into the field of disease treatment was Professor Mark Bednarski, a chemist.
Mark Bednarski, also a bowel cancer patient, had a chance to meet another chemist from ATK Theiokol at a utah ski resort.
ATK Theiokol is a well-known defense and aerospace contractor specializing in the design and manufacture of rocket fuel and military explosives.
the two chatted and painted molecular structures in the snow, one of which was associated with RRx-001, which aroused Professor Bednarski's strong interest! Sharp scientific thinking and intuition tell him that these molecules, which have very unique structures, may have potential medicinal value.
Bednarski believes the unique chemical properties of the RRx-001 molecule may help selectively destroy cancer cells in radiotherapy, and then began research and development of RRx-001 with Dr Susan Knox, a radiation oncologist colleague and co-founder of the company.
Mark Bednarski is a strong advocate and promoter of RRx-001, and thanks to his tireless efforts, RRx-001 has been able to test in five clinical trials of multiple cancer types, including colorectal cancer.
clinical studies have shown that RRx-001 can indeed show clinical benefits in colon cancer, lung cancer and other malignant tumors, and after treatment with RRx-001, patients can re-sensitive to platinum-containing chemotherapy.
Compared to FDA-approved surface genetic therapy drugs such as azatides and volinosine, RRX-001 showed only mild therapeutic side effects, mainly pain at the injection sites of level 1 and 2, with good overall tolerance.
, RRX-001, an epigenetic drug, has been developed by EpicentRX.
However, recent preclinical studies have confirmed that, in addition to its metagenetic effects, RRx-001 can also reduce CD47 and PD-L1 mRNA and associated protein levels, and enhance the phagocytoids' phagocytosphagy and phagocytos, stimulating an anti-tumor immune response.
subsequent case studies have shown that the treatment of RRX-001 showed false disease progression similar to PD-1/L1 immunotherapy and immunocellular immersion, indicating that RRX-001 did play a role in tumor immunotherapy.
RRX-0。