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Research progress of tumor immunotherapy targeting CD47
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Research progress of tumor immunotherapy targeting CD47
CD47, a transmembrane protein, is a cell surface glycoprotein molecule that belongs to the immunoglobulin superfamily and binds to a variety of proteins, including integrin, thrombospondin-1, and signal-regulated protein alpha ( SIRPα ). CD47 is an important tumor antigen and is related to the occurrence and development of various cancers.
Interaction of CD47 with SIRPα triggers ‘don’t eat me’ signaling in macrophages, inhibiting phagocytosis. I
n recent years, accumulating data have shown that the CD47-SIRPα axis is a key immune checkpoint in different cancers including hematological malignancies, similar to PD-1/PD-L1 in solid tumors. CD47-SIRPα blockade has emerged as a next-generation immune checkpoint blockade strategy for various malignancies after PD-1/PD-L1.
However, before becoming the current new focus of the field, the prospects for CD47 were rather bleak a few years ago. In 2017, the European Phase I clinical trial of CD47 mAb Ti-061 ( 2016-004372-22 ) was terminated. Then, in 2018, the CD47 monoclonal antibody CC-90002 failed a Phase I clinical trial ( NCT0264102 ).
Severe hemolysis by CD47 monoclonal antibody is a major problem in these clinical failures. Repeated setbacks make the prospects for developing CD47 for cancer therapy very pessimistic.
In 2019, when the CD47 mAb magrolimab and azacitidine were combined in the treatment of acute myeloid leukemia ( AML )/myelodysplastic syndrome ( MDS ), it showed excellent and sustainable efficacy with manageable hematologic toxicity.
Since then, the development of CD47-targeted drugs has gained a new lease of life and entered a new era.
Structure and ligands of CD47
CD47 is a glycosylated transmembrane protein expressed in various cell types. CD47 belongs to the immunoglobulin superfamily and is a supramolecular complex composed of integrins, G proteins and cholesterol.
The structure of CD47 includes an extracellular variable region that interacts with corresponding ligands, a transmembrane region formed by a highly hydrophobic transmembrane segment, and a hydrophilic carboxyl-terminal intracellular region.
After activation of CD47, it can mediate cell proliferation, migration, phagocytosis and A series of processes including apoptosis, immune homeostasis and inhibition of NO signaling.
Ligands for CD47 include SIRPα, thrombospondin-1 ( TSP-1 ) and integrins ( αvβ3 and α2β1 ). SIRPα, also known as SHPS-1, is a transmembrane protein whose extracellular domain contains three immunoglobulin superfamily-like domains: an NH2-terminal V-domain and two C1-like IgSF domains, NH2 The terminal domain is capable of binding to CD47.
SIRPα is highly expressed on the membrane of myeloid cells, such as macrophages, granulocytes, monocytes and myeloid dendritic cells. It regulates cell migration and phagocytic activity, as well as immune homeostasis and neural network formation.
TSP-1 is a homotrimeric multi-domain extracellular matrix glycoprotein belonging to the extracellular secretory protein family, consisting of a variety of domains known to bind extracellular matrix components and cell surface receptors.
TSP-1 is secreted by platelets, monocytes, macrophages and various other non-hematopoietic cells. Binding of TSP-1 to CD47 results in changes in intracellular calcium ion concentrations and cyclic adenylate/cyclophosphine concentrations that regulate cell survival and migration, and TSP-1 also induces cellular responses to tissue damage.
Pathophysiological function of CD47
Cancer cells take advantage of the “don’t eat me” function of CD47 and express higher levels of CD47 on the surface than non-malignant cells; numerous studies have shown that CD47 is overexpressed in different types of tumors, including myeloma, leiomyosarcoma, acute lymphoblastic leukemia , non-Hodgkin lymphoma, breast cancer, osteosarcoma, head and neck squamous cell carcinoma. High CD47 expression levels correlate with treatment response and prognosis of cancer progression.
The expression of CD47 is used by macrophages to distinguish ‘self’ or ‘non-self’. CD47 is expressed on the surface of non-malignant cells and various cancer cells, and can bind to the SIRPα transmembrane protein on myeloid cells ( especially macrophages ) to form the CD47-SIRPα signaling complex.
The extracellular IgV domain of SIRPα binds to CD47, resulting in tyrosine phosphorylation at the intracellular ITIM motif; SIRPα also binds to the SH2 domain containing tyrosine phosphatase, and both signals inhibit myosin IIA accumulates at phagocytic synapses and promotes the release of “don’t eat me” signals that inhibit macrophage-mediated phagocytosis and protect normal cells from damage by the immune system.
Conversely, when surface expression of CD47 is reduced, the CD47-SIRPα signaling pathway is attenuated, and macrophages can move toward and engulf these cells.
CD47 on normal erythrocytes binds to SIRPα on the surface of macrophages to generate inhibitory signals that prevent phagocytosis, but when erythrocytes become senescent, CD47 expression levels decrease, and senescent erythrocytes deficient in CD47 are considered foreign and are removed by erythrocytes in the spleen.
Macrophages are rapidly cleared. CD47 and its ligands not only regulate immune responses, but also mediate various pathophysiological processes, such as neutrophil chemotaxis and nervous system development, and play regulatory roles in immune tolerance and T cell activation.
Clinical progress of targeted CD47 therapy
In recent years, clinical research on CD47 monoclonal antibody has been carried out rapidly in the United States. As of August 28, 2021, 46 clinical trials of CD47-targeted therapy were registered in clinical trials. Patients with different types of cancer were studied in these clinical trials, including 29 trials in solid tumors and 14 trials in hematological malignancies and 3 mixed trials.
CC-90002 is the first-generation humanized anti-CD47 antibody to enter clinical research. The first clinical trial of CC-90002 ( NCT02641002 ) was terminated in late 2018 because its preliminary monotherapy data in R/R AML and high-risk MDS failed to provide sufficient evidence for further dose escalation/expansion. CC-90002 was restarted in a clinical trial ( NCT02367196 ) after modifying the dosing strategy and other procedures .
CC-90002 does not promote HA while maintaining high affinity binding to CD47 and inhibits CD47-SIRPα interaction. Studies on a panel of hematological cancer cell lines show concentration-dependent CC-90002-mediated phagocytosis in lenalidomide-resistant MM cell lines and patient AML cells. In non-human primates, CC-90002 exhibited acceptable pharmacokinetic properties and a favorable toxicity profile. These data demonstrate the potential activity of CC-90002 in hematological malignancies and provide the basis for clinical studies CC-90002-ST-001 ( NCT02367196 ) and CC-90002-AML-001 ( NCT0264102 ).
Hu5F9-G4 ( 5F9, Magrolimab ) is a humanized IgG4 antibody that targets CD47 with high affinity. 5F9 induces macrophage-mediated phagocytosis of primary human AML cells in vitro and completely eradicates human AML in vivo . 5F9 has entered clinical trials in patients with AML and solid tumors ( NCT02216409 ).
Studies have shown that Hu5F9-G4 alone or in combination with other antibodies may cause unexpected death of normal hematopoietic cells. For safety reasons, 5F9 has been designed with an improved dosing regimen. When 5F9 was used as monotherapy, response rates were relatively low in patients with relapsed/refractory AML/MDS and solid tumors.
This may be due to the reduced affinity of IgG4 for Fcγ receptors on macrophages, thereby limiting antibody-dependent cellular phagocytosis (ADCP). In addition, plasma samples from patients treated with Hu5F9-G4 showed strong responses to all red blood cells and platelets.
Another phase Ib/II clinical trial in 75 patients with R/R non-Hodgkin lymphoma showed an objective response rate ( ORR ) of 49% and a complete response rate ( CR ) of 5F9 in combination with rituximab 21%. In another phase Ib study, in combination with the DNA demethylating agent azacitidine, ORR was 100% and CR was 55% in 11 untreated MDS patients and 14 untreated AML patients The CR was 64%.
TTI-621 Japanese TTI-622
TTI-621 is a CD47-targeting SIRPα fusion protein that blocks CD47 through a decoy receptor ( SIRPα-Fc ). Clinical trials of TTI-621 in relapsed and refractory hematological malignancies demonstrated that systemic administration of TTI-621 resulted in CD47 blockade and a dose-dependent increase in phagocytosis-related cytokines, which correlated with transient reversible thrombocytopenia disease-associated, indicating enhanced macrophage-mediated clearance of circulating platelets, followed by a robust bone marrow regenerative response.
Phase I study of TTI-621 in combination with rituximab in 164 patients with B-cell non-Hodgkin’s lymphoma ( B-NHL ) showed that TTI-621 in combination with rituximab was effective in R/R B-NHL and T Cellular non-Hodgkin lymphoma ( T-NHL ) patients were well tolerated and showed good monotherapy activity in R/R B-NHL patients. ORR was 13% for all patients, 29% ( 2/7 ) for diffuse large B-cell lymphoma ( DLBCL ), 25% (8/32) for TTI-621 monotherapy in T-NHL, and 25% ( 8/32 ) for DLBCL The ORR of TTI-621 combined with rituximab was 21% ( 5/24 ).
Meanwhile, a phase I dose-escalation study of another CD47 receptor blocker TTI-622 in patients with advanced R/R lymphoma showed that one patient with stage 4 non-germinal center B-cell DLBCL initially achieved PR at week 8, CR was achieved at week 36.
The difference between these two drugs is the different Fc subtypes. TTI-621 and TTI-622 use IgG1 Fc and IgG4 Fc, respectively.
Since the interaction between the IgG4 Fc region of TTI-622 and the Fc receptor is more limited than that of IgG1, it is speculated that TTI-622 will deliver a milder “phagocytic” signal to macrophages.
ALX148 is a decoy receptor fusion protein consisting of a mutated SIRPα domain that binds CD47 with high affinity and an inactive Fc domain that alleviates HA and anemia.
Results to date suggest that ALX148 is generally well tolerated with moderate adverse events when administered in combination with other anticancer drugs, such as Herceptin and Keytruda , in patients with solid tumors.
Although no complete or partial responses were observed with monotherapy, the partial response rate was 22% in patients with HER2-positive gastric cancer in combination with trastuzumab and 16% in HNSC patients in combination with pembrolizumab.
Recent clinical data show that combining ALX148 with a standard dosing regimen of trastuzumab, ramucirumab, and paclitaxel has initially demonstrated a promising objective response rate of 72% and an estimated 12-month OS of 76%. Maximum tolerated dose not reached.
AO-176 is a humanized anti-CD47 monoclonal antibody. AO-176 not only binds preferentially to tumor cells over normal cells, and binds to tumors more efficiently in an acidic microenvironment ( low pH ), but also directly kills tumor cells in a cell-autonomous manner, rather than antibody-dependent cells Toxicity ( ADCC ). Compared with other CD47 blocking antibodies, AO-176 binds negligibly to erythrocytes and does not induce HA and transient anemia.
A first-in-human study in patients with advanced solid tumors demonstrated that AO-176 is a well-tolerated anti-CD47 therapy with durable antitumor activity observed. Currently, clinical trials of AO-176 in combination with paclitaxel in selected solid tumors ( NCT03834948 ) and multiple myeloma ( NCT04445701 ) are ongoing.
SRF231 is a fully human IgG4 anti-CD47 antibody previously granted orphan drug designation by the FDA for the treatment of patients with multiple myeloma.
SRF231 has dual antitumor activities: SRF231 can bind to CD32a on macrophages to induce FcγR-mediated phagocytosis of cancer cells, and it acts as a scaffold to deliver CD47-mediated death signals to tumor cells. Preclinical studies have shown that SRF231 can bind to CD47 with high affinity, kill cancer cells in vitro, and has strong anti-tumor activity.
Furthermore, a potential safety advantage of SRF231 is that it does not cause detectable hemagglutination or phagocytosis.
TG-1801 is a bispecific antibody against CD19 and CD47. By targeting CD47 and CD19 in combination, TG-1801 has the potential to overcome the limitations of existing CD47-targeted therapies and avoid the side effects of indiscriminate blocking of CD47 on healthy cells. Currently, TG-1801 is undergoing two Phase I clinical trials ( NCT03804996 and NCT04806305 ).
BI 765063 ( OSE-172 ) is a humanized IgG4 monoclonal antibody antagonist of SIRPα that blocks the SIRPα/CD47 axis. BI 765063 was a single-agent dose-escalation phase I study in 50 patients with advanced solid tumors, including ovarian, colorectal, lung, breast, melanoma and kidney tumors, and showed a well-tolerated safety profile, Pharmacokinetics and Efficacy. 1 patient with hepatocellular carcinoma ( HCC ) with liver and lung metastases and 7 previous treatments showed partial remission lasting 27 weeks after treatment.
There are other CD47 mAbs or doublets and fusion proteins in clinical trials, such as DSP107 ( NCT04937166, NCT04440735 ), IMC-002 ( NCT04306224 ) and STI-6643 ( NCT04900519 ).
Challenges of targeting CD47 in antitumor therapy
Preclinical studies using anti-CD47 antibodies in mice and rhesus monkeys have shown that these therapies are well tolerated.
However, in 2017, Arch Oncology terminated the phase I/II clinical trial of the anti-CD47 monoclonal antibody Ti-061, and in 2018, Celgene terminated the clinical trial of the anti-CD47 monoclonal antibody CC-90002 in the treatment of AML.
Given the widespread expression of CD47, potential issues with the use of anti-CD47 antibodies as anticancer therapy include possible off-target effects such as anemia. CD47 is also expressed on non-malignant cells of the hematopoietic system, including normal erythrocytes, senescent erythrocytes, and platelets.
Buatois et al. showed that Hu47F9-G4 alone or in combination with other antibodies could cause the unexpected death of normal red blood cells, potentially leading to anemia.
However, the toxicity of anti-CD47 antibodies appears to be Fc-dependent, given that anti-CD47 antibodies and SIRPα-Fc fusion proteins cause this toxicity, whereas high-affinity SIRPα monomers do not.
These findings suggest that future research should focus on optimizing the structure of anti-CD47 therapeutics with a view to designing new drugs without adverse side effects.
In addition, considering that aged RBCs may be more easily phagocytosed, patient age should be considered in future studies of CD47/SIRPα-targeted therapy.
The so-called “antigen silencing” effect may also pose problems for the development of anti-CD47 therapy.
The ubiquitous expression of CD47 means that a drug may require large initial doses and/or frequent dosing to achieve effective CD47 blockade. In addition, compared with CD47, SIRPα has a more limited histological distribution, which may make it less toxic and more blocking when targeted therapy.
However, the side effects of SIRPα in the central nervous system should be considered. Furthermore, cross-reactivity with other SIRP family members ( SIRPβ and SIRPγ ) is possible due to sequence similarity, and while at least 10 polymorphisms have been identified in human SIRPα, the consequences of targeting these different receptor subtypes are unclear .
In future studies, approaches to targeting CD47 and its ligands, especially tumor cells, should be investigated; these approaches may include novel drug carriers such as modified biomimetic nanoparticles or quorum-sensing bacteria.
In addition to new methods of administration, intratumoral administration also has the potential to lead to greater drug delivery and efficacy and reduced toxicity compared to intraperitoneal or subcutaneous routes of administration.
As noted above, the challenges of anti-CD47 therapy have led to investigations into the use of combination therapies, including tumor cell-specific opsonizing antibodies and T-cell checkpoint inhibitors.
For example, in a mouse model of non-Hodgkin lymphoma, an anti-CD47 antibody ( BRIC126 or B6H12 ) combined with an anti-CD20 antibody ( rituximab ) resulted in ablation of human lymphoma cells in a xenograft tumor model.
These approaches can be used to increase tumor specificity and reduce targeted toxicity to CD47-expressing non-malignant cells. In a similar approach, another bispecific antibody targeting CD47 and CD19 ( NI-1701 ) was designed for B-cell lymphoma and refractory leukemia, while a fusion protein targeting CD47 and PD-L1 also Proven antitumor efficacy by activating adaptive immune responses.
CD47-SIRPα signaling enables malignant cells to evade macrophage-mediated phagocytosis, inhibition of the CD47-SIRPα signaling axis is a promising strategy for cancer treatment, and a variety of CD47-targeting drugs have entered clinical trials.
However, a series of challenges remain for this type of treatment, including safety concerns, and the signaling mechanisms upstream and downstream of the CD47-SIRPα complex are not fully understood.
Therefore, a better understanding of the mechanisms by which tumor cells evade immune clearance, as well as improved routes of administration of anti-CD47 drugs, will facilitate the development of new and effective anticancer therapeutics that enhance phagocytosis of malignant cells.
1. Advances in Anti-Tumor Treatments Targeting the CD47/SIRPα Axis. FrontImmunol. 2020; 11: 18.
2. Targeting CD47 for cancer immunotherapy. JHematol Oncol. 2021; 14: 180.
Research progress of tumor immunotherapy targeting CD47
(source:internet, reference only)