Antib Ther: Clinical application potential for CD47-SIRP alpha macrophage immunophhagic immune checkpoint pathway target blocking

Recently, Antibody Therapeutics, a journal of the Chinese Antibody Association and published by Oxford University Press, published a review paper entitled "Macrophage checkpoint blockade: a perspective on the results from the initial clinical trials and on CD47-SIRP structure-function"is worth mentioning: Antibody Therapeutics published a review paper on CD47/SIRP alpha by Professor Zhu Yuwen of Fudan University in 2018
, entitled "Insights into CD47/SIRP alpha axis-targeting immunotherapy" (https://academic.oup.com/abt/article/1/2/37/5085238)CD47/SIRP alpha has made rapid progress in recent yearsBased on the analysis of CD47-SIRP alpha structure and functional characteristics, combined with the currently known preclinical results and clinical data, the authors review and look forward to the research strategy and direction of CD47-SIRP alpha macrophage immunodeficiency path blockingThis article is intended to provide a brief introduction to this overviewThe abstract and highlights of the papermacrophage immune checkpoint pathway is a signal-regulating protein alpha (SIRP alpha) expressed on the surface of macrophages and expressed in cd47 on the surface of the target cell to form an anti-phage signal axisIn the past decade, cd47-SIRP alpha signaling pathways have become a potential target for tumor therapy, and several candidates for CD47 and SIRP alpha have been developed in preclinical and clinical studiesThe results of several preclinical trials showed that the single therapy of targeted CD47 showed some therapeutic effect on the homogenic mouse modelBut clinical trials have found that, with the exception of some skin cancers and peripheral lymphoma, single-treatment cd47 is ineffective for most tumorsAnd combination therapy, such as targeted CD47 antibody-resistant anti-CD20 antibody lytuxixim, can effectively treat lymphoma, is a more promising treatment strategyThis review analyzes the structure and binding key characteristics of CD47-SIRP alpha, summarizes the current preclinical and clinical trial data, and points out the future research strategies and directions in this fieldthis review paper includes the following aspects
1, CD47 structure and function
2, THE structure and function of SIRP alpha
3, CD47 and SIRP alpha binding and other ligand 4, immune checkpoint CD47-SIRP and its inhibitors 5, immune checkpoint CD47-SIRP The current status of alpha clinical research 6, the relationship between the sequence, structure and function of immunocheckpoint CD47-SIRP alpha
7, the future cd47-SIRP alpha immunocheckpoint inhibitor development outlook introduction
authors cut into the current clinical deficiencies of T cell tumor immunotherapy It is pointed out that macrophages also play an important role in tumor immunotherapy Macrophages are widely present in solid tumors and clear target cells by activating phagocytosis Among them, the "balance" between macrophages SIRP alpha and target cell CD47 controls the phagocytocyte's phagocytosis on the target cell In this review, the author analyzes the sequence, structure and function of SIRP alpha and CD47, discusses the role of SIRP alpha-CD47 in the body's inherent immune system, and summarizes the current therapeutic antibody and clinical use strategies for SIRP alpha-CD47 1, CD47 structure and function CD47, also known as an integral-related protein, is widely expressed in normal and diseased tissues CD47 belongs to the Ig super family member, is a membrane receptor glycoprotein consisting of the N-end extracellular IgV-like domain, 5 transmembrane spirals, and C-end cytoplasmic tail regions Cd47's main receptors are in three categories: 1 integrator; 2 platelet reactive protein-1; 3 SIRP alpha; CD47's binding with the receptor affects cell adhesion, migration, inflammatory regulation, and phagocytosis When red blood cells are missing CD47, they can be quickly removed by the spleen macrophages, so CD47 was first discovered as a "self-identification" sign The signaling pathway formed by CD47 and SIRP alpha and its action is shown in Figure 1 (Original English Figure 1) Figure 1, the "Don't eat me" signaling pathway and its role in the inherent immune system 2, the structure and functional of SIRP alpha
SIRP alpha is also a member of the Ig superfamily, a transmembrane protein that is mainly expressed in myelinal hematopoietic cells such as macrophages, mononucleosis, dendritic cells, and the surface of granulocytes SIRP alpha has three Ig super-family domains, an N-end V-like domain (D1) and two C1-like domains; SIRP alpha has several ligands, including CD47, Sp-A and Sp-D Studies have found that SIRP alpha is also involved in insulin secretion and muscle formation, but what is most clearly explained is that SIRP alpha inhibits macrophages by binding CD47 to other cell surfaces 3, CD47 and SIRP alpha In the genus of rats, rabbits and humans, CD47 is the most important ligand of SIRP alpha, but the affinity is not high The author summarizes the ligands and their affinity for CD47 and SIRP alpha, which are currently known (Table 1, English original Table 1) In general, the N-side IgV domain of CD47 is combined with the D1 domain of SIRP alpha Through the analysis of X-ray crystal structure, three specific high density binding sites of CD47/SIRP alpha complex sit between the BC, CD, DE and FG ring areas of CD47 beta-chain FG and SIRP alpha In addition, other ligands such as integrator, platelet reactive protein-1 and platelet reaction protein-1 derived peptides are also combined with CD47 through CD47's N-end IgV domain SIRP alpha can also be combined with ligands Sp-A and Sp-D, respectively It has been found that Sp-D is bound with the D3 domain of SIRP alpha, but it is not clear that the domain of Sp-A and SIRP alpha is bound Table 1, CD47-SIRP alpha ligand affinity 4, immune checkpoint CD47-SIRP alpha and its inhibitors immunosuppressive signal CD47 binding to SIRP alpha, phosphorylation SIRP alpha ITIM matrix sequence, and then recruit and activate cytoplasm phosphatase SHPassase SHP-1 and SHP-2, phosphoric acid downstream including pile protein, non-smooth muscle-muscular sphere 2A and other macrophages When IgG activates the Fc receptor, it "swallows synaptic synapses" on the cell surface by rapid skeleton recombination and signal protein accumulation within macrophages, thus swallowing target cells, bacteria, particles, etc The author summarizes the currently known immunocheckpoint inhibitors of CD47-SIRP alpha, such as humanized anti-CD47 antibodies, anti-SIRP alpha antibodies, SIRP alpha fusion proteins, etc (Original Table 2) 5, the current clinical study of immune checkpoint CD47-SIRP alpha
30 years ago, in ovarian cancer patients, the first detection of radioactive element-labeled antibody antibodies can identify tumors The study opened the door to research into the treatment of tumors by CD47 Then, for decades, CD47 has become a potential target for cancer immunotherapy in clinical studies Several clinical phases 1 and 2 trials of targeted CD47-SIRP alpha are being carried out In this paper, the authors reviewed the key strategies and results in these trial reports and found that anti-CD47 monotherapy had no significant therapeutic effect on most tumors and often led to significant reductions in red blood cells Combined therapies, such as Hu5F9-G4 combined ritrusion, can effectively improve the patient's objective remission rate and complete remission rate and treatment of tumors, is a more promising treatment strategy At the same time, the authors also provide an in-depth summary of clinical trials based on individual or joint applications of candidate drugs such as TTI-621, TTI-622, CC-90002, ALX148, etc (Table 2, Table 3) Table 2, clinical trial spree of CD47-SIRP alpha therapeutic antibodies
6 The sequence, structure and function of the immune checkpoint CD47-SIRP alpha explore the end residuals that affect the binding and function of CD47 and SIRP alpha, which is of great significance to the development of new checkpoint inhibitors Through sequence comparison and crystal structure analysis, the author reveals the structural basis of the binding of CD47 and SIRP alpha and its ligands across genus (Figure 2) the crystal structure of figures 2, CD47 and SIRP alpha and their inhibitors 7, the future CD47-SIRP alpha immunocheckpoint inhibitor development prospects with the deepening of research, more and more targeted immunocheckpoint CD47-SIRP alpha monotherapy and combination therapy into clinical trials This reflects the current clinical demand for new, safe and effective cancer immunotherapy drugs and technologies The current immune checkpoint CD47-SIRP alpha inhibitor test data show that we still need to further find more suitable and better candidates The authors believe that more promising drugs will be developed in the coming years to meet growing clinical demand References 1 AbdelAziz R Jalil, Jason C Andrechak, Dennis E Discher, Macrophage checkpoint blockade: a perspective on initial from clinical trials and on CD47-SIRP alpha structure-function Antibody Therapeutics, 2020, 3, 80-94 2 Zhang, X.; Fan, J.; Ju, D Insights into CD47/SIRPa axis-targeting tumor immunotherapy Antibody Therapeutics 2018, 1, 27-32 3 Feng, M., Jiang, W., Kim, B.Y.S et al Phagocytosis checkpoints as new targets for cancer immunotherapy Nature Reviews Cancer 2019, 19, 568-586 Chinese Translator: Zhang Xuyao, Li Yubin, Chinese Review: Wang Shouye Chinese Editor: Wang Baolong Author: Chinese Antibodies Source: Chinese Antibodies