Macrocyclic Peptide-Mediated Blockade of the CD47-SIRPα Interaction as a Potential Cancer Immunotherapy

Hazama, Daisuke; Yin, Yizhen; Murata, Yoji; Matsuda, M.; Okamoto, Takeshi; Tanaka, Daisuke; Terasaka, Naohiro; Zhao, Jinxuan; Sakamoto, Mariko; Kakuchi, Yuka; Saito, Yasuyuki; Kotani, Takenori; Nishimura, Yoshihiro; Nakagawa, Atsushi; Suga, Hiroaki; Matozaki, Takashi

doi:10.1016/j.chembiol.2020.06.008

Cited by 35 publications

(26 citation statements)

References 50 publications

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“…Blockade of CD47-SIRPα interaction has been shown to dramatically enhance tumor cell phagocytosis by macrophage in preclinical models of cancer [ 21 , 22 ]. To investigate whether luteolin can increase the macrophage-mediated phagocytosis of cancer cells, we performed in vitro phagocytotic assay by culturing H929 cells with mouse bone marrow-derived macrophages.…”

Section: Resultsmentioning

confidence: 99%

Luteolin promotes macrophage-mediated phagocytosis by inhibiting CD47 pyroglutamation

Rao

et al. 2021

Translational Oncology

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Highlights Interception of CD47-SIRPα signaling is an elusive yet intriguing goal for anti-tumor immunotherapy since unbiased CD47 blockade by its antibody cannot avoid erythrocyte destruction. We previously reported that isoQC, a Golgi-resident enzyme lacking in mature erythrocyte, disrupts the binding of CD47 to SIRPα by downregulating pGlu-CD47 and its interaction with SIRPα (Cell research 2019. 29:502–505). In this study, we explored the possibility of utilizing isoQC inhibition to address the challenge of CD47 antibody treatment induced anemia. We discovered a new lead compound of isoQC inhibitor, Luteolin, and revealed that posttranslational modification may work as an immunotherapeutic target by abolishing immune checkpoint signaling.

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Section: Resultsmentioning

confidence: 99%

Luteolin promotes macrophage-mediated phagocytosis by inhibiting CD47 pyroglutamation

Rao

et al. 2021

Translational Oncology

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“…With relatively restricted expression, an SIRPα blockade could enhance the macrophage mediated innate immunity with reduced side effects such as anemia. Therapeutics targeting SIRPα including antibodies and macrocyclic peptide are rapidly developing [ 45 ]. PVR, the major ligand of TIGIT, plays a pivotal role in multitudinous biological processes, especially the tumor immune escape.…”

Section: Discussionmentioning

confidence: 99%

Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47/SIRPα and TIGIT/PVR Pathways for Cancer Immuno-Therapy

et al. 2021

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Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8+ T cell in tumor and systematic immune response in the tumor-draining lymph node and spleen in a CD8+ T cell dependent manner. Our research suggests that the anti-hypertensive drug azelnidipine could be repositioned for cancer immunotherapy.

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“…Therefore, blocking the CD47-SIRPα interaction has been indicated to potentially inhibit tumor progression (Hazama et al, 2020;Kauder et al, 2018;Veillette and Chen, 2018). However, CD47 is widely distributed in normal human tissues (especially in blood as represented by red blood cells), which causes certain obstacles to the clinical application of antibody-based treatments.…”

Section: Discussionmentioning

confidence: 99%

Selection and Characterization of FD164, a High-Affinity Signal Regulatory Protein α Variant with Balanced Safety and Effectiveness, from a Targeted Epitope Mammalian Cell-Displayed Antibody Library

Wang

et al. 2021

Mol Pharmacol

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Phagocytic resistance plays a key role in tumor-mediated immune escape, so phagocytosis immune checkpoints are a potential target for cancer immunotherapy. Cluster of differentiation 47 (CD47) is one of the important phagocytosis immune checkpoints, thus, blocking the interaction between CD47 and signal regulatory protein α (SIRPα) hopefully provides new options for cancer treatment. Using computer-aided targeted epitope mammalian cell-displayed antibody library, we screened and obtained an engineered SIRPα variant Fc fusion protein, FD164, with higher CD47-binding activity than wild-type SIRPα.Compared with wild-type SIRPα, FD164 has approximately 3-fold higher affinity for binding to CD47, which further enhanced its phagocytic effect in vitro and tumor suppressor activity in vivo. FD164 maintains the similar anti-tumor activity of the clinical research drug Hu5F9 in the mouse xenograft model. Furthermore, FD164 combined with rituximab can significantly improve the effect of single-agent therapy. On the other hand, compared with Hu5F9, FD164 does not cause hemagglutination, and its ability to bind to red blood cells or white blood cells is weaker at the same concentration. Finally, it was confirmed by computer structure prediction and alanine scanning experiments that the N 45 , E 47 , 52 TEVYVK 58 , K 60 , 115 EVTELTRE 122 , E 124 residues of CD47 are important for SIRPα or FD164 recognition. In a word, we obtained a high affinity SIRPα variant FD164 with balanced safety and effectiveness.

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Macrocyclic Peptide-Mediated Blockade of the CD47-SIRPα Interaction as a Potential Cancer Immunotherapy

Cited by 35 publications

References 50 publications

Luteolin promotes macrophage-mediated phagocytosis by inhibiting CD47 pyroglutamation

Luteolin promotes macrophage-mediated phagocytosis by inhibiting CD47 pyroglutamation

Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47/SIRPα and TIGIT/PVR Pathways for Cancer Immuno-Therapy

Selection and Characterization of FD164, a High-Affinity Signal Regulatory Protein α Variant with Balanced Safety and Effectiveness, from a Targeted Epitope Mammalian Cell-Displayed Antibody Library

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