CD47, an immunoglobulin also called integrin-associated protein (IAP), is a tumor-associated antigen (TAA) expressed on the surface of normal, healthy, hematopoietic stem cells (HSC) and over-expressed on the surface of many types of solid tumors. It forms a signaling complex with signal-regulatory protein α (SIRPα), which consists of three immunoglobulin-like extracellular domains and putative tyrosine phosphorylation sites in the cytoplasmic region.

SIRPα is widely expressed on cellular surfaces of myeloid cells including several types of macrophages.[1] And in the treatment of cancer and hematological malignancies this CD47/SIRPɑ signaling complex is associated with poor prognosis disease progression and metastasis.[1]

CD47 was first identified inn the 1980s as a tumor antigen on human ovarian cancer. [2]. Following the initial discovery, CD47 has been found to be over-expressed on multiple solid tumors, including breast cancer [3], pancreatic ductal adenocarcinoma (PDAC) [4], nonsmall cell lung cancer (NSCLC) [5][6] and hematologic malignancies including chronic myeloid leukemia (CML), non-Hodgkin’s lymphoma (NHL), [7] and multiple myeloma. [8]

“Do not eat me’ -signal
Over-expression of CD47 on the surface of tumors cells allows malignant cells to escape innate immune surveillance through a process of evasion of phagocytosis by interacting with SIRPα on myeloid cells. This allows cancer cells exploit the “do not eat me signal” provided by CD47.

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Advances in synthetic biology and the growing understanding of the CD47/SIRPɑ axis may provide new opportunities for the development of novel, targeted agencies, that act through the inhibition of CD47 signaling in cancer cells. Anti-CD47 antibodies block the interaction between SIRPα and tumor surface CD47. Data from preclinical studies have shown that CD47/SIRPɑ interacts as a myeloid immune checkpoint in cancer. [9]

Inhibiting the CD47/SIRPα signaling pathway promotes the adaptive immune response and enhances the phagocytosis of tumor cells by macrophages, which are components of the innate immune system, play a critical role in anti-tumor responses, and neutrophils. [9] Targeting of the CD47/SIRPα axis may also promote antigen-presenting cell function and thereby stimulate adaptive T cell-mediated anti-cancer immunity.

Results from ongoing preclinical studies suggest that the CD47/SIRPα axis is a key immune checkpoint in a variety of hematological malignancies, similar to that of the PD-1/PD-L1 checkpoint for solid tumors.

Blocking CD47/SIRPα interactions has been shown to promote the destruction of cancer cells by phagocytes, including macrophages and neutrophils. [9] Despite difference in ligand expression, binding partners, and function, preclinical studies have validating the CD47/SIRPα axis as a fundamental myeloid checkpoint pathway and its blockade as promising therapeutic intervention for treatment of human malignancies. As a results CD47/SIRPα blockade has emerged as a next-generation immune checkpoint disruption strategy in the treatment of various malignancies after PD-1/PD-L1.

Other studies have shown that CD47 mAbs not just block CD47 from engaging SIRPα, but also engage the activating Fc gamma receptor (FcγR) on macrophages. When combined, this deliver a potent phagocytic (“eat me”) signal to macrophages.

BYON4228 – a different approach
Researchers at Dutch-based Byondis (Nijmegen, The Netherlands) have developed a novel clinical candidate, called BYON4228. This investigational agent is an antibody directed against SIRPɑ and recognizes both of the common allelic variants of human SIRPɑ which maximizes its potential clinical application in the broad human population.[10][11][12]

Most anti-SIRPɑ antibodies in clinical development today either lack binding to both polymorphic SIRPα variants that are present in the human population, or they block the related SIRPγ, which is required for optimal T-cell responses. SIRPγ inhibition may therefore curtail durable anti-tumor immunity. In contrast to these SIRPɑ targeting antibodies, BYON4228 does not recognize SIRPγ that has been reported to

BYON4228 binds to the N-terminal part of SIRPɑ and its epitope overlaps with the CD47-binding site. As a result, BYON4228 prevents binding of CD47 to SIRPɑ and blocks inhibitory signaling through the CD47/SIRPɑ axis.

A number of preclinical studies have shown that BYON4228 potentiates both macrophage- and neutrophil-mediated elimination of hematologic and solid cancer cells in vitro in the presence of several different tumor targeting antibodies, including trastuzumab, rituximab, daratumumab and cetuximab.  These results demonstrate the broad potential clinical benefit and application of BYON4228.

The preclinical data demonstrates that BYON4228 enhances the efficacy of rituximab treatment in vivo when administered to human Non-Hodgkin lymphoma (NHL)-engrafted transgenic mice with a selective expression of huSIRP aBIT on myeloid cells (huSIRP aBIT-scid mice).

The investigational agent is also well tolerated. A single intravenous infusion of up to 100 mg/kg BYON4228 to male and female cynomolgus monkeys did not elicit any adverse effects.

Based on the initial, preclinical data, BYON4228 can be defined as a panallelic anti-SIRPɑ antibody without T-cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. First-in Humans clinical trials are planned to start in 2023.

[1] Catalán R, Orozco-Morales M, Hernández-Pedro NY, Guijosa A, Colín-González AL, Ávila-Moreno F, Arrieta O. CD47-SIRPα Axis as a Biomarker and Therapeutic Target in Cancer: Current Perspectives and Future Challenges in Nonsmall Cell Lung Cancer. J Immunol Res. 2020 Sep 19;2020:9435030. doi: 10.1155/2020/9435030. PMID: 33015199; PMCID: PMC7520676.
[2] Poels LG, Peters D, van Megen Y, Vooijs GP, Verheyen RN, Willemen A, van Niekerk CC, Jap PH, Mungyer G, Kenemans P. Monoclonal antibody against human ovarian tumor-associated antigens. J Natl Cancer Inst. 1986 May;76(5):781-91. PMID: 3517452.
[3] Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. doi: 10.1073/pnas.1121623109. Epub 2012 Mar 26. PMID: 22451913; PMCID: PMC3340046.
[4] Michaels AD, Newhook TE, Adair SJ, Morioka S, Goudreau BJ, Nagdas S, Mullen MG, Persily JB, Bullock TNJ, Slingluff CL Jr, Ravichandran KS, Parsons JT, Bauer TW. CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer. Clin Cancer Res. 2018 Mar 15;24(6):1415-1425. doi: 10.1158/1078-0432.CCR-17-2283. Epub 2017 Dec 29. PMID: 29288236; PMCID: PMC6296745.
[5] Zhao H, Wang J, Kong X, Li E, Liu Y, Du X, Kang Z, Tang Y, Kuang Y, Yang Z, Zhou Y, Wang Q. CD47 Promotes Tumor Invasion and Metastasis in Non-small Cell Lung Cancer. Sci Rep. 2016 Jul 14;6:29719. doi: 10.1038/srep29719. PMID: 27411490; PMCID: PMC4944213.
[6] Nigro A, Ricciardi L, Salvato I, Sabbatino F, Vitale M, Crescenzi MA, Montico B, Triggiani M, Pepe S, Stellato C, Casolaro V, Dal Col J. Enhanced Expression of CD47 Is Associated With Off-Target Resistance to Tyrosine Kinase Inhibitor Gefitinib in NSCLC. Front Immunol. 2020 Jan 31;10:3135. doi: 10.3389/fimmu.2019.03135. PMID: 32082304; PMCID: PMC7004973.
[7] Chao MP, Tang C, Pachynski RK, Chin R, Majeti R, Weissman IL. Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. Blood. 2011 Nov 3;118(18):4890-901. doi: 10.1182/blood-2011-02-338020. Epub 2011 Aug 9. PMID: 21828138; PMCID: PMC3208297.
[8] Kim D, Wang J, Willingham SB, Martin R, Wernig G, Weissman IL. Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells. Leukemia. 2012 Dec;26(12):2538-45. doi: 10.1038/leu.2012.141. Epub 2012 May 30. PMID: 22648449.
[9] Matlung HL, Szilagyi K, Barclay NA, van den Berg TK. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol Rev. 2017 Mar;276(1):145-164. doi: 10.1111/imr.12527. PMID: 28258703.
[10] Helden MV, Arends R, Zwarthoff S, et al BYON4228, a pan-allelic SIRPα blocking antibody with a favorable pre-clinical safety profile, enhances anti-tumor immunity in vitro and in vivo. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0495
[11] Helden MV, Zwarthoff S, Olsman H, Paradé M, Mattaar E, de Laat K, Lodewijks I, et al.BYON4228 is a pan-allelic SIRPα antibody that potentiates killing of antibody-opsonized tumor cells and lacks binding to T-cells; 129P. Annals of Oncology Volume 32, Sup 7, S1433-S1434, December 1, 2021,
[12] van Helden, Zwarthoff S, Paradé M, de Laat-Art K, Olsman H, Mattaar E, Glaudemans D, van Wijk D, Driessen-Engels L, et al. BYON4228 is a pan-allelic blocking SIRPα antibody that potentiates killing of antibody-opsonized tumor cells and lacks binding to T cells. Abstract # 1457 In: Proceedings of the 113th Annual Meeting of the American Association for Cancer Research; 2022 April 8-13; New Orleans LA.

Featured image: © 2016 – 2022 Byondis. Used with permission.

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