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The Netherlands-based Byondis has planned a first-in-human study with BYON4228, a humanized monoclonal antibody directed against the immune checkpoint signal regulatory protein α (SIRPα). the study is expected to start later this year.

SIRPα, also known as SHPS-1/BIT/CD172a, is a transmembrane immunoglobulin superfamily protein that binds to the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is selectively expressed by myeloid cells which are part of the innate immune system. The signaling via SIRPα blocks the innate immune system.

CD47-SIRPα axis
SIRPα interacts with the phagocytic check point protein CD47, or integrin-associated protein, a widely expressed transmembrane protein generally over-expressed on cancer cells.

Expression of CD47 has been found to be considerably elevated in numerous hematological malignancies, as well as solid cancers.[1][2] Furthermore, CD47, expressed by different cell types in the tumor microenvironment, is required for establishing tumor metastasis. Hence, over-expression of CD47 has been associated with a poor clinical outcomes.[2][3]

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CD47 is also ligand for SIRPα, with the two proteins forming a cell-cell communication system known as the CD47-SIRPα axis.[1][2]

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In preclinical studies, the CD47-SIRPα axis has been identified as an immune checkpoint associated with tumor phagocytosis (a ‘don’t eat me’ signal submitted to the immune system) [2] that inhibits myeloid-derived antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). As a result, the CD47-SIRPα axis limits efficacy of anti-tumor antibodies.[3] However, CD47 not only binds SIRPα, but also mediates functional interactions with other ligands.[4]

Ongoing clinical trials to inhibit the CD47-SIRPα axis through targeting CD47 have shown promising results in a reduced tumor burden. However, unlike CD47 which is ubiquitously expressed, SIRPα is relatively restricted. Hence, researchers hypothesized that targeting SIRPα potentially results in a differential safety and efficacy profile compared to CD47-targeted approaches.[5] But SIRPα-targeting antibodies currently included in clinical studies today either lack binding to all SIRPα variants that are present in the human population, or they block the closely related T cell-expressed SIRPγ, which reduces or limits durable anti-tumor immunity.[5]

Innate immune system
BYON4228, Byondis’ lead cancer immunotherapeutic investigational agent, is a pan-allelic antibody which recognizes and binds to all known SIRPα variants. However, the investigational agent does not recognize SIRPγ which is instrumental in T cell extravasation and activation. The interactions between SIRPγ with CD47 on the surface of the cell results in enhanced cell-cell adhesion in an integrin-independent manner. Hence, SIRPγ is thought to be an accessory protein.

BYON4228 is designed to stimulate the innate immune system and blocks the binding of SIRPα to CD47 and because it does not recognize SIRPγ, it does not compromise T cell activity. This unique difference distinguishes BYON4228 from anti-SIRPα antibodies currently in clinical development, allowing the novel drug candidate to provide a broad benefit to patients.

BYON4228, binds to the N-terminal part of SIRPα where its epitope overlaps with the CD47-binding site, preventing the binding of CD47 to SIRPα and, in turn, blocking inhibitory signaling through the CD47-SIRPα axis.

Preclinical studies
Preclinical studies have demonstrated that BYON4228 increases the power of both macrophage- and neutrophil-mediated elimination of both hematologic and solid cancer cells in vitro in the presence of several different tumor targeting antibodies like trastuzumab (Herceptin®; Genentech/Roche), rituximab (Rituxan®; Genentech/Biogen and MabThera®; Roche), daratumumab (Darzalex®; Janssen Biotech) and cetuximab (Erbitux®; Eli Lilly and Company), In addition, these early studies have shown that a single intravenous infusion of up to 100 mg/kg of BYON4228 to male and female cynomolgus monkeys was well tolerated and did not elicit any adverse effects.

Study design
The new, first-in-human clinical study is designed to evaluate BYON4228 alone and in combination with rituximab in patients with relapsed/refractory CD20-positive B-cell non-Hodgkin’s lymphoma and includes a dose escalation part (Part 1) in which the maximal tolerated dose (MTD) and dose regimen for expansion (RDE) will be determined, and an expansion part (Part 2) to evaluate efficacy and safety in specific patient cohorts.

Clinical trial
First-in-human Dose Escalation and Expansion Study With the SIRPα-directed Monoclonal Antibody BYON4228 – NCT05737628

Highlights of prescribing information
Rituximab (Rituxan®; Genentech/Biogen and MabThera®; Roche)[Perscription Information]
Trastuzumab (Herceptin®; Genentech/Roche) [Prescription Information]
Daratumumab (Darzalex®; Janssen Biotech)[Prescription Information]
Cetuximab (Erbitux®; Eli Lilly and Company)[Prescription Information]

Reference
[1] Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, 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.
[2] Behrens LM, van den Berg TK, van Egmond M. Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils. Cancers (Basel). 2022 Jul 11;14(14):3366. doi: 10.3390/cancers14143366. PMID: 35884427; PMCID: PMC9319280.
[3] Eladl E, Tremblay-LeMay R, Rastgoo N, Musani R, Chen W, Liu A, Chang H. et al. Role of CD47 in Hematological Malignancies. J Hematol Oncol. 2020 Jul 16;13(1):96. doi: 10.1186/s13045-020-00930-1. PMID: 32677994; PMCID: PMC7364564.
[4] Van Helden M, Zwarthoff S, Paradé M, De Laat-Art K, Olsman H, Mattaar E, Glaudemans D, Van Wijk D, Driessen-Engels L, Boersema P, Hanckmann E, Van der Vleuten M, Arends R, Rouwendal G, Verheijden G, Van der Lee M, Dokter W, Van den Berg T. BYON4228 is a pan-allelic blocking SIRPα antibody that potentiates killing of antibody-opsonized tumor cells and lacks binding to T cells. In: Proceedings of the 113th Annual Meeting of the American Association for Cancer Research; 2022 April 8-13; New Orleans LA. Philadelphia (PA): AACR; 2022. Abstract nr. #5589.[Online]
[5] Barclay AN, Van den Berg TK. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu Rev Immunol. 2014;32:25-50. doi: 10.1146/annurev-immunol-032713-120142. Epub 2013 Nov 6. PMID: 24215318.

Featured image: Byondis.  Photo courtesy: © 2016 – 2023 Byondis. Used with permission.

This article was updated on March 8, 2023.

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