Preclinical studies have shown that the Cluster of Differentiation 47-Signal Regulatory Protein alpha (CD47/SIRPα) axis plays a critical regulatory in myeloid cell activation.
CD47, a cell surface molecule often over-expressed on cancer cells, forms a signaling complex with SIRPα, limiting macrophage-mediated phagocytosis of cancer cells by transducing a “don’t eat me” signal to the immune system, allowing the escape of these cancer cells. As a result, CD47 is associated with poor patient prognosis in various types of cancer.
In preclinical, novel therapies designed to block the CD47/SIRPα axis stimulate phagocytosis of cancer cells in vitro and anti-tumor immune responses in vivo. Based on these findings researcher believe that targeting the CD47/SIRPα axis represents a promising strategy to promote anti-tumor immunity.
Findings of an extensive, preclinical characterization, including direct comparisons to other anti-SIRPα antibodies, shows that BYON4228, a novel, investigational SIRPα-directed humanized therapeutic monoclonal antibody designed to stimulate the innate immune system, has a unique and favorable preclinical profile.
This profile was published in the April 2023 edition of the Journal for ImmunoTherapy of Cancer, the official journal of the Society for Immunotherapy of Cancer (SITC)
BYON4228, being developed by Byondis, a privately held, Netherlands-based clinical-stage biopharmaceutical research and development company, is scheduled to enter First-in-Human (Phase 1) study later this year. The Phase 1 clinical study (NCT05737628) is designed to evaluate BYON4228 alone and in combination with rituximab in patients with relapsed/refractory CD20-positive B-cell non-Hodgkin’s lymphoma. 
“BYON4228 is a pan-allelic antibody, meaning it recognizes the two major SIRPα variants in humans. In addition, because BYON4228 does not recognize SIRPγ, a related molecule on T-cells, it should not compromise T-cell activity,” explained Wim Dokter, Ph.D., Byondis Chief Scientific Officer.
“This implies that the therapy could benefit all eligible patients. Used in combination, BYON4228 can potentially increase the efficacy of a wide range of therapeutic mAbs in different blood and solid cancers,” Marco Timmers, Ph.D., Byondis Chief Executive Officer added.
Innate immune system
BYON4228 is designed to stimulate the innate immune system, the body’s first line of defense. The investigational agent binds to SIRPα expressed on innate immune cells, especially monocytes, macrophages and neutrophils, and blocks the binding of SIRPα to CD47. As a result, BYON4228 prevents signaling through the CD47/SIRPα axis.
By inhibiting the CD47-SIRPα axis, BYON4228 prevents the inhibitory “don’t eat me” signal to be detected, thereby stimulating the immune cell to do what it is supposed to do: destroy the tumor cell.
As a pan-allelic antagonistic SIRPα antibody that lacks binding to SIRPγ on T cells, BYON4228 has the potential to become best in class. It distinguishes itself from previously reported SIRPα antibodies that in all probability are representative of antibodies currently being tested in clinical trials.
According to the published data, BYON4228 potentiates macrophage- and neutrophil-mediated killing of both hematologic and solid cancer cells in vitro in the presence of a variety of tumor-targeting antibodies, including trastuzumab, rituximab, daratumumab, panitumumab and cetuximab. In vivo, BYON4228 promotes the anti-tumor activity of such antibodies. The preclinical data also shows that BYON4228 has a favorable preclinical safety profile.
First-in-human Dose Escalation and Expansion Study With the SIRPα-directed Monoclonal Antibody BYON4228 – NCT05737628
 van Helden MJ, Zwarthoff SA, Arends RJ, Reinieren-Beeren IMJ, Paradé MCBC, Driessen-Engels L, de Laat-Arts K, Damming D, et al. BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells. J Immunother Cancer 2023;11:e006567 DOI: 10.1136/jitc-2022-006567 [Article]
 Garcia D. Byondis Plans First-in-human Dose Escalation/Expansion Study With the SIRPα-directed BYON4228. Onco’Zine. February 27, 2023. Online. Last accessed on April 15, 2023
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