BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells

Helden, Mary J. van; Zwarthoff, Seline A.; Arends, Roel J; Reinieren-Beeren, Inge; Paradé, Marc; Driessen-Engels, Lilian; Laat-Arts, Karin de; Damming, Désirée; Santegoeds-Lenssen, Ellen W H; Kuppeveld, Daphne W J van; Lodewijks, Imke; Olsman, Hugo; Matlung, Hanke L.; Franke, Katka; Mattaar-Hepp, Ellen; Stokman, Marloes E M; Wit, Benny de; Glaudemans, Dirk H R F; Wijk, Daniëlle E J W van; Joosten-Stoffels, Lonnie; Schouten, Jan P.; Boersema, Paul J.; Vleuten, Monique van der; Sanderink, Jorien W H; Kappers, Wendela A; Dobbelsteen, Diels van den; Timmers, Marco; Ubink, Ruud; Rouwendal, Gerard J A; Verheijden, Gijs; Lee, Miranda M C van der; Dokter, Wim H.A.; Berg, Timo K. van den

doi:10.1136/jitc-2022-006567

Cited by 7 publications

(2 citation statements)

References 70 publications

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“…DS-1103a has an IgG4 Fc format, an effectorless isotype, to minimize unwanted immune attack to SIRPα-expressing myeloid cells. For this regard, van Helden MJ et al showed that anti-human SIRPα Ab in IgG1 isotype induced ADCP against SIRPα-expressing myeloid cells, while the Ab in IgG1 containing L234A/L235A mutations did not [ 37 ]. Further, Sim J et al showed that anti-human SIRPα Ab clone 21 enhanced cetuximab-induced ADCP both with and without Fc fragment of the anti-SIRPα Ab [ 38 ], suggesting the blocking of SIRPα-CD47 interaction is sufficient to enhance ADCP.…”

Section: Discussionmentioning

confidence: 99%

Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates

Sue,

Tsubaki,

Ishimoto

et al. 2024

PLoS ONE

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Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous self-associated molecule. SIRPα-CD47 interaction is exploited by cancer cells to suppress anti-tumor activity of myeloid cells, therefore emerging as a novel immune checkpoint for cancer immunotherapy. In blood cancer, several SIRPα-CD47 blockers have shown encouraging monotherapy activity. However, the anti-tumor activity of SIRPα-CD47 blockers in solid tumors seems limited, suggesting the need for combination therapies to fully exploit the myeloid immune checkpoint in solid tumors. Here we tested whether combination of SIRPα-CD47 blocker with antibody-drug conjugate bearing a topoisomerase I inhibitor DXd (DXd-ADC) would enhance anti-tumor activity in solid tumors. To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. DS-1103a inhibited SIRPα-CD47 interaction and enhanced antibody-dependent cellular phagocytosis of Dato-DXd and T-DXd against human cancer cells. In a whole cancer cell vaccination model, vaccination with DXd-treated cancer cells led to activation of tumor-specific T cells when combined with an anti-mouse SIRPα (anti-mSIRPα) Ab, implying the benefit of combining DXd-ADCs with anti-SIRPα Ab on anti-tumor immunity. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.

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Section: Discussionmentioning

confidence: 99%

Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates

Sue,

Tsubaki,

Ishimoto

et al. 2024

PLoS ONE

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“…Anti-SIRPα antibodies tested in human clinical trials for malignant diseases. References [ 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ] are cited in the Supplementary Materials.…”

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confidence: 99%

A Perspective on the CD47-SIRPA Axis in High-Risk Neuroblastoma

Tang,

Shimada,

Ikegaki

2024

Current Oncology

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Neuroblastoma is a pediatric cancer with significant clinical heterogeneity. Despite extensive efforts, it is still difficult to cure children with high-risk neuroblastoma. Immunotherapy is a promising approach to treat children with this devastating disease. We have previously reported that macrophages are important effector cells in high-risk neuroblastoma. In this perspective article, we discuss the potential function of the macrophage inhibitory receptor SIRPA in the homeostasis of tumor-associated macrophages in high-risk neuroblastoma. The ligand of SIRPA is CD47, known as a “don’t eat me” signal, which is highly expressed on cancer cells compared to normal cells. CD47 is expressed on both tumor and stroma cells, whereas SIRPA expression is restricted to macrophages in high-risk neuroblastoma tissues. Notably, high SIRPA expression is associated with better disease outcome. According to the current paradigm, the interaction between CD47 on tumor cells and SIRPA on macrophages leads to the inhibition of tumor phagocytosis. However, data from recent clinical trials have called into question the use of anti-CD47 antibodies for the treatment of adult and pediatric cancers. The restricted expression of SIRPA on macrophages in many tissues argues for targeting SIRPA on macrophages rather than CD47 in CD47/SIRPA blockade therapy. Based on the data available to date, we propose that disruption of the CD47-SIRPA interaction by anti-CD47 antibody would shift the macrophage polarization status from M1 to M2, which is inferred from the 1998 study by Timms et al. In contrast, the anti-SIRPA F(ab’)2 lacking Fc binds to SIRPA on the macrophage, mimics the CD47-SIRPA interaction, and thus maintains M1 polarization. Anti-SIRPA F(ab’)2 also prevents the binding of CD47 to SIRPA, thereby blocking the “don’t eat me” signal. The addition of tumor-opsonizing and macrophage-activating antibodies is expected to enhance active tumor phagocytosis.

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Tumor‐associated macrophages: A sentinel of innate immune system in tumor microenvironment gone haywire

Malik,

Sureka,

Ahuja

et al. 2024

Cell Biology International

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The tumor microenvironment (TME) is a critical determinant in the initiation, progression, and treatment outcomes of various cancers. Comprising of cancer‐associated fibroblasts (CAF), immune cells, blood vessels, and signaling molecules, the TME is often likened to the soil supporting the seed (tumor). Among its constituents, tumor‐associated macrophages (TAMs) play a pivotal role, exhibiting a dual nature as both promoters and inhibitors of tumor growth. This review explores the intricate relationship between TAMs and the TME, emphasizing their diverse functions, from phagocytosis and tissue repair to modulating immune responses. The plasticity of TAMs is highlighted, showcasing their ability to adopt either protumorigenic or anti‐tumorigenic phenotypes based on environmental cues. In the context of cancer, TAMs' pro‐tumorigenic activities include promoting angiogenesis, inhibiting immune responses, and fostering metastasis. The manuscript delves into therapeutic strategies targeting TAMs, emphasizing the challenges faced in depleting or inhibiting TAMs due to their multifaceted roles. The focus shifts towards reprogramming TAMs to an anti‐tumorigenic M1‐like phenotype, exploring interventions such as interferons, immune checkpoint inhibitors, and small molecule modulators. Noteworthy advancements include the use of CSF1R inhibitors, CD40 agonists, and CD47 blockade, demonstrating promising results in preclinical and clinical settings. A significant section is dedicated to Chimeric Antigen Receptor (CAR) technology in macrophages (CAR‐M cells). While CAR‐T cells have shown success in hematological malignancies, their efficacy in solid tumors has been limited. CAR‐M cells, engineered to infiltrate solid tumors, are presented as a potential breakthrough, with a focus on their development, challenges, and promising outcomes. The manuscript concludes with the exploration of third‐generation CAR‐M technology, offering insight into in‐vivo reprogramming and nonviral vector approaches. In conclusion, understanding the complex and dynamic role of TAMs in cancer is crucial for developing effective therapeutic strategies. While early‐stage TAM‐targeted therapies show promise, further extensive research and larger clinical trials are warranted to optimize their targeting and improve overall cancer treatment outcomes.

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BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells

Cited by 7 publications

References 70 publications

Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates

Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates

A Perspective on the CD47-SIRPA Axis in High-Risk Neuroblastoma

Tumor‐associated macrophages: A sentinel of innate immune system in tumor microenvironment gone haywire

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