Targeting the CD47/SIRPα axis: advancing innate immune checkpoint blockade through translational humanized mouse models

The CD47/SIRPα (signal regulatory protein alpha) axis has emerged as one of the most intensively investigated innate immune checkpoints in oncology. Unlike PD-1/PD-L1 and CTLA-4, which primarily regulate adaptive T-cell responses, CD47/SIRPα signaling controls the interaction between target cells and myeloid phagocytes, particularly macrophages and dendritic cells. As growing evidence highlights the critical role of innate immunity in tumor control, the CD47/SIRPα pathway has become an attractive therapeutic target for next-generation immunotherapies (Weiskopf, 2017; Feng et al., 2019).

Under physiological conditions, CD47 is a ubiquitously expressed transmembrane protein that functions as a marker of self. By engaging SIRPα expressed on macrophages, monocytes, dendritic cells, and neutrophils, CD47 delivers an inhibitory signal that prevents the phagocytosis of healthy cells. Intracellularly, SIRPα activation recruits SHP-1 and SHP-2 phosphatases, which inhibit cytoskeletal rearrangements required for engulfment, thereby maintaining tissue homeostasis and preventing inappropriate immune-mediated destruction of host cells (Murata et al., 2018; Matlung et al., 2017). This mechanism is particularly important for the preservation of circulating erythrocytes and platelets, which continuously rely on CD47 signaling to avoid clearance by the reticuloendothelial system.

Cancer cells frequently hijack this physiological mechanism to evade immune surveillance. Numerous hematological and solid malignancies overexpress CD47, enabling tumor cells to escape macrophage-mediated elimination by generating a potent “don't eat me” signal (Willingham et al., 2012; Jia et al., 2021). Elevated CD47 expression has been associated with poor prognosis in several cancer types, highlighting the pathway's relevance to disease progression and immune escape. Importantly, blockade of the CD47/SIRPα interaction removes this inhibitory signal, restoring tumor cell phagocytosis and promoting antigen uptake by antigen-presenting cells. This process can subsequently stimulate tumor-specific T-cell responses, thereby creating an important bridge between innate and adaptive antitumor immunity (Van Duijn et al., 2022; Feng et al., 2019).

Therapeutic targeting of the CD47/SIRPα axis

These findings have led to the development of a broad range of therapeutic approaches targeting the CD47/SIRPα pathway. First-generation strategies focused primarily on anti-CD47 monoclonal antibodies, such as magrolimab, which demonstrated encouraging preclinical activity and early clinical responses, particularly in hematological malignancies when combined with tumor-opsonising antibodies or cytotoxic agents (Son et al., 2022; Maute et al., 2022). However, because CD47 is expressed on virtually all healthy cells, these agents face significant challenges including anemia, thrombocytopenia and antigen sink effects, which can complicate dosing and limit therapeutic windows (Son et al., 2022; Jiang et al., 2024).

To address these limitations, several next-generation approaches have emerged. These include anti-SIRPα antibodies, engineered SIRPα-Fc fusion proteins, Fc-silenced decoy receptors, and tumor-targeted bispecific molecules designed to improve selectivity while reducing systemic toxicity (Bouwstra et al., 2022; Liu et al., 2020). Importantly, preclinical and clinical studies have demonstrated that CD47/SIRPα blockade rarely acts as an effective monotherapy. Instead, maximal therapeutic benefit is generally observed when combined with tumor-opsonising antibodies such as rituximab, trastuzumab or cetuximab, which provide the activating signals required to trigger efficient antibody-dependent cellular phagocytosis (ADCP) and tumor clearance (Weiskopf, 2017; Son et al., 2022).

Recent mechanistic studies have further refined our understanding of how anti-CD47 therapies function. Notably, Osorio et al. demonstrated that Fcγ receptor (FcγR) engagement is essential for optimal antitumor efficacy of anti-CD47 antibodies. Their work showed that CD47 blockade alone is insufficient to generate robust tumor responses; instead, activating FcγR signaling and macrophage activation are required simultaneously (Osorio et al., 2023). These findings established FcγR engagement as a key determinant of therapeutic efficacy and highlighted Fc engineering as a critical consideration for future drug development.

Humanized mouse models for preclinical evaluation of CD47-targeted therapies

As CD47-targeted therapeutics become increasingly sophisticated, the need for highly predictive preclinical models has become more evident. Conventional mouse models often fail to accurately reproduce human CD47/SIRPα interactions because of species-specific binding differences. Furthermore, murine FcγR biology differs substantially from its human counterpart, limiting the predictive value of efficacy and safety studies involving human therapeutic antibodies (Smith et al., 2012). Consequently, drug candidates that appear promising in traditional mouse models may fail to demonstrate comparable activity in clinical settings.

To address these translational challenges, genOway has developed a portfolio of humanized mouse models designed to reproduce key components of human innate immune checkpoint biology. These include humanized CD47-SIRPα models (genO-hCD47/hSIRPα), and humanized FcγR models (genO-hFcγR) that enable the evaluation of therapeutic antibodies within a biologically relevant human receptor context. By replacing their murine counterparts with human genes while preserving physiological expression patterns, these models allow more reliable assessment of target engagement, pharmacology, efficacy, and safety of human therapeutic antibodies. The genO-hCD47/hSIRPα model was shown to be a useful model for testing both the efficacy and safety of magrolimab, as magrolimab treatment induced transient decrease of red blood cells and hemoglobin in these mice (De la Rochere, poster presented at EACR 2025), which corroborates clinical findings. Building on these models, the genO-hCD47/hSIRPα/hFcγR triple-humanized model was also developed, specifically designed to address the growing recognition that effective anti-CD47 therapy requires coordinated CD47 blockade, SIRPα engagement, and FcγR-mediated effector activation. The model combines human CD47 and human SIRPα with a complete human FcγR repertoire, enabling investigators to evaluate simultaneously the checkpoint-blocking and Fc-dependent mechanisms that drive therapeutic efficacy.

Collectively, these advances highlight the promise of CD47/SIRPα blockade as a powerful strategy to harness innate immunity against cancer, while emphasizing the critical need for translationally relevant humanized models to accelerate the development of safe and effective next-generation immunotherapies.

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参考文献

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