How can CD172a (SIRPα) become a new strategy for macrophage-directed tumor immunotherapy?

1. Why is the CD47-SIRPα pathway a key mechanism for tumor immune evasion?

In the tumor microenvironment, malignant cells evade immune system attacks by expressing specific "don't eat me" signals, with the CD47-SIRPα axis being one of the core pathways that has garnered significant attention in recent years. Signal regulatory protein α (SIRPα, also known as CD172a) is an immunosuppressive receptor primarily expressed on myeloid cells (such as macrophages and dendritic cells). Its extracellular domain contains three immunoglobulin-like domains that recognize and bind to CD47, a ligand widely expressed on both normal and tumor cells. When SIRPα binds to CD47, its intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) is phosphorylated, recruiting and activating protein tyrosine phosphatases SHP-1 and SHP-2, thereby transmitting strong inhibitory signals to macrophages and actively preventing their phagocytosis of CD47-positive cells. Many types of tumor cells exploit this physiological "self"-recognition mechanism by upregulating CD47 expression, disguising themselves as normal cells to evade immune surveillance and clearance by macrophages. Therefore, blocking the interaction between CD47 and SIRPα is considered a promising immunotherapeutic strategy to dismantle the tumor's "protective shield" and reactivate macrophages' antitumor functions.

2. How do SIRPα (CD172a)-targeting antibodies exert antitumor effects?

Based on the above mechanism, developing blocking antibodies targeting SIRPα or CD47 has become a research hotspot. Compared to CD47-targeting antibodies (which may cause nonspecific depletion of normal cells like red blood cells), SIRPα-targeting antibodies offer potential advantages: they primarily act on myeloid effector cells (e.g., macrophages) expressing SIRPα, potentially offering greater cellular specificity.

Mechanisms of anti-SIRPα (CD172a) antibodies:

1. Blocking "don't eat me" signals: The antibody binds to SIRPα on the macrophage surface, competitively blocking or sterically hindering its interaction with CD47 on tumor cells, thereby lifting the inhibitory signal and unleashing macrophage phagocytic activity.

2. Inducing programmed tumor cell death: Some studies suggest that anti-CD47/SIRPα treatment not only promotes phagocytosis but may also directly induce a unique form of programmed cell death in tumor cells, characterized by actin cytoskeleton rearrangement, mitochondrial damage, and phosphatidylserine externalization.

3. Synergizing with other therapies: When combined with tumor-associated antigen-targeting antibodies (e.g., CD20), anti-SIRPα antibodies exhibit powerful synergistic effects. The principle is that tumor antigen-targeting antibodies provide "eat me" signals via their Fc segments binding to Fcγ receptors on macrophages, while anti-SIRPα antibodies block "don't eat me" signals. The dual-signal synergy significantly enhances antibody-dependent cellular phagocytosis (ADCP) and antitumor efficacy.

3. What is the core value of humanized SIRPα (hSIRPA) mouse models in drug development?

To more accurately evaluate the efficacy and safety of human SIRPα-targeting antibodies in the preclinical stage, traditional immunodeficient mouse models (expressing murine SIRPα) face limitations due to species differences. Thus, developing genetically engineered animal models expressing human SIRPα protein on murine myeloid cells is crucial.

Taking the humanized SIRPα (hSIRPA) mouse model constructed on a B-NDG background as an example, this model offers the following features and advantages:

- Human target expression: The endogenous SIRPα gene is replaced with the human SIRPα gene (typically the extracellular domain), enabling myeloid cells (macrophages, DCs, etc.) to express human SIRPα protein, which can directly bind and interact with human anti-SIRPα antibodies.

- Immunodeficient background: Based on the B-NDG background (lacking T, B, and NK cells), this model significantly reduces host adaptive immune rejection of transplanted human tumors or immune cells while eliminating interference from murine T/NK cells in efficacy evaluation, allowing for a purer assessment of macrophage-mediated antitumor effects.

- Model validation: Flow cytometry analysis confirms stable human SIRPα expression in the spleen and peritoneal cells of these mice, with myeloid cell subsets (monocytes, DCs, macrophages) maintaining proportions and distributions similar to wild-type immunodeficient mice, indicating that humanization does not significantly affect baseline cell development or distribution, ensuring model reliability.

4. How do CD172a (SIRPα) antibodies function and get validated in related research?

High-specificity, high-functionality CD172a (SIRPα) antibodies are critical reagents in the research chain, with applications in basic mechanism and preclinical efficacy studies including:

1. Target validation and mechanism studies: These antibodies can be used for immunofluorescence, flow cytometry, or Western Blot to detect human/murine SIRPα expression levels and localization in different cells or tissues. In functional experiments, treating macrophages with blocking anti-SIRPα antibodies can validate their enhancement of tumor cell phagocytosis in vitro.

2. Animal model characterization: When constructing and validating humanized SIRPα (hSIRPA) mice, specific anti-human SIRPα antibodies (with no cross-reactivity to murine protein) must be used to confirm successful human protein expression on myeloid cells, a core step in model validation.

3. In vivo efficacy evaluation: After engrafting human tumor cells (e.g., Raji lymphoma cells) into hSIRPA mouse models, candidate anti-human SIRPα therapeutic antibodies can be tested alone or in combination (e.g., with anti-CD20 antibodies). Dynamic monitoring of tumor growth, mouse survival, and ex vivo analysis of tumor-infiltrating immune cells objectively assess the antibodies' in vivo antitumor activity, optimal dosing, and combination synergy.

4. Biomarker analysis: In post-treatment tumor tissues or peripheral blood samples, CD172a antibodies combined with other myeloid cell markers can analyze activation states, quantitative changes in effector cells (e.g., macrophages), and their correlation with efficacy, exploring potential pharmacodynamic biomarkers.

5. Summary and Outlook

Targeting CD172a (SIRPα) to block the CD47-SIRPα immune checkpoint pathway represents an emerging approach to cancer treatment by activating macrophages' innate immune functions. The humanized SIRPα (hSIRPA) mouse model, as a bridge connecting in vitro mechanistic studies to human clinical trials, provides a highly relevant in vivo pharmacodynamic platform for efficiently screening and evaluating anti-human SIRPα antibodies. High-quality CD172a (SIRPα) antibodies are indispensable tools driving this field from basic discovery to drug development. Future research into SIRPα subtypes, expression regulation, and its complex roles in the tumor microenvironment, along with more combination strategies (e.g., with chemotherapy, radiotherapy, or other immune checkpoint inhibitors), may offer new treatment options for refractory cancer patients.

6. Which manufacturers provide CD172a antibodies?

Hangzhou Startbio Biotechnology Co., Ltd. has independently developed the "Rat Anti-Mouse CD172a (SIRPα) Antibody" (product name: Rat Anti-Mouse CD172a (SIRPα) Antibody (S-R713), catalog number: S0B5183), a highly specific, high-affinity, and exceptionally stable immunoregulatory receptor detection tool. This product precisely recognizes murine signal regulatory protein α (SIRPα/CD172a) and holds significant value in macrophage function studies, immune checkpoint regulation, and tumor immunotherapy mouse models.

Technical support: We provide detailed product documentation, including complete specificity validation data, experimental protocols, and professional technical support to assist clients in advancing innate immunity and tumor immunotherapy research.

Hangzhou Startbio Biotechnology Co., Ltd. is committed to providing high-quality, high-value biological reagents and solutions for global innovative pharmaceutical companies and research institutions. For more details about the "Rat Anti-Mouse CD172a (SIRPα) Antibody" (catalog number S0B5183) or to request sample testing, please contact us.

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