What CD47 modulators are in clinical trials currently?

Introduction to CD47
CD47 is a ubiquitously expressed transmembrane glycoprotein that belongs to the immunoglobulin superfamily. It has long been recognized for its “don’t eat me” signal function—it communicates with immune effector cells, particularly macrophages, by binding to the counter-receptor signal regulatory protein alpha (SIRPα). This interaction normally prevents phagocytosis of healthy cells and plays key roles in self‐recognition. Over the past few decades, research has revealed that cancer cells exploit this mechanism by overexpressing CD47 to escape immune surveillance. In addition, CD47 has important roles beyond immune evasion, such as participation in cell adhesion, migration, apoptosis, and even in normal tissue remodeling and repair.

Biological Role of CD47
At the cellular level, CD47 interacts with several endogenous ligands. Its binding to SIRPα on macrophages triggers inhibitory signals that help prevent the phagocytosis of normal cells, such as red blood cells, thereby maintaining self‐tolerance. Beyond SIRPα, CD47 also binds to thrombospondin-1 (TSP-1) and various integrins, which modulate cell adhesion and migration as well as downstream signaling pathways that can influence the fate of cancer cells. Its ability to coordinate these diverse signals makes CD47 a central regulatory node in both immune surveillance and cellular homeostasis.

CD47 in Disease Pathology
In disease states, particularly in cancer, CD47 is frequently upregulated and serves as a key mechanism through which tumor cells avoid immune destruction. Elevated CD47 expression has been associated with aggressive tumor behavior, metastasis, and resistance to standard therapies in a variety of malignancies such as leukemia, non-Hodgkin’s lymphoma, triple-negative breast cancer, hepatocellular carcinoma (HCC), and even in solid tumors like glioblastoma. Aside from its role in cancer, modulation of CD47 signaling influences inflammatory processes and tissue repair, and it has been implicated in conditions ranging from autoimmune diseases to neurodegeneration. This multifaceted role of CD47 in both normal physiology and pathological conditions underlines why targeting CD47 has become a promising avenue in drug development.

CD47 Modulators
CD47 modulators are therapeutic agents crafted to inhibit or alter the function of CD47. By blocking its interaction with SIRPα, these agents aim to disable the “don’t eat me” signal that tumors leverage, thereby reactivating macrophage-mediated phagocytosis and enabling both innate and adaptive immune responses against cancer cells.

Types of CD47 Modulators
Current CD47 modulators primarily fall into several structural categories:

• Monoclonal Antibodies (mAbs):
These are engineered antibodies that directly bind CD47 and block its interaction with SIRPα. One of the most advanced examples is Hu5F9-G4 (also known as magrolimab), a humanized IgG antibody that has been tested as a monotherapy and in combination (for example, with rituximab) in hematological malignancies and some solid tumors. Other antibody candidates include CC-90002, a humanized mAb that has entered early-phase clinical studies, and BI 765063, a selective humanized IgG4 mAb developed to alleviate inflammatory conditions as well as target CD47 in cancers.

• Recombinant Fusion Proteins:
These utilize a recombinant SIRPα extracellular domain fused to an Fc portion from immunoglobulin (e.g., SIRPα-Fc fusion proteins such as TTI-621 and ALX148). These proteins act as decoy receptors, competing with native SIRPα, and have demonstrated preclinical antitumor activity with promising safety profiles, especially given concerns related to red blood cell binding and anemia.

• Bispecific and Multispecific Antibodies:
A newer approach involves designing antibodies that can simultaneously bind CD47 and another tumor-associated antigen or immune checkpoint. These bispecific antibodies increase functionality by both directing immune cell activity against the tumor and limiting off-tumor toxicities. Novel agents such as bifunctional SIRPα-CD40L antibodies have been reported in clinical studies, aiming to switch on antigen-presenting cell function along with blocking CD47.

• Peptides and Small Molecule Inhibitors:
While the majority of clinical candidates are large biologics, there is ongoing research to identify small molecules and peptide mimetics capable of inhibiting the CD47-SIRPα interaction selectively. Such agents often come with improved tissue penetration and easier manufacturability, although most small molecule inhibitors are still in preclinical development and are not yet widely reported in clinical trials.

Mechanisms of Action
CD47 modulators function primarily by preventing the interaction between CD47 on tumor cells and SIRPα on macrophages. Without this negative signal, macrophages are able to recognize and phagocytose tumor cells more effectively. In several instances, CD47 blockade also leads to the induction of apoptosis in cancer cells via caspase-independent pathways, and it can even impact other intracellular signaling pathways such as cAMP, integrin-mediated adhesion, and cytoskeleton reorganization.
Furthermore, some modulators (especially fusion proteins) leverage Fc receptor engagement on phagocytic cells, providing a dual mode of action: concurrently blocking the inhibitory checkpoint while promoting the activating signals such as antibody-dependent cellular phagocytosis (ADCP). These combined effects help reeducate the tumor microenvironment and can stimulate not only innate immune killing but also enhance subsequent CD8+ T cell responses, facilitating a more robust adaptive immune response.

Clinical Trials of CD47 Modulators
The clinical development of CD47 modulators is progressing rapidly. Early-phase trials in both hematologic malignancies and solid tumors are actively evaluating these agents. According to recent clinical data, 23 distinct CD47 modulator agents have been registered in clinical trials with a range of therapeutic designs—either as monotherapies or in combination with other cytotoxic or immune-targeting agents, across multiple trial phases.

Current Clinical Trials
At present, multiple CD47-targeting agents are in clinical trials, and they represent different structural classes. Some key examples include:

• Hu5F9-G4 (Magrolimab): This is one of the most extensively investigated CD47 monoclonal antibodies. In both hematologic malignancies—especially in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and non-Hodgkin’s lymphoma—and in select solid tumors, Hu5F9-G4 is being evaluated either as a single agent or in combination with established therapies such as rituximab or chemotherapy. Early-phase trials have reported promising efficacy with manageable side effects and have prompted phase Ib/II studies to further assess its safety and response rates.

• CC-90002: Another humanized anti-CD47 monoclonal antibody, CC-90002 entered clinical studies with an emphasis on hematological cancers. However, its development has been challenged by issues related to antidrug antibodies (ADAs) and suboptimal monotherapy results. Some clinical trials are still ongoing or being restructured with combination regimens to mitigate these challenges.

• TTI-621: This is a SIRPα-IgG1 fusion protein designed to act as a decoy receptor for CD47, thereby blocking the CD47-SIRPα signaling pathway. TTI-621 is currently undergoing phase I clinical trials in patients with hematologic malignancies and solid tumors, and early clinical data demonstrate that it can promote macrophage-mediated phagocytosis without provoking significant hemolytic anemia.

• ALX148: Also a SIRPα-Fc fusion protein, ALX148 is designed with an engineered Fc region to minimize adverse effects while retaining therapeutic efficacy. Clinical trials are evaluating ALX148, both as monotherapy and in combination with other immune checkpoint inhibitors (e.g., anti-PD-1 monoclonal antibodies) across various tumor types. ALX148 has shown promising safety profiles and preliminary signals of antitumor effectiveness, leading to further phase I/II studies.

• BI 765063: This selective humanized IgG4 monoclonal antibody aims to block CD47 more specifically while avoiding excessive activation of Fc-mediated effects on normal cells. BI 765063 has been evaluated in early-phase clinical trials, particularly focusing on inflammatory conditions and oncologic settings such as ovarian cancer. Although its use is less widespread compared to Hu5F9-G4, it represents an important alternative approach to modulating CD47 activity.

• TJ011133: Though mentioned less frequently, TJ011133 is an example of a candidate that has been combined with azacytidine (AZA) in a phase III clinical trial setting, particularly in higher-risk myelodysplastic syndrome (MDS). This combination underscores the strategy of using CD47 modulators to complement other therapeutic agents to overcome treatment resistance.

Collectively, these modulators cover a spectrum of therapeutic strategies—from direct blocking antibodies to fusion protein decoys—and they are being tested in various cancers covering both hematologic and solid malignancies. The diversity of trial designs also involves evaluation in combination regimens with chemotherapies, other immunotherapies, and targeted agents, based on the rationale that a multimodal immunomodulatory approach may enhance clinical response while reducing resistance and off-target toxicities.

Phases and Status
Clinical trials of CD47 modulators are predominantly in the early phases (phase I and phase II), although some agents are advancing toward later-stage trials. The distribution of clinical trial phases, as reported from the NCT registry platform, indicates that among CD47-targeting therapies there are:

• Phase I Trials: The majority of CD47 modulators are in phase I trials where the principal focus is on safety, tolerability, dose escalation, and pharmacokinetic/pharmacodynamic profiling. In the United States, there are approximately 31 phase I trials evaluating these agents, while in regions such as China, around 9 phase I trials are reported.

• Phase I/II Trials: Some trials have progressed to combined phase I/II studies (for example, the phase 1b study with Hu5F9-G4 in combination with chemotherapeutic agents or rituximab) to better assess efficacy signals while continuing to monitor safety in a larger cohort.

• Phase II Trials: A smaller number of trials, around 14 in the USA and 6 in China, are in phase II with more mature endpoints such as objective response rates, progression-free survival, and longer-term safety data. These trials are essential to establish clinically meaningful antitumor activities and define the therapeutic window.

• Phase III Trials: Although most current trials are in early stages, at least one phase III trial has been reported in the context of combination therapies with CD47 modulators (for example, TJ011133 in combination with azacytidine for high-risk MDS). The eventual progress to phase III is expected as more extensive data regarding safety and efficacy emerge from earlier-phase studies.

Given that the vast majority of CD47 modulator trials are in early phases, the investigational drugs are still being optimized for parameters such as dosing schedules, combination partners, and on-target/off-target effects. It is noteworthy that many of these trials are also exploring strategies to mitigate the hematologic toxicities—such as anemia—that have been observed with systemic CD47 blockade, by using antibody preloading or engineering Fc domains that minimize red blood cell binding.

Implications and Future Directions
The clinical development of CD47 modulators is reflective of a broader trend toward leveraging the innate immune system for significant antitumor effects. Their ongoing assessment in clinical trials is building the foundation for an entirely new class of immunotherapies that could complement or even supersede existing checkpoint blockade therapies.

Therapeutic Potential
The therapeutic potential of CD47 modulators lies in their capacity to disrupt a central immune evasion mechanism. By blocking the CD47-SIRPα interaction, these agents can permit enhanced phagocytosis of tumor cells by macrophages, facilitate the “re-education” of the tumor microenvironment, and stimulate adaptive immune responses via antigen presentation. The dual or multiple functionalities—ranging from direct induction of apoptosis in tumor cells to boosting cytotoxic T cell responses—make them attractive candidates for treating cancers that have traditionally been resistant to many other therapies. The clinical data accumulated thus far are promising; for instance, the combination of Hu5F9-G4 with rituximab has achieved significant objective responses in patients with aggressive non-Hodgkin lymphoma, and similar efficacy signals are being pursued in AML, MDS, and solid tumors. Additionally, their potential synergy with other immunomodulatory agents, targeted therapies, and even conventional chemotherapy positions CD47 modulators to be integral components of combination therapeutic strategies.

Challenges and Considerations
Despite the exciting promise, there are considerable challenges associated with CD47 modulators. One of the principal concerns is safety, particularly the hematologic toxicity that arises from the ubiquitous expression of CD47 on normal cells such as red blood cells. This on-target binding can inadvertently lead to anemia and, in some cases, thrombocytopenia. Clinical trials are actively addressing these issues by modifying the antibody structure (for instance, using an IgG4 backbone or engineering the Fc portion to reduce Fcγ receptor binding) and through priming regimens that aim to “pre-clear” older red blood cells without compromising overall safety.
Furthermore, preclinical studies have highlighted potential discrepancies arising from differences between xenograft models and syngeneic models. The species-specific affinities of CD47-SIRPα interactions complicate the translation of preclinical efficacy to humans and require careful evaluation in clinical trial designs. Another challenge relates to the optimal dosing strategies. Determining the right dose that maximizes tumor cell clearance while minimizing adverse effects remains a central focus of current phase I/II studies. The diverse strategies—including monotherapy versus combination therapy—must also be explored to understand potential additive or synergistic benefits. These multifaceted challenges underscore the need for refined biomarkers and companion diagnostics to determine which patients are most likely to benefit from CD47-modulating therapy and to monitor the extent of target modulation in real time.

Future Research Directions
Future research into CD47 modulators is likely to pursue several complementary strategies:

• Optimization of Antibody Constructs: Further refinement of humanized antibodies and fusion proteins is needed to improve safety profiles. Approaches will include designing next-generation constructs with lower affinity for normal cells, improved specificity for tumor cells, and enhanced ability to stimulate the desired immune responses without inciting systemic toxicity.

• Better Preclinical Models: There is a critical need for more predictive preclinical models that accurately reflect human CD47-SIRPα interactions. Novel animal models or in vitro systems, including patient-derived organoids and humanized mouse models, could help in predicting clinical outcomes more reliably.

• Combination Therapies: The next wave of clinical research will likely emphasize combination regimens that integrate CD47 modulators with other immunotherapeutic agents (e.g., PD-1/PD-L1 inhibitors), targeted therapies, or chemotherapeutic agents. Such combinations have the potential to overcome resistance mechanisms and produce more sustained responses in refractory patients.

• Biomarker Development: Robust biomarkers need to be identified to select patient subpopulations that are most likely to benefit from CD47-modulating therapies. Companion diagnostics that measure CD47 expression levels, assess tumor microenvironment characteristics, and monitor immune cell infiltration will be crucial in tailoring treatment plans and enhancing clinical outcomes.

• Exploration of New Modalities: Although most current efforts focus on mAbs and fusion proteins, the development of small molecules and peptide mimetics that target CD47 is a promising area. These alternative modalities could offer improved tissue penetration and easier manufacturing processes while potentially reducing immunogenicity.

• Long-term Safety and Resistance Studies: As clinical trials mature, it will be important to assess the long-term effects of CD47 blockade, the durability of responses, and the mechanisms underlying acquired resistance. Such insights will help in designing maintenance regimens and in the development of strategies to prevent tumor escape.

Conclusion
In summary, current clinical trials of CD47 modulators include several key candidates that span a range of molecular designs—from humanized monoclonal antibodies such as Hu5F9-G4 (magrolimab), CC-90002, and BI 765063 to recombinant SIRPα-Fc fusion proteins like TTI-621 and ALX148, as well as emerging agents such as TJ011133. These agents are primarily in phase I and phase I/II clinical trials with some extensions into phase II and, in select instances, phase III trials. They are being investigated across a variety of indications including hematologic malignancies like AML, MDS, and non-Hodgkin lymphoma, as well as solid tumors such as ovarian cancer, triple-negative breast cancer, and glioblastoma. From multiple perspectives—including immune activation, re-education of the tumor microenvironment, and direct tumor cell apoptosis—these modulators offer a promising avenue for cancer immunotherapy.

However, challenges remain, notably in balancing therapeutic efficacy with safety concerns such as hematologic toxicity, and in designing and executing clinical trials that faithfully recapitulate the complexity of human CD47 signaling. The development of combination regimens, improved biomarker-guided patient stratification, and novel antibody engineering strategies will be critical to advancing CD47 modulators further through the clinical pipeline.

On a general level, the clinical trial landscape for CD47 modulators is dynamic and promising, touching many facets of oncologic therapy while simultaneously cautioning against unexpected toxicities or resistance mechanisms. The early-phase trials indicate that although there is substantial progress, careful attention must be paid to detailed pharmacodynamic monitoring and the development of robust, clinically translatable preclinical models. Specific modulators such as Hu5F9-G4 and TTI-621 have already demonstrated encouraging efficacy signals with manageable safety profiles, paving the way for combination therapy trials that may expand their applicability across a broader range of tumor types.

In a specific sense, the variety of molecular strategies—from monoclonal antibodies to engineered fusion proteins—illustrates the depth of approaches under investigation. Each modality brings its unique advantages and challenges, whether it is the potential for direct immune activation through Fc receptor engagement or the possibility of reduced off-target effects through more refined antibody engineering. The promise of CD47 blockade, when combined with other therapeutic modalities, could revolutionize the treatment paradigms for cancers that have historically been resistant to conventional approaches.

From a general perspective and looking toward the future, further research will be essential to enable these treatments to deliver on their full potential. Continuous improvements in the understanding of CD47 biology, iterative enhancements in modulator design, and comprehensive clinical trials that evaluate both short-term efficacy and long-term safety will drive the next generation of immunotherapies. Ultimately, the success of these therapies will hinge on our ability to integrate detailed mechanistic insights with clinical innovations, ensuring that patients receive treatments that are not only effective but also precisely tailored to the complex immune landscapes of their tumors.

In conclusion, as the CD47 modulators progress through their various clinical trial phases—from phase I safety and tolerability studies to expanded phase II efficacy trials and beyond—the future of CD47-targeted therapy appears bright, offering new hope for patients by opening up additional therapeutic windows. The ongoing evolution of these technologies, coupled with rigorous clinical evaluation and modular combination strategies, is likely to establish CD47 modulating agents as a crucial component of personalized cancer immunotherapy in the coming years.