What are the new molecules for CD47 modulators?

CD47 and Its Role in Immunotherapy
CD47 is a ubiquitously expressed transmembrane glycoprotein that plays a crucial role as a “don’t eat me” signal by binding to its counter‐receptor, signal‐regulatory protein alpha (SIRPα), on phagocytic cells. Its ability to modulate the immune system is rooted in multiple ligand interactions—not only with SIRPα but also with thrombospondin‑1 (TSP‑1), integrins, and other partners—which in turn regulate processes such as phagocytosis, cellular adhesion, migration, and apoptosis. In immunotherapy, this signaling axis has emerged as an “innate immune checkpoint” that prevents macrophages and other antigen‐presenting cells from engulfing tumor cells, thereby facilitating immune evasion by cancers.
CD47 Function and Mechanism
At the molecular level, CD47 functions by interacting laterally with other membrane receptors and by clustering in nanodomains. In healthy tissues, this interaction with SIRPα sends inhibitory signals via immunoreceptor tyrosine-based inhibition motifs (ITIMs), recruiting phosphatases such as SHP‑1 and SHP‑2 that block downstream signals necessary for phagocytosis. This elegant system of self‐recognition is key to maintaining immune homeostasis and, as a consequence, is exploited by many types of tumors. In neoplastic cells, overexpression of CD47 results in an enhanced “don’t eat me” signal that disrupts the normal clearance of abnormal cells, leading to resistance against both innate and adaptive immune attack.
Importance in Cancer Treatment
Because of its pivotal role in suppressing immune-mediated clearance, CD47 has become a prime target in cancer immunotherapy. Blockade of CD47 can reawaken macrophage activity, promote antigen presentation, and ultimately enhance T‑cell responses against tumor antigens. Moreover, combined therapeutic strategies targeting CD47 with other checkpoint inhibitors or traditional chemotherapies have shown synergies that improve overall treatment response—in solid tumors and hematologic malignancies alike. The significance of CD47 targeting is further underscored by its involvement in tumor invasiveness, metastasis, and even the recruitment and polarization of tumor-associated macrophages (TAMs), all of which are vital parameters for the prognosis of cancer patients.

Discovery of New CD47 Modulators
Recent years have seen the discovery and early validation of a broad spectrum of novel CD47 modulators. These new molecules extend beyond classical monoclonal antibodies to include engineered antibodies with optimized Fc formats, fusion proteins, novel peptide inhibitors, and even antibody-conjugated nanoconstructs. Such molecules are being designed to overcome the challenges traditionally associated with CD47-targeted therapies—especially issues with off-target toxicity and hematologic side effects—with a view toward increasing tumor specificity and enhancing therapeutic efficacy.
Recent Discoveries
The discovery of new candidate modulators has primarily revolved around two strategies. The first, through the engineering of novel antibodies and fusion proteins, has yielded promising molecules such as AK117 and the fully human anti-CD47 antibody, ZF1. AK117, a novel humanized immunoglobulin G4 (IgG4) monoclonal antibody, has been reported to demonstrate excellent receptor occupancy, safety profile (with no dose-limiting toxicities noted even at high doses such as 45 mg/kg weekly), and a potent capability to bind and block CD47 on tumor cells, thereby stimulating macrophage-mediated phagocytosis. In contrast, ZF1 represents another line of innovative research, developed using phage display library techniques to provide a fully human anti-CD47 option with potential therapeutic value and reduced immunogenicity.
Simultaneously, innovative approaches have led to the design of soluble recombinant CD47-Fc fusion proteins. These constructs typically feature the extracellular domain of CD47 linked to the Fc portion of human immunoglobulins, and have demonstrated the ability to modulate inflammatory responses via inhibition of pro-inflammatory cytokines in dendritic cells and rheumatoid arthritis models. By acting as decoys, these fusion proteins can bind SIRPα and block the inhibitory signaling on macrophages while avoiding some of the drawbacks of full-length antibodies.
A second notable strategy involves the development of nanoconstructs that integrate CD47 targeting into chemoimmunomodulatory platforms. For instance, researchers have successfully fabricated CD47-conjugated human serum albumin (HSA) nanosystems loaded with chemotherapeutic agents such as dabrafenib. These nanoconstructs not only enhance drug delivery to tumor-specific receptors via receptor-mediated targeting but also facilitate the preferential release of the chemotherapeutic payload in the acidic tumor microenvironment. This multi-functional design enables the combination of direct cytotoxic effects with immune checkpoint modulation and represents a hybrid approach that merges conventional chemotherapy with immunotherapeutic strategies.
Furthermore, innovative bispecific antibody formats have been engineered to dual-target both CD47 and a tumor-specific antigen (e.g., PD-L1, CD20, or EGFR). These bispecific molecules are designed to focus the blockade of CD47 primarily on tumor cells, thereby minimizing binding to normal cells—a significant step towards reducing systemic toxicity and enhancing therapeutic selectivity. Taken together, these discoveries illustrate how the new generation of CD47 modulators is not merely a replication of earlier designs but rather a re-imagination using multiple molecular scaffolds and engineering techniques tailored to overcome the limitations of previous approaches.
Key Molecules and Their Characteristics
Among the key new molecules, AK117 is emerging as a frontrunner thanks to its favorable safety profile and high CD47 receptor occupancy on peripheral T cells, achieving 100% occupancy at low doses and maintaining this occupancy with subsequent dosing schedules. AK117’s IgG4 backbone, specifically engineered to minimize Fc effector function and thereby limit adverse effects such as red blood cell (RBC) agglutination or anemia, stands out as a critical design feature in its development. This approach contrasts with earlier anti-CD47 antibodies that had to rely on priming-dose strategies to mitigate hematologic toxicity.
Another molecule, ZF1, developed via phage display techniques, is designed as a fully human antibody with therapeutic potential. Its development seeks to avoid the immunogenic complications seen with humanized or chimeric antibodies that carry residual murine sequences. ZF1 is reported to block CD47/SIRPα interaction effectively, thereby reinvigorating macrophage-mediated phagocytosis against tumor cells.
In the realm of fusion proteins, the CD47-Fc fusion constructs are characterized by their ability to interfere with the CD47 signaling axis without the full spectrum of effector functions associated with conventional antibodies. These modulators take advantage of the fact that only the extracellular portion of CD47 is necessary for binding to SIRPα, and by fusing it with an Fc domain optimized for reduced effector function, these molecules can serve both as therapeutic agents and diagnostic tools in various inflammatory and oncologic conditions.
Nanoconstructs, such as the CD47-conjugated HSA-based systems loaded with dabrafenib, combine targeted drug delivery with CD47 blockade. The use of acid-labile linkers (e.g., cis-aconityl-PEG-maleimide) ensures that these nanoconstructs release their chemotherapeutic payload preferentially within the acidic tumor microenvironment. This dual mechanism of action not only directly attacks tumor cells with cytotoxic drugs but also removes the “don’t eat me” signal on tumor cells, thereby enhancing their clearance by macrophages.
Moreover, bispecific antibodies that target both CD47 and a tumor-associated antigen are being actively developed. For example, bispecific constructs that simultaneously bind to CD47 and PD-L1 or other markers can provide a coordinated therapeutic attack that interrupts multiple immune evasion pathways simultaneously. Such bispecific constructs provide improved specificity and may have synergistic effects by combining checkpoint blockade with targeted cytotoxicity.
Finally, small molecules and peptide-based inhibitors—although still in earlier stages of development compared to antibody-based therapeutics—are also being investigated as inhibitors of the CD47 pathway. These molecules aim to disrupt the CD47-SIRPα interaction through competitive binding or by modulating post-translational modifications (such as the formation of N‑terminal pyroglutamate on CD47 required for SIRPα binding) via inhibition of enzymes like QPCTL. Such approaches, if optimized, might offer the convenience of oral administration and more straightforward manufacturing processes.

Development and Testing of CD47 Modulators
The translation of novel CD47 modulators from discovery to clinical application has involved rigorous preclinical studies followed by early-phase clinical trials. The development process is intricately designed to assess both efficacy and safety parameters such as immune reactivation, tumor cell phagocytosis, and, importantly, potential off-target effects—most notably related to anemia and other hematologic toxicities.
Preclinical and Clinical Trials
In preclinical models, many of these new molecules have demonstrated promising results. Novel antibodies like AK117 have been shown in animal models to achieve 100% receptor occupancy on T cells at relatively low doses and maintain this occupancy with dosing regimens ranging up to 45 mg/kg weekly while displaying an excellent safety profile. Animal studies using mouse xenograft models have further demonstrated that antibody-mediated blockade of the CD47-SIRPα axis reactivates macrophage activity and suppresses tumor growth both as monotherapy and in combination with other chemotherapeutic agents. For instance, the preclinical evaluation of CD47 conjugated nanoconstructs has shown enhanced uptake by tumor tissue compared to non-targeted formulations, along with superior cytotoxicity and apoptosis induction in vitro and in vivo.
Clinical trials have also started to bear fruit in terms of efficacy and safety. Some of the most advanced CD47 modulators include humanized anti-CD47 monoclonal antibodies such as Hu5F9-G4 (magrolimab), which have been evaluated in early-phase trials in both hematologic malignancies and solid tumors. Although Hu5F9-G4 has shown remarkable anti-tumor activity, its clinical development has been accompanied by the challenge of hematologic toxicities, prompting the exploration of new dosing strategies and the design of antibodies with modified Fc regions to reduce such side effects.
Moreover, bispecific antibodies are undergoing clinical testing, as their dual-targeting capability is anticipated to improve tumor specificity and reduce the adverse effects associated with ubiquitous CD47 expression. Early-phase clinical trials using these bispecific constructs have reported preliminary efficacy signals with improved therapeutic indices, though further clinical validation is required to confirm their long-term benefits.
Preclinical studies on fusion proteins—where CD47’s extracellular domain is fused to an Fc portion to create a decoy receptor—have demonstrated that these molecules can inhibit CD47-SIRPα signaling and stimulate the innate immune system, setting the stage for further clinical evaluation.
Challenges in Development
Despite these promising developments, several challenges remain in the development of CD47 modulators. One of the principal complications is the ubiquitous expression of CD47 on healthy cells, particularly RBCs, which leads to an antigen sink effect and increases the risk of hematologic toxicities such as anemia, thrombocytopenia, and neutropenia. Modifying the Fc region to limit effector functions is one strategy under investigation, but this must be balanced against the need to engage immune effector mechanisms for anti-tumor responses.
Another challenge is related to the heterogeneity of CD47 expression among different tumor types and even among cells within the same tumor. This variability necessitates precision in dosing and targeted delivery to ensure that therapeutic levels of the modulator are achieved in the tumor microenvironment without causing unacceptable levels of off-target toxicity.
Furthermore, the development of bispecific antibodies and novel nanoconstructs requires highly sophisticated manufacturing processes. These modalities, while promising in their ability to combine multiple mechanisms of action, introduce additional complexity in terms of pharmacokinetics, stability, and regulatory approval. For example, the conjugation efficiency of payloads and the maintenance of stability in the tumor microenvironment represent significant hurdles that must be overcome.
Another issue arises with the use of fusion proteins and small molecule inhibitors. While they may offer advantages in terms of reduced immunogenicity or ease of administration, ensuring that these molecules can maintain sufficient specificity and affinity to disrupt the CD47-SIRPα interaction in a physiologically relevant context remains an ongoing area of research.
Collectively, while the preclinical and early clinical data on these novel CD47 modulators are promising, additional work is needed to optimize dosing regimens, refine molecular designs, and confirm efficacy in larger, more diverse patient populations.

Future Directions and Implications
The advances in CD47 modulator discovery and development are opening new horizons for cancer immunotherapy. The next generation of CD47-targeting molecules is expected to address current challenges and provide improved therapeutic efficacy with minimized side effects. Future strategies will likely center on combining multiple modalities to enhance tumor specificity and functional potency while integrating state-of-the-art delivery systems and personalized medicine approaches.
Potential Therapeutic Applications
Future applications of new CD47 modulators may span a broad spectrum of cancer types, including solid tumors that are typically less responsive to conventional immunotherapies. One promising direction is the integration of CD47 modulators with other immune checkpoint inhibitors—such as PD-1/PD-L1 or CTLA-4 blockers—in combination therapies. This approach could leverage the innate immune activation from CD47 blockade with the adaptive immune system’s cytotoxic T-cell responses, thereby maximizing anti-tumor activity. Early clinical studies using combinations like Hu5F9-G4 with rituximab have already shown promising response rates in conditions such as non-Hodgkin’s lymphoma.
Beyond hematologic malignancies and solid tumors like breast cancer, head and neck squamous cell carcinoma, and glioblastoma, CD47 modulators have potential application in overcoming resistance to conventional therapies. As tumor cells overexpress CD47 to evade immune clearance, modulating this pathway may re-sensitize these cells to both chemotherapy and radiation therapies, as evidenced by preclinical studies where CD47 blockade is synergistic with agents like doxorubicin.
Nanoconstructs and bispecific antibodies represent strategies where combinations of cytotoxic drugs and CD47 inhibitors can be selectively delivered to the tumor microenvironment. Such platforms not only facilitate targeted drug delivery but may also re-educate tumor-associated macrophages and enhance antigen presentation. These multifaceted therapeutic approaches could yield durable anti-tumor responses with a lower toxicity profile and provide a significant advantage over traditional chemotherapy.
In addition, the potential to use CD47 modulators in the context of viral infections and inflammatory disorders is an emerging concept. Given that CD47 signaling can modulate inflammatory cytokine production and immune cell migration, inhibitors targeting this pathway might find applications beyond oncology, such as in the treatment of rheumatoid arthritis or in controlling inflammatory responses during viral infections such as HIV or influenza.
Future Research Directions
Future research on CD47 modulators is likely to focus on several key areas. First, there is an ongoing effort to engineer molecules that can retain high affinity and selectivity for CD47 on tumor cells while sparing normal cells—a critical balancing act given the antigen sink issue. Protein engineering techniques, including Fc region modifications and bispecific antibody designs, will be instrumental in achieving this goal.
Research will also concentrate on elucidating the precise molecular mechanisms that govern CD47 expression and regulation in various tumor types. Understanding the differential regulation of CD47 at transcriptional, post-transcriptional, and post-translational levels (as highlighted by factors like microRNAs and cytokines) may reveal additional targets that can be manipulated in concert with CD47 inhibition. Such insights could lead to the development of combination therapies that simultaneously target multiple axes of immune evasion.
Another promising avenue is the continued development of advanced nanoconstructs. The ability to couple CD47 targeting with the controlled release of chemotherapeutic agents not only enhances drug delivery but also mitigates systemic toxicity. Research into the physicochemical properties of these nanoconstructs—including size, charge, and stability under physiological conditions—will be paramount for translating these technologies from bench to bedside.
Moreover, the advent of next-generation sequencing and single-cell transcriptomics provides an unprecedented view of the tumor microenvironment. These tools will allow researchers to identify patient-specific patterns of CD47 expression and immune cell infiltration, paving the way for personalized immunotherapy regimens. Clinical trials using these biomarkers to stratify patient populations can help tailor the use of CD47 modulators to those most likely to benefit, ultimately improving clinical outcomes.
The development of small molecule inhibitors and peptide-based modulators also remains an important research focus. While these molecules may not yet have the potency of antibody-based therapies, their potential for oral administration, easier synthesis, and favorable pharmacokinetic profiles make them a valuable area of exploration. Ongoing work on inhibitors of enzymes like QPCTL—which modify CD47 post-translationally—is an example of how targeting the biochemical processing of CD47 can be an effective strategy to modulate its function.
Finally, as more CD47 modulators enter clinical trials, long-term studies will be necessary to monitor not only efficacy but also potential resistance mechanisms. Over time, tumors might adapt to CD47 blockade by upregulating alternative “don’t eat me” signals or by altering the tumor microenvironment in ways that impede immune cell infiltration. Future research will need to combine CD47 inhibitors with agents that target these compensatory mechanisms, forming a comprehensive, multi-pronged therapeutic strategy.

Conclusion
In summary, new molecules for CD47 modulation have been discovered through innovative approaches ranging from fully human monoclonal antibodies (such as AK117 and ZF1) to fusion proteins, bispecific antibodies, and multifunctional nanoconstructs. These new modulators aim to disrupt the CD47-SIRPα signaling axis, thereby enhancing macrophage-mediated phagocytosis and reactivating innate and adaptive anti-tumor immunity. Preclinical studies have demonstrated compelling results in various cancer models, and early-phase clinical trials have begun to validate their efficacy and tolerability. However, significant challenges remain in optimizing specificity, minimizing hematologic toxicity, and overcoming the antigen sink effect caused by CD47’s ubiquitous expression.
Future research directions focus on refining molecular engineering techniques to obtain high-affinity, tumor-selective molecules; combining CD47 modulators with other immunotherapies or conventional chemotherapies for synergistic effects; and developing advanced drug delivery systems like nanoconstructs to target the tumor microenvironment more effectively. Additionally, a deeper understanding of the molecular regulation of CD47 expression in different tumor types will provide broader insights into personalized and precision immunotherapy. Overall, these developments represent an exciting frontier in cancer immunotherapy with the potential to transform treatment paradigms and improve patient outcomes.