A New Perspective on Tumor Immunotherapy: Mechanistic Insights, Clinical Challenges, and Structural Innovations of the CD47 Target

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Recently, at the 2026 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2026), clinical research data targeting metastatic pancreatic ductal adenocarcinoma (mPDAC) attracted widespread attention. In this study, spevatamig, a bispecific antibody new drug from the overseas pharmaceutical company Phanes Therapeutics, extended the overall survival of "the king of cancers," pancreatic cancer, by nearly half (13.2 months) compared to existing chemotherapy drugs. Moreover, spevatamig demonstrated good safety as a monotherapy, with no observed cytokine release syndrome (CRS) or dose-limiting toxicity (DLT).

Spevatamig is an innovative bispecific antibody targeting CLDN18.2/CD47. Although the clinical trial is still in the preliminary validation stage, the significant potential it has demonstrated brings new hope for the treatment of pancreatic cancer. Meanwhile, CD47, the "black hole target" that has faced repeated setbacks, may be approaching a breakthrough moment.

Phanes Therapeutics is a clinical-stage biotechnology company focused on the discovery and development of innovative drugs in the field of oncology, with proprietary technology platforms PACbody, SPECpair, and ATACCbody for developing novel bispecific antibodies with enhanced stability, manufacturability, and tunable immune activity.

Spevatamig, independently developed by Phanes Therapeutics, is a bispecific antibody with a natural IgG structure targeting CLDN18.2 and CD47. Based on the SPECpair and PACbody technology platforms, Phanes Therapeutics utilizes the single-arm anti-CD47 and the single-arm anti-CLDN18.2 antibody.Based on the IgG1 framework, constructAnd so on. Spevatamig has only one anti-CD47 arm, which makes its binding to red blood cells that do not express CLDN18.2 relatively weak. Therefore, spevatamig, through its two single arms with high binding ability to cancer cells, limits off-tumor (gastrointestinal) toxicity while exerting its potential therapeutic effects.

Presented at the ASCO GI 2026 ConferenceTWINPEAK Study, a multi-cohort Phase I clinical study for patients with gastrointestinal tumors, showed that in 107 mPDAC patients who received spevatamig as monotherapy or combination therapy,At 2mg/kg spevatamig+GnP（Standard Chemotherapy Regimen: Gemcitabine + Albumin-bound Paclitaxel）In the first-line treatment of mPDAC (n=15), the disease control rate (DCR) was 93%, the objective response rate (ORR) was 40%, the median progression-free survival (mPFS) was 7.3 months, and the median overall survival (mOS) was 13.2 months and still maturing.

More importantly,spevatamigDemonstrated good safety characteristics, with no CRS or DLT observed. No treatment-emergent adverse events (TEAE) of Grade ≥3 anemia, neutropenia, or thrombocytopenia were observed during the study period. Additionally, treatment responses were observed in all patients with CLDN18.2 scores ≥10%.

In summary, compared with previously published data on the GnP regimen as first-line treatment for mPDAC, the spevatamig 2mg/kg + GnP regimen has shown encouraging efficacy. Meanwhile,Despite being a small-sample clinical study,ButThese clinical conceptsOutstanding in ValidationData show that the molecular design of spevatamig reduces blood toxicity and improves gastrointestinal tolerability.

This is crucial for the development of the CD47 target, as it was previously hindered bySevere hematotoxicity,MakeMany CD47 star pipelinesClinical Development Hits a Snag.

CD47, also known as integrin-associated protein, is a widely expressed transmembrane glycoprotein. As an immune checkpoint, CD47 is highly present on the surface of tumor cells and, when bound toOn the surface of macrophagesSignal Regulatory Protein α (SIRPα）When combined, it releases a "don't eat me" signal, preventing macrophages from phagocytosing tumor cells. Therefore, after blocking the binding ability of CD47, macrophages canRestore the phagocytosis of tumor cells.

CD47/SIRPαThe mechanism of action shares some commonality with the fundamental principles between PD-1 and PD-L1, so the CD47 pathway is also referred to as "the next PD-1." Moreover, in theory, CD47 drugs have stronger anti-tumor activity than PD-1 inhibitors because targeting CD47 can activate both innate and adaptive immune responses against cancer, whereas PD-1 inhibitors only activate the adaptive immune response. Therefore, the industry has higher expectations for CD47.

In 2020, CD47 became a popular financing target in the pharmaceuticals industry. In March of that year, Gilead spent $4.9 billion to acquire Forty Seven, a pioneer in CD47 monoclonal antibody research. In July, SciClone Pharmaceuticals invested $120 million to introduce the Greater China rights to RRx-001, an immunostimulatory small molecule drug targeting CD47/SIRPα developed by EpicentRx. In September, I-Mab Biopharma entered into a global strategic partnership with AbbVie for its CD47 monoclonal antibody lemzoparlimab, with a total value of $2.94 billion.In September, CD47 star company Trillium TherapeuticsSecures $25 Million Investment from Pfizer；In October, the cancer immunotherapy development companySurfaceOncology（Targets under development include CD47.）Received GSK's Acquisition Intention。In November 2021, Pfizer spent $2.26 billion to acquire Trillium Therapeutics, obtaining two CD47-targeted drugs, maplirpacept and ontarpacept.

The entry of giants has quickly made the CD47 target a focal point of attention in the capital market, but the capital's enthusiasm has not been reciprocated with corresponding returns so far.Exploration of Pharmaceutical Companies in the CD47 FieldDoes not count asSmoothly。

In January 2022, Gilead announced that Magrolimab, its heavily invested CD47 antibody, was suspended by the FDA from clinical trials for the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) in combination with azacitidine due to suspected serious adverse events. Although the trial was later resumed after review, this target subsequently faced a series of setbacks.

In 2023, I-Mab and AbbVieLasted for three yearsCooperationAnnouncement of Termination, This Outcome ReflectsTwo Companies in CD47 TargetDrug DevelopmentThe failure.At the beginning of 2024, Gilead updated its pipeline progress while releasing its financial report. All six trials related to magrolimab were removed, indicating that Gilead has completely abandoned the development of this drug, resulting in a loss of $4.9 billion.

In April 2025, ALX Oncology announced that its developed CD47 inhibitor, Evorpacept, did not meet the primary endpoint goals in two Phase II clinical trials, ASPEN-03 and ASPEN-04, when used in combination with Keytruda: compared to Keytruda alone, Evorpacept + Keytruda failed to improve the objective response rate (ORR) in patients with advanced head and neck squamous cell carcinoma. Previously, the company had terminated clinical trials of Evorpacept for MDS and AML.

2025June, Pfizer announcedCD47-targeting drug acquired through acquisitionmaplirpaceptInPhase II Study for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Terminated Due to Difficulty in Patient Recruitment,PreviouslyontorpaceptHas also disappeared from the R&D pipeline.

The consecutive failures of pharmaceutical giants and Biotech companies have confirmed that the development difficulty of CD47 far exceeds expectations. Comprehensive analysis shows that the failure in CD47 drug development is due to both safety and efficacy issues. Since CD47 is widely expressed on the surface of normal cells such as red blood cells and platelets, if drugs targeting CD47 (such as antibodies or SIRPα-Fc fusion proteins) bind to red blood cells, they may cause red blood cells to agglutinate through the conjugation effect of antibodies, damaging their structure and function, and subsequently leading to hematological toxicity symptoms like anemia. Additionally, if the Fc segment of the drug can bind to the Fcγ receptor on the surface of macrophages, activating the phagocytic function of macrophages, it might direct the macrophages to engulf red blood cells, causing more severe hematological toxicity.

To avoid hematological toxicity, some pharmaceutical companies have attempted to weakenCD47 DrugsAndThe binding capacity of red blood cells is utilized to avoid damage to red blood cells. For example, Pfizer's maplirpacept employs an SIRPα-IgG4 FC fusion protein structure, where the SIRPα portion is responsible for binding with CD47, while the IgG4 FC segment has been engineered to reduce its affinity for CD47 on the surface of red blood cells, minimizing non-specific binding of the drug to red blood cells. However, excessive weakening of the binding affinity leads to insufficient efficacy, necessitating a higher dosage for treatment, which in turn increases the risk of hematological toxicity.

Therefore, forFollowerFor them, how to balance efficacy and safety has become a thorny issue.

CD47 is crucial for tumor survival, but equally vital for red blood cell survival. The inherent contradiction between the physiological function of this target and therapeutic goals poses significant challenges to the drugability of CD47, yet the difficulties have not shaken the industry's determination to continue exploring.

At the 2025 ASCO meeting, ImmuneOncia Therapeutics presented interim results from the Phase Ib clinical trial of its next-generation CD47 antibody IMC-002 in combination with lenvatinib for the treatment of advanced hepatocellular carcinoma (HCC). IMC-002 has a unique binding conformation and epitope, which minimizes binding to red blood cells. Preliminary clinical results demonstrated that IMC-002 exhibited a favorable safety profile, with no reported cases of neutropenia or thrombocytopenia, and 96% of adverse events were grade 1-2. Among 10 evaluable patients, the ORR was 30%, the DCR was 70%, and the median time to progression (TTP) was 8.3 months.

Some pharmaceutical companies in China have also explored a series of innovative solutions in the CD47 target field and will welcome the rational return of capital in 2025.

In June 2025, Henlius and FBD Biologics Limited, a subsidiary of Hancong Biotech, signed a cooperation agreement,Henlius will obtain the exclusive rights for the development, production, and commercialization of HCB101, a SIRPα-Fc fusion protein independently developed by Phanes Therapeutics, in China (excluding Taiwan), specific countries in Southeast Asia, and specific countries in the Middle East and North Africa (MENA) regions, as well as the preferential negotiation rights for the Japanese market. Phanes Therapeutics is expected to receive a $10 million upfront payment.AndPotential milestone payments of $192 millionetc.

HCB101, as aSIRPα-Fc fusion protein possesses high selectivity for tumor-targeting binding while reducing red blood cell binding, minimizing common side effects such as anemia and thrombocytopenia, and has demonstrated excellent hemocompatibility in early clinical studies. A Phase Ib/IIa study of HCB101 in combination with standard therapy for the treatment of advanced solid tumors is currently underway in mainland China, the United States, and other regions.

This transaction adopts a low down payment + high milestone risk-sharing model, indicating that as long as molecular design can effectively address the issue of "erythrocyte toxicity," industrial capital is willing to pay a premium for safety.

In August 2025, Zhejiang Onlly Pharmaceutical Co., Ltd. announcedEnter into a "Strategic Cooperation Agreement and License Agreement" with Yafei (Shanghai) Biomedical Technology Co., Ltd. and Shanghai Qinhe Force Biomedical Technology Co., Ltd. The company will obtain the drug molecule IMD-1005 targeting CD47 in China.Including ChinaMainland China, Hong Kong, Macao Special Administrative Regions, and Taiwan, China)Anglikang plans to pay a total of 150 million RMB as an upfront payment to Yafei Biologics and Qinheli in stages, along with milestone payments of up to 620 million RMB and a 12.8% sales royalty after the product's market launch.

IMD-1005 is a globally innovative tumor microenvironment-activated masked antibody drug, with the antibody portion being an anti-CD47 monoclonal antibody. The binding activity of this CD47 antibody to the CD47 target is significantly reduced due to the masking, and it exhibits high stability in the bloodstream, thereby avoiding blood toxicity caused by CD47 antibody activity. Once the drug is delivered to the tumor microenvironment, the linker connecting the mask and the antibody is cleaved by enzymes highly expressed in the tumor microenvironment, eliminating the masking effect and restoring the activity of the CD47 antibody. This promotes macrophage attacks on tumor cells within the tumor locale while also enhancing antibody-dependent cell-mediated cytotoxicity (ADCC), achieving a dual antitumor immune therapeutic effect.

ImmunophageOfIMM01It is a SIRPα-Fc fusion protein targeting CD47.The engineered human SIRPα domain that binds to CD47 significantly inhibited the drug's binding to human red blood cells in in vitro studies.

Currently, the product is proposed to be developed for the indication ofMyelodysplastic Syndromes (MDS), Classical Hodgkin Lymphoma (cHL), and Chronic Myelomonocytic Leukemia (CMML)As well as cardiovascular diseases, and has already entered the late clinical stage. Previous studies have shown that the adverse reactions of IMM01 are all within a controllable range.

Phanes Therapeutics' AK117 is a humanized IgG4 monoclonal antibody against CD47. In erythrocyte agglutination assays, AK117 did not induce erythrocyte agglutination at concentrations up to 3000 nM, indicating significant safety. Phanes Therapeutics has initiated a global Phase II clinical trial of AK117 in combination with azacitidine for the treatment of newly diagnosed higher-risk MDS, among others.

In addition, Innovent Biologics has developed a CD47/PD-L1 bispecific antibody, and Darsun Biopharma has developed a HER2/CD47 bispecific antibody, etc.

Although there are quite a few in the CD47 fieldThere are still many successful cases despite previous failures.InGradual Disclosure。As giants frequently encounter setbacks, industrial capital has quietly started a new round of reverse layout. Different from the wave of enthusiasm in 2020, this time the return of capital's rationality is paying for verified efficacy and safety.

In this wave of enthusiasm, pharmaceutical companies have proposed a series of innovative solutions: either reducing the binding of CD47 drugs to red blood cells, or abandoning the direct killing effect of CD47 antibodies to seek new mechanisms of action, or developing bispecific antibodies, fusion proteins, and exploring combination drug strategies, etc. The diversity of drug molecules demonstrates the indomitable innovative spirit of pharmaceutical companies in facing the challenges of CD47. In the next 1-2 years, the CD47 field will usher in critical data readings, at which point the CD47 target may no longer be the "unfulfilled wish" of the pharmaceutical industry.

Source: Yao Innovation

Editor: Sheep

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