ENPP3: A Potential Target for Tumor Therapy with Broad Prospects
By Lauren He
July 7, 2026
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ENPP3 is rapidly emerging as a highly promising therapeutic target in oncology. As its expression is strictly apically restricted in normal tissues but becomes depolarized and widely overexpressed across various solid tumors, it offers an ideal profile for precision treatments. This potential is already translating into exciting clinical progress: A prime example is JNJ-89862175, a novel antibody-drug conjugate (ADC) targeting ENPP3 with a microtubule inhibitor payload. Following preclinical studies that demonstrated specific binding, rapid internalization, potent cytotoxicity, and a favorable safety profile, this drug has recently advanced into phase I clinical trials - a milestone that perfectly highlights the broad and expanding prospects of ENPP3-targeted therapies[1].
Structure and Function of ENPP3
Seven members (ENPP1-7) of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family have been identified to date. Among them, ENPP1, ENPP3, ENPP4, and ENPP5 possess nucleotide hydrolysis activity; whereas ENPP2, ENPP6, and ENPP7 have evolved into phospholipases through the adaptive evolution of their catalytic domains. ENPP3 (also known as CD203c) is a type II single-pass transmembrane ectoenzyme. Its structure contains two N-terminal SMB domains (SMB 1/2), a PDE catalytic domain, a lasso loop (LL), and a C-terminal NUC domain lacking catalytic activity. The PDE domain is common to the ENPP family and possesses pyrophosphatase/phosphodiesterase activity, with its active site containing two Zn2+ ions. Early studies confirmed that ENPP3 has a substrate preference for ATP and acts as a regulator of the purinergic signaling pathway. It primarily functions in basophils and mast cells, regulating purinergic signaling by degrading extracellular ATP and negatively modulating chronic allergic inflammatory responses.
Structure of ENPP3[2]
Cyclic GMP-AMP (cGAMP) is an important second messenger molecule that is synthesized when cells recognize cytosolic double-stranded DNA (dsDNA). It is transmitted between cells to initiate downstream immune signaling pathways. Previously, ENPP1 was considered the only regulatory enzyme capable of hydrolyzing cGAMP, weakening its activation of the stimulator of interferon genes (STING) pathway through cGAMP hydrolysis, thereby suppressing anti-tumor immunity. In recent years, studies have confirmed that ENPP3 is also a key cGAMP hydrolase, playing an important role in tumor immune evasion[3]. There are significant differences in the tissue expression profiles between ENPP1 and ENPP3. ENPP1 is mainly enriched in the liver, skeletal muscle, adipose tissue, and vascular endothelium, while ENPP3 is primarily distributed in the intestines, kidneys, placenta, and specific immune cell subsets; this difference also persists in malignant tumors[4].
In von Hippel–Lindau (VHL)-deficient clear cell renal cell carcinoma (ccRCC), the loss of VHL function prevents the ubiquitination and degradation of HIF-1α. This causes it to accumulate intracellularly, enter the nucleus, bind to the hypoxia response element (HRE) in the promoter region of the ENPP3 gene, and directly induce the high expression of membrane-bound ENPP3. As an extracellular cGAMP hydrolase, ENPP3 can degrade the cGAMP released by tumor cells into the extracellular space into inactive AMP and GMP, blocking the transmission of cGAMP to immune cells. This suppresses the activation of the STING pathway and the secretion of downstream type I interferons (IFNs), ultimately forming an immunosuppressive microenvironment and promoting tumor immune evasion. Conversely, after using specific antibodies to block ENPP3, its hydrolysis activity is inhibited, allowing extracellular cGAMP to be transported intact to activate the STING pathway in immune cells, triggering a type I interferon response and reactivating anti-tumor immunity.
Model of the Pro-tumorigenic Role of ENPP3 in Clear Cell Renal Cell Carcinoma[4]
Drug Development Progress of ENPP3
Currently, several domestic and international pharmaceutical companies, including Johnson & Johnson, Xencor, and Simcere, have actively positioned themselves in the development of ENPP3-targeted drugs. The research direction is primarily focused on ADCs and TCEs. Except for ALY301 by Alys Pharmaceuticals for allergic skin diseases, all other pipelines are focused on tumor therapy.
ADC
The world's first ADC targeting ENPP3 is AGS16C3F, developed by Agensys, which had advanced to phase II clinical trials. This drug is composed of an anti-ENPP3 IgG2 antibody (AGS16-7.8), an MC non-cleavable linker, and the microtubule inhibitor MMAF, targeting the NUC domain of ENPP3[5]. However, a randomized phase II study showed that its efficacy in metastatic renal cell carcinoma was inferior to the standard drug axitinib, and Agensys terminated its development in 2019[6]. Meanwhile, JNJ89862175, internally developed by Johnson & Johnson, has now entered phase I clinical trials. With its excellent preclinical anti-tumor activity and safety profile, it is expected to break the clinical development bottleneck of ENPP3 ADCs. 
Structural Diagram of AGS-16C3F[5]
TCE
There are currently two ENPP3 TCEs in clinical trials, namely XmAb819 developed by Xencor and JNJ-87890387 developed by Johnson & Johnson. XmAb819 adopts a 2+1 configuration, containing two ENPP3 binding domains and one CD3 binding domain. It can precisely kill tumor cells with high ENPP3 expression while reducing damage to normal cells. It also optimizes the Fc region to enhance drug stability and prolong the half-life. Its phase I study for advanced clear cell renal cell carcinoma enrolled a total of 69 multi-line treated patients. Preliminary data showed that the drug possesses anti-tumor activity, with good overall safety and tolerability. Adverse reactions were primarily mild to moderate cytokine release syndrome, rash, and gastrointestinal reactions, with no severe neurotoxicity or fatal adverse events[7].
Structural Diagram of XmAb819 and Its Selective Killing Effect on Cells with Different ENPP3 Expression Levels[8]
JNJ-87890387 is a fully human bispecific antibody with a high affinity for ENPP3 on tumor cells and a lower affinity for CD3. In vitro, JNJ-87890387 exhibited potent T-cell activation and cytotoxicity against tumor cell lines with varying endogenous ENPP3 membrane expression levels, while showing no killing effect on cells lacking ENPP3 expression, confirming the specificity of JNJ-87890387. In vivo, JNJ-87890387 demonstrated strong ENPP3 expression-dependent anti-tumor activity in multiple cell line-derived and patient tumor-derived RCC and HCC xenograft models. This drug is currently undergoing a first-in-human phase I study to evaluate its safety and preliminary anti-tumor activity in advanced solid tumors with high ENPP3 expression[9].
| Drug Name | Drug Type | Target | Company | Highest Clinical Stage | Indications |
| JNJ-89862175 | ADC | ENPP3 | Janssen Biotech | Phase I Clinical | Advanced Malignant Solid Tumors |
| XmAb819 | TCE | ENPP3×CD3 | Xencor | Phase I Clinical | Advanced Clear Cell Renal Carcinoma |
| JNJ-87890387 | TCE | ENPP3×CD3 | Janssen Biotech | Phase I Clinical | Advanced Malignant Solid Tumors |
| ALY-301 | Bispecific Antibody | ENPP3×c-Kit | Alys Pharmaceuticals | Phase I Clinical | Dermographism; Chronic Urticaria |
| SIM0680 | ADC | ENPP3 | Simcere | Preclinical | Solid Tumors |
| AGS-16C3F | ADC | ENPP3 | Agensys | Phase II Clinical (Terminated) | _ |
A selection of ENPP3 targeted drugs
KACTUS Supplies High-Quality ENPP3 Proteins
As the value of the ENPP3 target continues to be validated, the development of ENPP3-targeted drugs continues to heat up. ENPP3 has become a potential target for the treatment of various solid tumors, such as renal cancer, and also holds broad prospects in the treatment of allergic diseases. To comprehensively support the development of ENPP3-targeted drugs, Kactus Biosystems can provide high-quality ENPP3, ENPP3 Domain, and ENPP family recombinant proteins. The products cover different species and various tags, undergo strict quality control, and are suitable for multiple R&D needs such as immunization, screening, and epitope identification.
Immobilized Human ENPP-3, His Tag at 1 μg/ml (100μl/well) on the plate. Dose response curve for Anti-ENPP-3 Antibody, hFc Tag with the EC50 of 27.2 ng/ml determined by ELISA.
Measured by its ability to hydrolyze thymidine 5'-monophosphate p-nitrophenyl ester. The specific activity is > 8000 pmol/min/μg.
Immobilized Human ENPP-3 (558-875), His Tag at 2 μg/ml (100μl/well) on the plate. Dose response curve for Anti-ENPP-3 Antibody, hFc Tag with the EC50 of 0.57 μg/ml determined by ELISA.
Measured by its ability to hydrolyze thymidine 5'-monophosphate p-nitrophenyl ester. The specific activity is > 40000 pmol/min/μg.
Product List
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Target |
Catalog Number |
Product Name |
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ENPP3 |
Human ENPP-3 Protein, His Tag |
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Human ENPP-3 Protein, Ultra Low Endotoxin, His Tag |
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Human ENPP-3 Protein, hFc (IgG1) Tag |
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Biotinylated Human ENPP-3 Protein, His-Avi Tag |
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Human ENPP-3 (558-875) Protein, His Tag |
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Biotinylated Human ENPP-3 (558-875) Protein, His-Avi Tag |
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Biotinylated Human ENPP-3 (48-157) Protein, His-Avi Tag |
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Biotinylated Human ENPP-3 (48-157) Protein, Ultra Low Endotoxin, His-Avi Tag |
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Rat ENPP-3 Protein，His Tag |
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Rat ENPP-3 Protein, Ultra Low Endotoxin, His Tag |
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Canine ENPP-3 Protein, His Tag |
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Canine ENPP-3 Protein, Ultra Low Endotoxin, His Tag |
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|
ENPP1 |
Human ENPP-1 Protein, His Tag |
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Human ENPP-1 Protein, His Tag |
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Human ENPP-1 Protein, Ultra Low Endotoxin, His Tag |
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Biotinylated Human ENPP-1 Protein, His-Avi Tag |
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Mouse ENPP-1 Protein, His Tag |
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Canine ENPP-1 Protein, His Tag |
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|
ENPP2 |
Human ENPP-2 Protein, His Tag |
|
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Human ENPP-2 Protein, Ultra Low Endotoxin, His Tag |
||
|
Mouse ENPP-2 Protein, His Tag |
References
[1] https://www.aacr.org/blog/2026/04/20/live-updates-from-the-aacr-annual-meeting-2026-monday-april-20/
[2] Borza R , Salgado-Polo F , Moolenaar W H ,et al.Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity[J].The Journal of biological chemistry, 2022, 298(2):101526.DOI:10.1016/j.jbc.2021.101526.
[3] Rachel Mardjuki, Songnan Wang, Jacqueline Carozza, Bahar Zirak, Vishvak Subramanyam, Gita Abhiraman, Xuchao Lyu, Hani Goodarzi, Lingyin Li. Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint, Cell Reports, Volume 43, Issue 5, 2024,114209, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2024.114209.
[4] Jiaxing Ma , Yayun Wu , Guangzheng Lin , Xin Sun , Hao Geng , Tao Zhang & Dexin Yu (2026) ENPP3 drives ccRCC progression by cGAMP hydrolysis and STING–IFN suppression, Cancer Biology & Therapy, 27:1, 2632995, DOI: 10.1080/15384047.2026.2632995
[5] Avina, H. (2016). AGS16F Is a Novel Antibody Drug Conjugate Directed against ENPP3 for the Treatment of Renal Cell Carcinoma. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-15-1542
[6] Christian Kollmannsberger, Toni K. Choueiri, Daniel Y.C. Heng, Saby George, Fei Jie, Ruslan Croitoru, Srinivasu Poondru, John A. Thompson, A Randomized Phase II Study of AGS‐16C3F Versus Axitinib in Previously Treated Patients with Metastatic Renal Cell Carcinoma, The Oncologist, Volume 26, Issue 3, March 2021, Pages 182–e361, https://doi.org/10.1002/onco.13628
[7] https://xencor.com/pipeline/xmab819/
[8] https://xencor.com/wp-content/uploads/Xencor-XmAb819-Update-2025-10-24-FINAL.pdf
[9] Vijayaraghavan, S., Seth, P., Winkis, A., Chevalier, K., Marthaler, A., Sproesser, K., Torti, V., Shah, N., Lacy, E., Frisk, A.-L., Deutsch, H., Chu, G., Sharp, M., Pabalan, J., Tilegenova, C., Thorton, K., Lauring, J., Mattson, B., Tian, K., … Laquerre, S. (2024). Abstract LB122: JNJ-87890387, a novel ENPP3 bispecific T-cell redirector (ENPP3xCD3) with tumor selectivity through targeting apical surface antigens. Cancer Research, 84(7_Supplement), LB122–LB122. https://doi.org/10.1158/1538-7445.am2024-lb122
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