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DRUG CLASS:

CD39 inhibitor

2ms
CD39 inhibitor (POM-1) enhances radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells by promoting apoptosis through the Bax/Bcl-2/Caspase 9/Caspase 3 pathway. (PubMed, Int Immunopharmacol)
These results suggested that POM-1 had synergistic effect with radiotherapy by enhancing cell apoptosis through Bax/Bcl-2 signal pathway in ESCC. The combination of POM-1 and radiotherapy is expected to enhance the anti-tumor effect in ESCC.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • CASP9 (Caspase 9) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
ENTPD1 expression
3ms
A Study of ES014 in Subjects With Advanced Solid Tumors (clinicaltrials.gov)
P2, N=15, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences
New P2 trial • Metastases
3ms
A Study of ES014 in Patients With Locally Advanced or Metastatic Solid Tumours (clinicaltrials.gov)
P1, N=120, Recruiting, Elpiscience (Suzhou) Biopharma, Ltd. | N=70 --> 120
Enrollment change • Metastases
4ms
Combination treatment with TTX-030, a first-in-class anti-CD39 antibody, in patients with advanced pancreatic cancer (ESMO 2024)
HLA-DQ is an HLA class II molecule expressed on APCs. Patients were enrolled May 2020 to Feb 2022 and treated with standard dosing of G/nP (d1, 8, 15) and either TTX-030 40mg/kg followed by 20mg/kg every two weeks (n = 31) or TTX-030 every 2 weeks and budigalimab (anti-PD1 Ab) 500mg every 4 weeks (n = 28). TTX-030 combinations show promising clinical activity in 1L PDAC with HLA-DQhigh having marked benefit. A randomized phase 2 study (NCT06119217) is underway to further evaluate TTX-030 combination treatment based on HLA-DQ status in metastatic PDAC.
Clinical • PD(L)-1 Biomarker • IO biomarker • Metastases
|
ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
nCounter® PanCancer Immune Profiling Panel
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budigalimab (ABBV-181) • TTX-030
4ms
INT-1B3, an LNP formulated miR-193a-3p mimic, promotes anti-tumor immunity by enhancing T cell mediated immune responses via modulation of the tumor microenvironment and induction of immunogenic cell death. (PubMed, Oncotarget)
Live cell imaging demonstrated PBMC-mediated cytotoxicity against 1B3-transfected tumor cells. These data demonstrate for the first time that miR-193a-3p induces long-term immunity against tumor development via modulation of the tumor microenvironment and induction of immunogenic cell death.
Journal
|
CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • MIR193A (MicroRNA 193a)
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INT-1B3
6ms
Characterization of AB598, a CD39 Enzymatic Inhibitory Antibody for the Treatment of Solid Tumors. (PubMed, Mol Cancer Ther)
In cynomolgus monkeys, systemically dosed AB598 results in effective enzymatic inhibition in tissues, full peripheral and tissue target engagement, and a reduction in cell surface CD39 both in tissues and in the periphery. Taken together, these data support a promising therapeutic strategy of harnessing the eATP generated by standard-of-care chemotherapies to prime the tumor microenvironment for a productive anti-tumor immune response.
Journal
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ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
AB598
6ms
Study of SRF617 With AB928 (Etrumadenant) and AB122 (Zimberelimab) in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov)
P2, N=16, Terminated, Coherus Biosciences, Inc. | Completed --> Terminated; The study was terminated for strategic reasons, not due to any safety concerns.
Trial termination • Combination therapy • Metastases
|
Yutuo (zimberelimab) • etrumadenant (AB928) • perenostobart (SRF617)
7ms
TTX-030 in Combination With Immunotherapy and/or Chemotherapy in Subjects With Advanced Cancers (clinicaltrials.gov)
P1, N=185, Completed, Trishula Therapeutics, Inc. | Active, not recruiting --> Completed
Trial completion • Combination therapy • Metastases
|
Keytruda (pembrolizumab) • gemcitabine • docetaxel • 5-fluorouracil • albumin-bound paclitaxel • oxaliplatin • budigalimab (ABBV-181) • leucovorin calcium • TTX-030
8ms
Phase 2 Study of TTX-030 and Chemotherapy With or Without Budigalimab for 1L mPDAC Patients (clinicaltrials.gov)
P2, N=180, Recruiting, Trishula Therapeutics, Inc. | Not yet recruiting --> Recruiting | Initiation date: Dec 2023 --> Mar 2024
Enrollment open • Trial initiation date • Metastases
|
gemcitabine • albumin-bound paclitaxel • budigalimab (ABBV-181) • TTX-030
10ms
ARL67156, a small-molecule CD39 inhibitor, enhances natural killer cell cytotoxicity against gastric cancer cells in vitro and in nude mice (PubMed, Nan Fang Yi Ke Da Xue Xue Bao)
ARL67156 activates NK cells through the vav1-Syk signaling pathway to enhance their cytotoxicity against gastric cancer cells, which may serve as a new strategy for NK cell immunotherapy for gastric cancer.
Preclinical • Journal • IO biomarker
|
IFNG (Interferon, gamma) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • SYK (Spleen tyrosine kinase) • LAMP1 (Lysosomal Associated Membrane Protein 1) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1) • VAV1 (Vav Guanine Nucleotide Exchange Factor 1) • B3GAT1 (Beta-1,3-Glucuronyltransferase 1) • NKG2D (killer cell lectin like receptor K1)
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ENTPD1 expression
1year
New P2 trial • Metastases
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gemcitabine • albumin-bound paclitaxel • budigalimab (ABBV-181) • TTX-030
1year
Study of AB598 Monotherapy and Combination Therapy in Participants With Advanced Cancers (clinicaltrials.gov)
P1, N=81, Recruiting, Arcus Biosciences, Inc. | Trial completion date: Nov 2025 --> Aug 2025 | Trial primary completion date: Nov 2025 --> Aug 2025
Trial completion date • Trial primary completion date • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 negative
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carboplatin • 5-fluorouracil • pemetrexed • oxaliplatin • Yutuo (zimberelimab) • leucovorin calcium • AB598
1year
TTX-030 Single Agent and in Combination With Immunotherapy or Chemotherapy for Patients With Advanced Cancers (clinicaltrials.gov)
P1, N=56, Completed, Trishula Therapeutics, Inc. | Active, not recruiting --> Completed
Trial completion • Combination therapy • Metastases
|
ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
ENTPD1 expression
|
Keytruda (pembrolizumab) • gemcitabine • albumin-bound paclitaxel • TTX-030
1year
KEYNOTE-A62: Study of SRF617 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
P1, N=85, Completed, Surface Oncology | Active, not recruiting --> Completed | N=177 --> 85
Trial completion • Enrollment change • Metastases
|
HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
HER-2 negative
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Keytruda (pembrolizumab) • gemcitabine • albumin-bound paclitaxel • perenostobart (SRF617)
1year
CD39 inhibition and VISTA blockade may overcome radiotherapy resistance by targeting exhausted CD8+ T cells and immunosuppressive myeloid cells. (PubMed, Cell Rep Med)
Clinically, high VISTA expression is associated with poor prognosis in patients with NSCLC. Altogether, our data provide deep insight into acquired resistance to RT from an immune perspective and present rational combination strategies.
Journal
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CD8 (cluster of differentiation 8) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1) • VSIR (V-Set Immunoregulatory Receptor)
over1year
Study of AB598 Monotherapy and Combination Therapy in Participants With Advanced Cancers (clinicaltrials.gov)
P1, N=81, Recruiting, Arcus Biosciences, Inc. | Not yet recruiting --> Recruiting
Enrollment open • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 negative
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carboplatin • 5-fluorouracil • pemetrexed • oxaliplatin • Yutuo (zimberelimab) • leucovorin calcium • AB598
over1year
A phase II multicenter, open label, non-randomized study of neoadjuvant and adjuvant treatment with IPH5201 and durvalumab in patients with resectable, early-stage (II to IIIA) non-small cell lung cancer (MATISSE) (ESMO 2023)
Assessment of exploratory biomarkers is also planned. A Safety Review Committee will conduct evaluations on an ongoing basis and two interim analyses will be performed.
Clinical • P2 data • PD(L)-1 Biomarker • IO biomarker
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ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
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CD73 expression
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Imfinzi (durvalumab) • IPH5201
over1year
IPH5201 and Durvalumab in Patients With Resectable Non-Small Cell Lung Cancer (MATISSE) (clinicaltrials.gov)
P2, N=70, Recruiting, Innate Pharma | Initiation date: Feb 2023 --> Jun 2023
Trial initiation date
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EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase)
|
cisplatin • carboplatin • Imfinzi (durvalumab) • paclitaxel • pemetrexed • IPH5201
over1year
New P1 trial • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 negative
|
carboplatin • 5-fluorouracil • pemetrexed • oxaliplatin • Yutuo (zimberelimab) • leucovorin calcium • AB598
over1year
TTX-030 Single Agent and in Combination With Immunotherapy or Chemotherapy for Patients With Advanced Cancers (clinicaltrials.gov)
P1, N=56, Active, not recruiting, Trishula Therapeutics, Inc. | Trial completion date: Dec 2022 --> Dec 2023
Trial completion date • Combination therapy • Metastases
|
ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
ENTPD1 expression
|
Keytruda (pembrolizumab) • gemcitabine • albumin-bound paclitaxel • TTX-030
over1year
CD39-Expressing CD8 T Cells as a New Molecular Marker for Diagnosis and Prognosis of Esophageal Squamous Cell Carcinoma. (PubMed, Cancers (Basel))
The expression of CD39 on CD8 T cells in the CK region was higher in cancer tissue than in paracancerous tissue (p = 0.011), and high CD39-expressing CD8 T cells in the CK region (HR, 2.587; p = 0.033) and high CD39-expressing CD8 T cells in the CK region (HR, 3.090; p = 0.008) were independent risk factors for prognosis in ESCC patients; the expression of ENTPD1 was upregulated in ESCC tissues compared to normal tissues (adjusted p < 0.001; log fold change = 1.99), and its expression was significantly positively correlated with the expression of PDCD1, CTLA4, and HAVCR2. High CD39-expressing CD8 T cells can be used as a new molecular marker for the diagnosis and prognosis of ESCC, and the restoration of partially exhausted CD8 T cells by inhibiting CD39 may be a new strategy for treating ESCC.
Journal • PD(L)-1 Biomarker • IO biomarker
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CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
PD-1 expression • CD8 expression • CTLA4 expression • ENTPD1 expression
over1year
New P2 trial
|
PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase)
|
cisplatin • carboplatin • Imfinzi (durvalumab) • paclitaxel • pemetrexed • IPH5201
almost2years
Inhibition of CD39 unleashes macrophage antibody-dependent cellular phagocytosis against B-cell lymphoma. (PubMed, Leukemia)
Importantly, inhibition of CD39 augmented in vivo anti-lymphoma effects by therapeutic antibodies including rituximab and daratumumab. Furthermore, the addition of a CD39 inhibitor to anti-CD20 and anti-CD47 combination therapy significantly improved survival in a disseminated model of aggressive B-cell lymphoma, supporting the benefit of dual targeting CD39-mediated eATP hydrolysis and CD47-mediated "don't eat me" signal. Together, preventing eATP degradation may be a potential approach to unleash macrophage-mediated anti-lymphoma immunity.
Journal
|
NT5E (5'-Nucleotidase Ecto) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
CD73 expression
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Rituxan (rituximab) • Darzalex (daratumumab)
almost2years
KEYNOTE-A62: Study of SRF617 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
P1, N=177, Active, not recruiting, Surface Oncology | Recruiting --> Active, not recruiting | Trial completion date: Nov 2022 --> Oct 2023 | Trial primary completion date: Oct 2022 --> Aug 2023
Enrollment closed • Trial completion date • Trial primary completion date • Metastases
|
HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
HER-2 negative
|
Keytruda (pembrolizumab) • gemcitabine • albumin-bound paclitaxel • perenostobart (SRF617)
almost2years
Study of SRF617 With AB928 (Etrumadenent) and AB122 (Zimberelimab) in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov)
P2, N=40, Active, not recruiting, Surface Oncology | Recruiting --> Active, not recruiting | Trial completion date: Nov 2023 --> Jul 2023 | Trial primary completion date: Nov 2023 --> May 2023
Enrollment closed • Trial completion date • Trial primary completion date • Combination therapy • Metastases
|
CAST (Calpastatin)
|
Yutuo (zimberelimab) • etrumadenant (AB928) • perenostobart (SRF617)
almost2years
STAT3 promotes differentiation of monocytes to MDSCs via CD39/CD73-adenosine signal pathway in oral squamous cell carcinoma. (PubMed, Cancer Immunol Immunother)
Furthermore, we found that S3I-201 displayed prominent anti-tumor efficacy in C3H/He OSCC mouse model via inhibiting CD39/CD73-adenosine signal pathway and decreasing MDSCs. These results suggest that STAT3 signal can induce the differentiation of monocytes into MDSCs in tumor microenvironment depending on CD39/CD73-adenosine signal pathway and STAT3 blockade is a promising therapeutic strategy for OSCC.
Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3) • CD33 (CD33 Molecule) • NT5E (5'-Nucleotidase Ecto) • CD14 (CD14 Molecule) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
CD73 expression
|
GLG-302
almost2years
CD73 inhibits cGAS-STING and cooperates with CD39 to promote pancreatic cancer. (PubMed, Cancer Immunol Res)
CD73 expression on human and mouse PDAC tumor cells also protected against DNA damage induced by gemcitabine and irradiation. Moreover, cGAS expression in mouse KPC tumor cells was required for anti-tumor activity of the CD73 inhibitor AB680 in vivo. Our study, thus, illuminates molecular mechanisms whereby CD73 and CD39 seemingly cooperate to promote PDAC progression.
Journal
|
CD8 (cluster of differentiation 8) • STING (stimulator of interferon response cGAMP interactor 1) • NT5E (5'-Nucleotidase Ecto) • CGAS (Cyclic GMP-AMP Synthase) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
CD73 expression
|
gemcitabine • quemliclustat (AB680)
2years
Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment. (PubMed, Nat Commun)
In addition, a significant synergistic effect is observed between CD39i and cisplatin, but the CD39i + anti-PD-L1 (or anti-PD1) strategy does not show any synergistic effects in the BC model. Our results confirm that CD39 is a potential target for the immune therapy of BC.
Journal
|
CD8 (cluster of differentiation 8) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1) • BATF3 (Basic Leucine Zipper ATF-Like Transcription Factor 3)
|
cisplatin
2years
Combination of IPH5201, a blocking antibody targeting the CD39 immunosuppressive pathway, with durvalumab and chemotherapies: Preclinical rationale (ESMO-IO 2022)
Targeting the Ado pathway has recently been reported to improve Durvalumab (D) efficacy in early-stage NSCLC patients, through the use of Oleclumab, an anti-CD73 mAb...Finally, in vivo, in a mouse tumor model engrafted in huCD39KI mice, moIPH5201 improved the anti-tumor efficacy of gemcitabine and anti-PD-L1 combination. Conclusions IPH5201 was shown to block CD39 enzymatic activity, to lower Ado and increase ATP levels in the TME and finally to improve anti-tumor efficacy in preclinical models. Altogether, the expression profile of CD39 in early stage NSCLC and preclinical combination data support the clinical evaluation of IPH5201 in combination with D and CT in early stage NSCLC patients.
Preclinical • PD(L)-1 Biomarker • IO biomarker
|
ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
PD-L1 expression • CD73 expression • ENTPD1 expression
|
Imfinzi (durvalumab) • gemcitabine • oleclumab (MEDI9447) • IPH5201
2years
Enhanced radiation-induced immunogenic cell death activates chimeric antigen receptor T cells by targeting CD39 against glioblastoma. (PubMed, Cell Death Dis)
Radiation and CD39 inhibition-induced ICD of glioma stem cells as a vaccine enhance CAR-T expansion in peripheral blood, multifunctionality in the TME, and antitumor effect in a glioma model. The multispecificity of CAR-T cells, targeting CAR and tumor antigens, vastly enhances the function of conventional CAR-T cells, stimulates a native immune response, and overcomes obstacles of specific antigen loss or low expression of target cells in antitumor therapy.
Journal • CAR T-Cell Therapy • IO biomarker
|
IRF1 (Interferon Regulatory Factor 1) • STAT1 (Signal Transducer And Activator Of Transcription 1) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1) • NLRP3 (NLR Family Pyrin Domain Containing 3)
|
IRF1 expression
2years
AB598, a therapeutic anti-human CD39 antibody, binds and inhibits CD39 enzymatic activity in vivo to promote anti-tumor immunity (SITC 2022)
Results Real-time measurement of ATP showed the ability of oxaliplatin to induce ATP release in MC38 tumor cells in vitro . Relative percentages of the immune cells in the lymph nodes were unaffected, suggesting internalization or downregulation, not cellular depletion, as the mechanism for the decrease in cell-surface CD39. Conclusions Our results indicate the superb ability of AB598 to inhibit enzymatic activity and tumor growth in vivo and provide a rationale for the combination of CD39 inhibition with ICD-inducing chemotherapy in the clinic.
Preclinical • IO biomarker
|
ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
oxaliplatin • AB598
2years
CD39 expression in glioblastoma tumor microenvironment does not affect survival or T-cell exhaustion (SNO 2022)
Additionally, numerous exhaustion markers such as LAG3, TIGIT, and CTLA4 were decreased on tumor in comparison to peripheral blood (p < 0.01). These results demonstrate the complex nature of immune signaling in GBM tumor microenvironment that our team continues to investigate.
PD(L)-1 Biomarker • IO biomarker
|
LAG3 (Lymphocyte Activating 3) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
HAVCR2 expression
2years
Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 - a promising target for cancer immunotherapy. (PubMed, J Immunother Cancer)
CD39 inhibition might contribute to the effects of the powerful anticancer drug ceritinib. Ceritinib is a novel CD39 inhibitor with high metabolic stability and optimized physicochemical properties; according to our knowledge, it is the first brain-permeant CD39 inhibitor. Our discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future in vivo studies.
Journal • IO biomarker
|
ALK (Anaplastic lymphoma kinase) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
ALK positive
|
Zykadia (ceritinib)
2years
New P1 trial
|
ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
JS019
over2years
Targeting NAD metabolism regulates extracellular adenosine levels to improve the cytotoxicity of CD8+ effector T cells in the tumor microenvironment of gastric cancer. (PubMed, J Cancer Res Clin Oncol)
Restraining the function of NAMPT resulted in the functional improvement of effector CD8+ T cells by decreasing extracellular adenosine levels and inducing apoptosis of GC cells simultaneously. Therefore, this study demonstrates that NAMPT can be an effective target for gastric cancer immunotherapy.
Journal • PD(L)-1 Biomarker • IO biomarker
|
CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1) • NAMPT (Nicotinamide Phosphoribosyltransferase)
|
PD-1 expression
|
daporinad (APO866)
over2years
Combination of oxaliplatin and POM-1 by nanoliposomes to reprogram the tumor immune microenvironment. (PubMed, J Control Release)
The designed POL can effectively inhibit the growth of in situ, lung metastasis and postoperative recurrence melanoma model and form long-term immune memory. With the powerful clinical transformation potential of nanoliposome platforms, this new synergistic strategy is expected to enhance anticancer effects safely and effectively.
Journal
|
NT5E (5'-Nucleotidase Ecto) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
CD73 expression
|
oxaliplatin
over2years
A Phase 1 Study to Evaluate JS019 in Advanced Solid Tumors or Lymphomas (clinicaltrials.gov)
P1, N=172, Recruiting, Suzhou Kebo Ruijun Biotechnology Co., Ltd
New P1 trial
|
ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
|
JS019
over2years
Genetically driven CD39 expression affects Sezary cell viability, IL-2 production and detects two patient subsets with distinct prognosis. (PubMed, J Invest Dermatol)
Accordingly, CD39 enzymatic inhibition enhances SS cells viability and IL-2 production upon activation. These results strongly suggest a special caution for SS treatment with therapeutic inhibitors of CD39.
Journal • IO biomarker
|
CD4 (CD4 Molecule) • IL2 (Interleukin 2) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)