osunprotafib (ABBV-CLS-484) / AbbVie, Calico Life Sciences - LARVOL DELTA

ABBV-CLS-484: A Novel Oral PTPN2/1 Inhibitor for Cancer Immunotherapy (KCRS 2026) - P1 | "Methods M20-431 is a first-in-human Phase 1 clinical trial testing the safety and preliminary clinical activity of ABBV-CLS-484 alone and with pembrolizumab in patients with advanced solid tumors whose disease has progressed on standard therapies (NCT04777994). In tandem with these clinical cohorts, additional strategies that combine ABBV-CLS-484 with VEGF TKIs, CAR-T therapy, and T cell engagers are being tested in preclinical models. Keywords Phase 1 trial, immunotherapy, PTPN2/2 inhibitor, PD-1 blockade"

First-in-human • IO biomarker • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • PTPN2

PTPN1/2 Inhibition Remodels the Pulmonary Myeloid Landscape to Induce Alveolar Macrophage-Mediated Control of Lung Metastasis. (PubMed, Cancer Res) - "Here, using the clinical-stage inhibitor ABBV-CLS-484 (AC484) as a chemical probe, we demonstrated that systemic PTPN1/2 inhibition remodels the pulmonary myeloid landscape, specifically activating alveolar macrophages (AMs) toward a tumoricidal state...Mechanistically, inhibition of PTPN1/2 amplified IFNγ-STAT1 signaling in AMs, and disrupting this pathway impaired the tumor control capability of AC484. These findings delineate a distinct innate immune axis where PTPN1/2 acts as a molecular "brake" on AM activation, suggesting that pharmacologically unleashing tissue-resident macrophages offers a therapeutic strategy to overcome metastatic progression, particularly in microenvironments where adaptive immunity is insufficient."

Journal • Oncology • IFNG • PTPN1 • STAT1

PTPN2 INHIBITION RESTORES T-CELL FUNCTION AND POTENTIATES T-CELL ENGAGER ACTIVITY IN CHRONIC LYMPHOCYTIC LEUKEMIA (EHA 2026) - "Summary/Conclusion In conclusion, in this study we demonstrate the potential of combining PTPN2 inhibitor with the bispecific antibody mosunetuzumab to enhance antitumor T-cell activity in patient-derived CLL samples. Using this combination, we showed increased expression levels of surface activation markers,T cells proliferation, morphological changes that were compatible with T-cell activation, increased granzyme B secretion and improved anti-CLL T- cell cytotoxicity. The findings of our research may contribute to the development of novel approaches that use PTPN2 inhibition to enhance cellular therapies in CLL, potentially leading to better clinical outcomes."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • CD20 • CD4 • CD69 • CD8 • GZMB • IGH • IL2RA • PTPN2

OVERCOMING LACTATE-MEDIATED T CELL SUPPRESSION VIA PTPN1 INHIBITION: A NOVEL STRATEGY TO ENHANCE CAR-T CELL EFFICACY IN MULTIPLE MYELOMA (EHA 2026) - "Lactate suppresses T cell function, including that of CAR-T cells, by shifting the redox state of PTPN1 towards a less oxidized conformation, thereby impairing T cell signaling. Targeting PTPN1 restores T cell activation and effector functions under lactate stress, highlighting PTPN1 as a potential therapeutic target to enhance CAR-T cell persistence and efficacy in the acidic TME of hematological malignancies. These findings offer a novel strategy to overcome metabolic barriers and improve the clinical success of CAR-T cell immunotherapy."

CAR T-Cell Therapy • Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • CD8 • IL2 • IL2RA • PTPN1 • STAT5 • STAT5AWqe

Discovery of Novel Alkynylbenzene Scaffold-Based PTPN2-Selective Degrader PD-305 with Exceptional Potency and In Vivo Efficacy. (PubMed, J Med Chem) - "Moreover, it possessed excellent in vivo PTPN2 degradation potency and effectively suppressed tumor growth in mice. Collectively, PD-305 is a promising lead compound worthy of further study."

Journal • Preclinical • Oncology • Targeted Protein Degradation • CRBN • IFNG • PTPN1 • PTPN2

PTPN2/N1 inhibition drives a STAT3-mediated response in exhausted T cells and underscores targetable counter-regulatory mechanisms for T cell improvement (AACR 2026) - "Our next studies will elucidate the dynamic changes in signaling circuitry in PTPN2/N1–deficient T cells and leverage this knowledge to propose new strategies to counteract T cell exhaustion. These insights could inform the development of next–generation small molecule and cellular immunotherapies with improved efficacy and durability."

Oncology • JAK1 • PTPN1 • PTPN2 • SOCS3 • STAT3 • STAT5 • TYK2

A large language model for diverse 2D molecular generation (2DMG) and its application in focused library generation and rational design (AACR 2025) - "In a case study involving ABBV-CLS-484 (a molecule targeting both tumor and immune cells; PDBID: 7UAD), we analyzed the key binding fragment, thiadiazolidin-3-one, in the crystal structure...In summary, StoneWise 2D Molecular Generation model, trained on billions of data points, offers a robust platform for generating diverse and structurally rational molecules. The model supports focused library design for high-throughput or virtual screening and facilitates rational design to explore and expand chemical space, thus accelerating the drug discovery process."

Oncology

PTPN1/2 inhibition with AC484 inhibits tumor metastasis (AACR 2025) - "ABBV-CLS-484 (AC484) is a novel small molecule based immunotherapeutic drug that inhibits both PTPN2 and PTPN1 and is currently under clinical investigation for treating solid tumors...Taken together, our data demonstrate the ability of PTPN1/2 inhibition to inhibit metastasis by enhancing anti-tumor immunity and altering the metastasis niche. These data provide the preclinical rationale for pursuing AC484 treatment in the neoadjuvant/adjuvant setting as a means of promoting the efficacy of cancer therapies with curative intent."

IO biomarker • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • CTCs • PTPN1 • PTPN2

PTP1B Inhibitors for Type 2 Diabetes: From Natural Products, Synthetic Inhibitors, and Multi-Target Drug Design Strategies to Clinical Translation. (PubMed, Curr Drug Targets) - "The development of PTP1B inhibitors requires integrated approaches that include allosteric modulation, tissue-specific delivery, and patient stratification to achieve successful clinical translation across multiple disease indications."

Journal • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Oncology • Targeted Protein Degradation • Type 2 Diabetes Mellitus • PTPN1 • PTPN2

Dual PTPN2/PTPN1 inhibition augments bispecific T cell engager activity in patient-derived tumor models (ITOC 2026) - "The recent development of dual PTPN2/PTPN1 active‑site inhibitors, such as ABBV-CLS-484 (AC484), has introduced a new strategy, demonstrating promising results in preclinical cell‑based assays and mouse tumor models.1 This study investigates a novel combination of dual PTPN2/PTPN1 inhibition with a bispecific T cell engager to assess T cell activation and antitumor efficacy in patient‑derived tumor model systems...Conclusion Our findings demonstrate that the novel combination of dual PTPN2/PTPN1 inhibition with EpCAM/CD3 significantly enhances T cell activation and tumor cell killing in patient-derived PCTS and malignant effusion co-cultures. These results support further investigation of this combination as a promising approach to enhance antitumor immune responses."

Preclinical • Colorectal Cancer • Oncology • Solid Tumor • CD69 • PTPN1 • PTPN2

Targeted hyperactivation of oncogenic STAT5-signaling in acute lymphoblastic leukemia (ASH 2025) - P1 | "Interestingly, inhibitors of JAK2(ruxolitinib) and BCR-ABL1 (imatinib) suppressed STAT5 (MYC) activity and forced transition to aquiescent BCL6+ cell state. The tyrosine kinase inhibition paradigm is based on the dependency of B-ALL cells on high-level STAT5-signaling and activation of MYC. Our findings reveal a previously unrecognized dependencyof human B-ALL cells on negative STAT5-feedback regulation by CISH and SOCS and activation of BCL6.Every four hours, B-ALL cells transition between cell-states of higher (MYC) and lower (BCL6) STAT5activity. While traditional tyrosine kinase inhibitors target the MYC-dependent cell proliferation, ourfindings support a rationale for targeting BCL6-dependent quiescence."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Solid Tumor • ABL1 • BCL6 • BCR • SOCS2 • SOCS3 • STAT5 • STAT5AWqe • STAT5B

Pharmacologic overactivation of ALK activity by PTPN2/PTPN1 inhibition induces a combination of tumor-intrinsic oncogenic stress and immune responses to promote tumor eradication in ALK-positive lymphoma (ASH 2025) - P1 | "We tested in vitro and in vivo in mouse models the inhibitor ABBV-CLS-484 whichis currently evaluated in a Phase 1 trial in subjects with locally advanced or metastatic tumors(NCT04777994).Materials and MethodsIn vitro treatment with the ALK inhibitor crizotinib (TKI) or the PTPN2/PTPN1 phosphatase inhibitor ABBV-CLS-484 (AC484) with increasing concentrations at various time points was performed on ALK+ and ALK-ALCL cell lines. Remarkably, AC484 amplifies ALK signaling resulting in oncogenic stress and anti-tumoractivity selectively in ALK+ ALCL cells, even if resistant to ALK TKI. The anti-tumor activity of AC484 wasdemonstrated also in vivo, promoting the complete eradication of ALK+ lymphoma in immunocompetentbut not in immunodeficient mice, demonstrating the importance of inducing a more potent anti-ALKimmune response to achieve cure."

Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ALK • CD8 • NPM1 • PTPN1 • PTPN2

The PTPN2/PTPN1 Inhibitor Abbv-CLS-484 Augments Immune Responses Against Leukemic Blasts and Impedes Leukemia Cell Proliferation in AML Alone and in Combination with Venetoclax (ASH 2024) - "Therefore, therapy with ABBV-CLS-484 alone or in combination with venetoclax may represent a new effective therapeutic option in AML. Further investigations are warranted."

Combination therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • HAVCR2 • LAG3 • PD-1 • PTPN1 • PTPN2 • STAT1 • TIGIT

The First-in-Class PTPN2/1 Inhibitor Abbv-CLS-484 Disrupts Mitochondrial Renewal and Blocks Tfrc-Mediated PINK1-Prkn-Dependent Mitophagy to Exert Anti-Tumor Activities in ALK-Positive Anaplastic Large Cell Lymphoma (ASH 2024) - P1 | "Furthermore, the first-in-class PTPN2/1 inhibitor AC484 showed a great anti-tumor effect against ALK+ ALCL by disrupting mitochondrial function and mitophagy. Thus, we provide insight into the selection of treatment options for ALK+ ALCL with poor prognosis and provide the basis for the conduct of clinical trials on AC484."

Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • ALK • HIF1A • PTPN1 • PTPN2

Targeting Protein Tyrosine Phosphatase Nonreceptor Type 2 with a Novel Inhibitor for the Treatment of Melanoma. (PubMed, J Med Chem) - "It enhanced lymphocyte infiltration into tumors and modulated IFN-γ signaling pathways. These findings indicate that compound K-38 is a potent small molecule inhibitor of PTPN2, laying the groundwork for the future development of PTPN2-targeted therapeutics."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • IFNG • PTPN2

Inhibition of PTPN2/N1 by the small molecule inhibitor ABBV-CLS-484 enhances the efficacy of adoptive T cell therapy (SITC 2025) - P1 | "are employees of AbbVie Inc.Ethics Approval Animals: All in vivo experiments conducted at AbbVie were in compliance with the NIH Guide for Care and Use of Laboratory Animals guidelines in a facility accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC). All in vivo studies conducted at Calico Life Sciences was approved by the respective IACUC committee."

Clinical • IO biomarker • Hematological Malignancies • Oncology • Solid Tumor • IFNG • PTPN1 • PTPN2

Development of Novel PTPN2/1 Inhibitors for the Treatment of Melanoma. (PubMed, J Med Chem) - "In B16-OVA syngeneic models, WS35 monotherapy and its combination with an anti-PD-1 antibody achieved robust tumor growth suppression, outperforming AC484, with no observable systemic toxicity. Collectively, WS35 represents a preclinical candidate with validated efficacy and safety for developing novel antimelanoma therapeutics."

Journal • Melanoma • Oncology • Solid Tumor • CD8 • IFNG • PTPN1 • PTPN2

PTPN2 Inhibition Disrupts Mitochondrial Renewal and Blocks TFRC-Mediated Mitophagy to Exert Anti-Tumor Activities in ALK-Positive Anaplastic Large Cell Lymphoma. (PubMed, Adv Sci (Weinh)) - "Interestingly, TFRC is directly regulated by the transcription factor hypoxia-inducible factor 1 alpha (HIF1A) in its promoter. Notably, an orally bioavailable potent PTPN2/N1 active-site inhibitor ABBV-CLS-484 (AC484) demonstrates significant therapeutic potential against ALK+ ALCL by disturbing mitochondrial renewal and blocking TFRC-mediated PINK1-PRKN-dependent mitophagy to exert anti-tumor activities, providing critical insights into the selection of targeted treatment strategies for ALK+ ALCL patients and a strong rationale for advancing AC484 into clinical trials."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Targeted Protein Degradation • ALK • HIF1A • PTEN • PTPN2 • UBR5

PTPN2/PTPN1 inhibition induces tumor eradication in ALK-positive lymphoma by triggering a combination of ALK-induced oncogenic stress and immune responses (EACR 2025) - "In this context, PTPN2 and PTPN1 are dependance genes in ALK+ ALCL with a mechanism that is not fully elucidated yet.Material and ALK+ and ALK- ALCL cell lines were treated in vitro with the ALK inhibitor crizotinib (TKI) or the PTPN2/PTPN1 phosphatase inhibitor ABBV-CLS-484 (AC484) with increasing concentrations at various time points. We propose AC484 as one of the first drugs that exploits oncogenic signaling amplification, instead of blockade, as a novel therapeutic approach. AC484 markedly amplifies ALK signaling resulting in oncogenic stress and anti-tumor activity selectively in ALK+ ALCL even if resistant to ALK TKI. In addition, AC484 strongly boosts anti-ALK immune responses suggesting that the immune modulating activity of AC484 could contribute to its curative potential."

Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ALK • CD8 • PTPN1 • PTPN2

PTPN2 INHIBITION DISRUPTS MITOCHONDRIAL RENEWAL AND BLOCKS TFRC-MEDIATED PINK1-PRKN-DEPENDENT MITOPHAGY TO EXERT ANTI-TUMOR ACTIVITIES IN ALK-POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA. (EHA 2025) - P1 | "Notably, PTPN2 has been reported as a cancer immunotherapy target in vivo CRISPR screening, and the first-in-class potent PTPN2/1 active-site inhibitor ABBV-CLS-484 (AC484) has shown promising prospects for cancer treatments which is currently being investigated in phase I clinical trial concerning patients with solid tumors (NCT04777994) (Baumgartner CK, Nature; 2023)... This study demonstrates that PTPN2 promotes ALK+ ALCL progression through TFRC-mediated PINK1-PRKN-dependent mitophagy. Furthermore, AC484 disrupts mitochondrial function and mitophagy, highlighting its therapeutic potential for ALK+ ALCL. These findings provide a rationale for further clinical trials of AC484 and offer insights into treatment strategies for ALK+ ALCL patients with poor prognosis."

IO biomarker • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • ALK • HIF1A • PTPN2

Transcription factor STAT1 activation using molecular degrader-drugs as anti-lymphoma strategy in ALCL (OeGHO-AHOP 2025) - "Materials and Transgenic ALCL mouse model with and without STAT1 abrogation; Immunohistochemistry on ALCL patient tissues; resazurin assay, Annexin V/PI staining using flow cytometry, PTPN1/2 phosphatase inhibitor (ABBV-CLS-484) and PROTAC degrader DU-14; ALCL cells with and without CRISPR-mediated STAT1 knockout; Immuno-blotting; murine xenograft models of ALCL, ALK+... Paradoxically, activation of the JAK-STAT pathway by phosphatase degrader drugs leads to STAT1 and ALK-dependent cell death in ALCL cells and tumor abrogation in murine ALCL, ALK+ mouse models."

Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Targeted Protein Degradation • ALK • ANXA5 • CASP3 • CD4 • PTPN1 • STAT1 • STAT3 • STAT5 • TNFRSF8

Study With ABBV-CLS-484 in Participants With Locally Advanced or Metastatic Tumors (clinicaltrials.gov) - P1 | N=248 | Recruiting | Sponsor: AbbVie | Trial primary completion date: Aug 2025 ➔ Oct 2026

Trial primary completion date • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • MSI • PD-L1

A Medicinal Chemistry Perspective on Protein Tyrosine Phosphatase Nonreceptor Type 2 in Tumor Immunology. (PubMed, J Med Chem) - "This review outlines the structural modification processes of PTPN2-targeted agents, focusing primarily on inhibitors and degraders. Finally, this review endeavors to provide a comprehensive perspective on the evolving field of PTPN2-targeted drug discovery for tumor immunotherapy, offering valuable insights for future drug development."

Journal • Review • Oncology • IFNG • IL2 • PTPN1 • PTPN2

Activating strong anti-tumor immunity with PTPN2/PTPN1 inhibitor: AC484 (ESMO 2024) - P1 | "However, targeting phosphatases, especially at their active sites, presents challenges as drug targets. This study explores the biological impact of ABBV-CLS-484 (AC484), a pioneering, orally administered, potent inhibitor that specifically targets the active sites of PTPN2 and PTPN1... Our findings support the potential of PTPN2 and PTPN1 inhibition as a promising direction for cancer immunotherapy, currently being tested in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT04777994). Significantly, our research reveals that small-molecule inhibitors targeting internal immune regulators can achieve preclinical outcomes that match or surpass those of antibody-based immune checkpoint inhibitors. AC484 is, to our knowledge, the first active-site phosphatase inhibitor to enter clinical trials for cancer immunotherapy."

Oncology • Solid Tumor • CD8 • PTPN1 • PTPN2

The HIV latency reversing agent HODHBt inhibits the phosphatases PTPN1 and PTPN2. (PubMed, JCI Insight) - "The small molecule ABBV-CLS-484 (AC-484) is an active site inhibitor of PTPN1 and PTPN2 currently in clinical trials for advanced solid tumors. We compared AC-484 and HODHBt and found similar effects on STAT5 and immune activation albeit with different mechanisms of action leading to varying effects on latency reversal. Our studies provide the first specific evidence that enhancing STAT phosphorylation via inhibition of PTPN1 and PTPN2 is an effective tool against HIV."

Journal • Human Immunodeficiency Virus • Infectious Disease • Metabolic Disorders • Oncology • Solid Tumor • CD8 • PTPN1 • PTPN2 • STAT5