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

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

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

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

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

Targeting PTPN1/PTPN2 to improve HIV cure approaches (AIDS 2024) - "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... Given our findings that AC-484 is sufficient to promote immune activation despite reduced latency reversal activity compared to HODHBt. Future directions include investigation of the effects of AC-484 on the anti-HIV activity of immune effector cells including CD8T cells and NK cells and its latency reversal properties in synergy with other LRAs. Overall, our work highlights the possible therapeutic potential of PTPN1/PTPN2 inhibition in the search for globally applicable and efficient HIV cure strategies."

Human Immunodeficiency Virus • Infectious Disease • Metabolic Disorders • Oncology • Solid Tumor • CD4 • CD8 • IL15 • PTPN1 • PTPN2 • STAT5

Expanded Access to ABBV-CLS-484 (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Calico Life Sciences LLC

New trial • Oncology • Solid Tumor

A Phase 1 Study With ABBV-CLS-484 in Subjects With Locally Advanced or Metastatic Tumors (clinicaltrials.gov) - P1 | N=248 | Recruiting | Sponsor: Calico Life Sciences LLC | Trial completion date: Feb 2024 ➔ Oct 2026 | Trial primary completion date: Oct 2023 ➔ Aug 2025

Metastases • Trial completion date • 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

Small molecule. Big biology. Dual phosphatase inhibitor enters the immunotherapy fray. (PubMed, Immunol Cell Biol) - "The advent and clinical success of immune checkpoint inhibitors Ipilimumab, Nivolumab and Pembrolizumab has had a seismic impact on our drug discovery focus and rationale. In a recent publication, Baumgartner et al. demonstrate the pre-clinical efficacy of a first-in-class dual PTPN1/N2 active site inhibitor (ABBV-CLS-484/AC484) in cancer models."

Journal • Oncology • PTPN1 • PTPN2

PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumor immunity (SITC 2023) - P1 | "More broadly, our study shows that small molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics targeting this important class of enzymes."

Oncology • Solid Tumor • CD8 • PTPN1 • PTPN2

The PTPN2/N1 small molecule inhibitor ABBV-CLS-484 promotes NK cell activity driving primary tumor regression and preventing metastasis (SITC 2023) - "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 the Broad Institute or Calico Life Sciences were approved by the respective IACUC committees."

Breast Cancer • Oncology • Solid Tumor • B2M • JAK2 • PTPN1 • PTPN2

A Dual PTPN2/PTPN1 Active-Site Inhibitor Promotes Antitumor Immunity. (PubMed, Cancer Discov) - "ABBV-CLS-484, an active-site inhibitor of PTPN2/PTPN1, elicits immune-dependent antitumor efficacy."

Journal • Oncology • PTPN1 • PTPN2

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. (PubMed, Nature) - P1 | "More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes."

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