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

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

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

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

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

Nature Publishes Discovery and Preclinical Results for ABBV-CLS-484, a Potential First-in-Class PTPN2/N1 Inhibitor in Cancer Immunotherapy (PRNewswire) - "AbbVie...today announced the publication in Nature of the discovery and preclinical data that demonstrate investigational ABBV-CLS-484 is a potential first-in-class, orally bioavailable, PTPN2/N1 phosphatase inhibitor that enhances anti-tumor immunity....Preclinical findings presented demonstrate that ABBV-CLS-484 treatment amplifies the tumor intrinsic response to interferon and increases the activation and function of several immune cell subsets promoting cellular pathways including JAK-STAT signaling in animal models. In murine cancer models resistant to PD-1 blockade, monotherapy ABBV-CLS-484 treatment generates robust anti-tumor immunity."

Preclinical • Oncology • Solid Tumor

A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity. (PubMed, Nat Commun) - "ABBV-CLS-484 is a PTP1B/PTPN2 inhibitor in clinical trials for solid tumors...Importantly, treatment with Compound-182 rendered otherwise resistant tumors sensitive to α-PD-1 therapy. Our findings establish the potential for small molecule inhibitors of PTP1B and PTPN2 to enhance anti-tumor immunity and combat cancer."

Journal • Oncology • Solid Tumor • PTPN1 • PTPN2

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 | N=100 ➔ 248

Enrollment change • 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

First-in-human phase 1 studies of PTPN2/1 inhibitors ABBV-CLS-484 and ABBV-CLS-579 in locally advanced or metastatic tumors (AACR 2023) - P1 | "Preclinical data also indicated that PTPN2/1 inhibitors have improved efficacy when combined with PD-1-targeting agents (eg, pembrolizumab) or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in multiple tumor models. Evaluation of objective response rate (RECIST v1.1) is a primary objective in EXP phase and a secondary objective in ESC phase. Both studies are active, and as of 30 Nov 2022, 30 (ABBV-CLS-484) and 45 (ABBV-CLS-579) patients had been enrolled in ESC phase."

Metastases • P1 data • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • IFNG • MSI • PTPN2

Targeting the immune checkpoint PTPN2 with ABBV-CLS-484 inflames the tumor microenvironment and unleashes potent CD8+ T cell immunity (AACR 2022) - P1 | "Thus, the PTPN2/N1 inhibitor ABBV-CLS-484 is a highly effective immunotherapy with monotherapy efficacy across mouse tumor models. Small molecule inhibitors of PTPN2 offer a promising new strategy for cancer immunotherapy by targeting an IFN signaling checkpoint and are currently being evaluated clinically in patients with advanced solid tumors (NCT04777994)."

Biomarker • IO biomarker • Tumor microenvironment • Oncology • Solid Tumor • CD8 • IFNG • PTPN1 • PTPN2

ABBV-CLS-484: An active site PTPN2/N1 inhibitor that augments the immune response and sensitizes tumors to immune-mediated killing (AACR 2022) - P1 | "We have discovered a first-in-class PTPN2/N1 inhibitor, which represents a promising novel immunotherapy that both enhances the immune response and increases tumor sensitivity to immune-mediated killing. ABBV-CLS-484 is currently being evaluated in phase I clinical trials in patients with advanced solid tumors, as a monotherapy or in combination with a PD-1 targeting agent (NCT04777994)."

Oncology • Solid Tumor • ITGAE • PTPN1 • PTPN2

ABBV-CLS-484: An active site PTPN2/N1 inhibitor that augments the immune response and sensitizes tumors to immune-mediated killing (AACR 2022) - P1 | "We have discovered a first-in-class PTPN2/N1 inhibitor, which represents a promising novel immunotherapy that both enhances the immune response and increases tumor sensitivity to immune-mediated killing. ABBV-CLS-484 is currently being evaluated in phase I clinical trials in patients with advanced solid tumors, as a monotherapy or in combination with a PD-1 targeting agent (NCT04777994)."

Oncology • Solid Tumor • ITGAE • PTPN1 • PTPN2

An active site PTPN2/N1 small molecule inhibitor promotes anti-tumor efficacy by sensitizing tumor cells to inflammatory signals and enhancing immune cell activity (SITC 2022) - "This two-pronged mechanism leads to efficacy in murine tumor models unresponsive to PD-1 pathway blockade. Based on our preclinical data on this novel and efficacious therapeutic approach, ABBV-CLS-484 is currently under Phase I clinical evaluation in cancer patients with solid tumors."

Clinical • Oncology • Solid Tumor • CD8 • PTPN1 • PTPN2