The study will assess the safety, PK, PD, and preliminary efficacy of ABBVCLS-484 as monotherapy and in combination with a PD-1 targeting agent or with a or a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI).
The trial aims to establish a safe, tolerable, and efficacious dose of ABBVCLS-484 as monotherapy and in combination. The study will be conducted in three parts. Part 1 Monotherapy Dose Escalation, Part 2 Combination Dose Escalation and Part 3 Dose Expansion (Monotherapy and Combination therapy).
Part 1, ABBV-CLS-484 will be administered alone in escalating dose levels to eligible subjects who have advanced solid tumors.
Part 2, ABBV-CLS-484 will be administered at escalating dose levels in combination with a PD-1 targeting agent or with a VEGFR TKI to eligible subjects who have advanced solid tumors.
Part 3, ABBV-CLS-484 will be administered alone as a monotherapy at the determined recommended dose in subjects with locally advanced or metastatic, relapsed or refractory head and neck squamous cell carcinoma (HNSCC), relapsed or refractory non-small cell lung cancer (NSCLC), and advanced clear cell renal cell carcinoma (ccRCC). ABBV-CLS-484 will also be administered at the determined recommended dose in combination with a PD-1 targeting or with a VEGFR TKI agent in subjects with locally advanced or metastatic, HNSCC, NSCLC, MSI-H tumors refractory to PD-1/PD-L1, and advanced ccRCC.

Start Date09 Mar 2021

Sponsor / Collaborator

Calico LLC

NCT06188975

/ AvailableNot Applicable

Expanded Access to ABBV-CLS-484

This is an expanded access program (EAP) for eligible participants. This program is designed to provide access to ABBV-CLS-484 prior to approval by the local regulatory agency. Availability will depend on territory eligibility. A medical doctor must decide whether the potential benefit outweighs the risk of receiving an investigational therapy based on the individual patient's medical history and program eligibility criteria.

Start Date-

Sponsor / Collaborator

Calico LLC

100 Clinical Results associated with Osunprotafib

100 Translational Medicine associated with Osunprotafib

100 Patents (Medical) associated with Osunprotafib

Literatures (Medical) associated with Osunprotafib

27 Nov 2025·JOURNAL OF MEDICINAL CHEMISTRY

Targeting Protein Tyrosine Phosphatase Nonreceptor Type 2 with a Novel Inhibitor for the Treatment of Melanoma

Article

Author: Wang, Xiao ; Li, Qiannan ; Chen, Ya ; Yang, Peng ; Wang, Liping ; Tong, Chen ; Liu, Jianing ; Wang, Wenmu ; Chen, Anyan ; Han, Kailin ; Hao, Haiping ; Song, Mingge ; Wang, Dawei ; Xiao, Yibei ; Kuang, Wenbin

Melanoma is a highly aggressive skin cancer with strong metastatic potential, posing significant clinical challenges. Currently, melanoma treatment commonly includes chemotherapy and immunotherapy; nevertheless, the treatment modalities have specific limitations. PTPN2 (protein tyrosine phosphatase nonreceptor type 2) has emerged as a promising therapeutic target. Through rational drug design, we identified compound K-38, a potent PTPN2 inhibitor (IC₅₀ = 7.05 nM) with high safety (hERG IC₅₀ > 40 μM) and excellent liver metabolic stability (T_1/2 = 408 min). Compound K-38 also showed improved oral bioavailability (F = 10.46%) over AC-484 (F = 1.40%) (Zheng European Journal of Medicinal Chemistry 2024, 270, 116390, ). In vivo, compound K-38 significantly suppressed melanoma growth, especially when combined with anti-PD-1 therapy, outperforming AC-484. 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.

23 Oct 2025·JOURNAL OF MEDICINAL CHEMISTRY

Development of Novel PTPN2/1 Inhibitors for the Treatment of Melanoma

Article

Author: Wang, Liping ; Yang, Peng ; Chen, Ya ; Han, Kailin ; Tong, Chen ; Liu, Jianing ; Wang, Xiao ; Song, Mingge ; Wang, Wenmu ; Chen, Anyan ; Hao, Haiping ; Kuang, Wenbin ; Wang, Dawei ; Li, Qiannan ; Xiao, Yibei

The global incidence of melanoma has risen substantially over the past two decades, driving an urgent need for novel therapeutic strategies. The nonreceptor protein tyrosine phosphatases PTPN2/PTPN1 have emerged as promising therapeutic targets, yet developing effective inhibitors faces significant drug-like property challenges. Through rational drug design, we discovered WS35─a potent dual PTPN2/1 inhibitor exhibiting exceptional enzymatic activity (PTPN2 IC₅₀ = 5.8 nM, PTPN1 IC₅₀ = 12.8 nM), favorable safety profiles, and enhanced oral bioavailability (F = 7.1%). Mechanistic studies demonstrate that WS35 modulates the IFNγ-JAK-STAT signaling axis, significantly augmenting CD8⁺ T-cell tumor infiltration. 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.

01 Aug 2025·Advanced Science

PTPN2 Inhibition Disrupts Mitochondrial Renewal and Blocks TFRC‐Mediated Mitophagy to Exert Anti‐Tumor Activities in ALK‐Positive Anaplastic Large Cell Lymphoma

Article

Author: Jin-Hua Liang ; Wei Xu ; Zi-Wen Duan ; Kai-Xing Du ; Yi-Fan Wu ; Wei Hua ; Li Wang ; Jian-Yong Li ; Tong-Yao Xing ; Rui Gao ; Chun-Yu Shang ; Wei-Ting Wang

Abstract:

Anaplastic large cell lymphoma (ALCL) is a heterogeneous subtype of T‐cell lymphoma usually driven by genetic alterations affecting the anaplastic lymphoma kinase (ALK) gene. Despite the relatively favorable prognosis of ALK‐positive (ALK+) ALCL, approximately 30–40% of patients experience relapses or disease progression. This work identifies protein tyrosine phosphatase PTPN2 as a critical gene essential for the growth and survival of ALK+ ALCL by CRISPR/Cas9 editing. PTPN2 depletion can significantly suppress tumor cell proliferation, induce apoptosis, and provoke cell cycle arrest. Mechanistically, PTPN2 negatively regulates transferrin receptor (TFRC) expression to promote mitochondrial renewal via PTEN induced kinase 1 (PINK1)‐PRKN (parkin RBR E3 ubiquitin protein ligase)‐mediated mitophagy. The process functions independently of ferroptosis. 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.

News (Medical) associated with Osunprotafib

07 Aug 2024

·www.echemi.com

Boehringer Ingelheim's Path to Cancer Research and development: From Acquisitions to the Rise of Innovative Drugs

On July 29, Boehringer Ingelheim announced a major acquisition, with plans to buy Nerio Therapeutics for $1.3 billion. Nerio Therapeutics, a pharmaceutical company focused on phosphatase research, has successfully developed highly selective phosphatase PTPN2/N1 inhibitors for an innovative regimen of tumor immunotherapy. With a leading position in the global oncology market, Boehringer Ingelheim has continuously strengthened its strategic presence in oncology in recent years. According to preliminary statistics, the company has established cooperative relationships with a number of well-known pharmaceutical companies in recent years to accelerate the construction of tumor research and development pipelines: In December 2020, Boehringer Ingelheim acquired NBE Therapeutics for 1.18 billion euros to acquire novel antibody-coupled drugs to address the challenge of refractory solid tumors. In the same month, Boehringer Ingelheim acquired Labor Dr. Merk & Kollegen to increase its research and development and clinical manufacturing capabilities to support its next generation cancer immune drug development program. In January 2021, the company entered into a strategic partnership with Enara Bio to develop innovative cancer immunotherapies using its Dark Antigen™ platform. In September 2021, Boehringer Ingelheim acquired Abexxa Biologics to gain expertise in targeting cancer-specific proteins within cells, expanding the range of potential cancer antigen targets. In June 2022, the company entered into A global licensing agreement with the Agency for Science, Technology and Research of Singapore (A*STAR) to acquire the development and commercialization rights for A*STAR's series of innovative tumor-specific antibodies. In January 2023, Boehringer Ingelheim and 3T Biosciences entered into a strategic collaboration and licensing agreement to jointly explore and develop the next generation of cancer therapies. In March 2023, the company partnered with Covant Therapeutics to develop a covalent drug candidate for the ADAR1 cancer target. In November 2023, Boehringer Ingelheim acquired T3 Pharmaceuticals for CHF 450 million (approximately $508 million), which specializes in innovative therapeutic platforms that enhance immunotherapy with live bacteria. In the same month, Boehringer Ingelheim established a strategic collaboration and licensing agreement with Phenomic AI to jointly discover key targets in rich stromal cancers. In February 2024, Boehringer Ingelheim and CBmed entered into a long-term strategic partnership to accelerate the development of first-of-its-kind oncology drugs using translational medicine to improve the lives of patients. In May 2024, Boehringer Ingelheim and OSE expanded their collaboration to jointly develop first-of-its-kind therapies for tumor and cardio-renal metabolic diseases, including the anti-SIRRP α tumor Immunity program and the cis targeted anti-PD1 / cytokine platform. While Boehringer Ingelheim does not yet have a significant oncology product in the market, its oncology pipeline includes several promising candidates, such as Zongertinib(Phase 1), Brigimadlin (Phase two-thirds) and BI-764532 (Phase 2). Zongertinib is an innovative covalently bound, orally effective and selective HER2 small molecule inhibitor. It covalently binds to the tyrosine kinase domain (TKD) of both wild-type and mutant HER2 receptors, including exon 20 mutations, while preserving the wild-type signal of EGFR, thereby demonstrating good tolerability and safety while ensuring efficacy. Data from the Phase 1a/1b clinical study of Zongertinib monotherapy for HER2-variant advanced solid tumors (NCT04886804), presented at the ASCO meeting in 2024, showed that Zongertinib demonstrated superior efficacy and was well tolerated in patients with HER2-mutation-positive advanced NSCLC. Brigimadlin is a mouse dual microhomologous gene 2 (MDM2) -p53 antagonist targeting MDM2-amplified tumors such as biliary adenocarcinoma, non-small cell lung cancer, and pancreatic cancer. Currently, Brigimadlin's first-line treatment of dedifferentiated liposarcoma (DDLPS) has entered phase 2/3 of clinical trials. New results from the Phase 1a/1b study (NCT03449381) presented at the ASCO Meeting in 2024 show that Brigimadlin induces proteomic changes in DDLPS that may serve as potential biomarkers for predicting treatment response and adverse events. BI 764532 is a first-in-class T cell-mediated bisspecific antibody developed at Boehringer Ingelheim that induces a patient's own T cells to attack cancer cells expressing DLL3. BI 764532 has received fast track approval from the FDA for the treatment of advanced SCLC and advanced or metastatic extrapulmonary neuroendocrine carcinoma. In both DLL3-positive cell and xenograft models, BI 764532 showed potential preclinical antitumor activity. PTPN2 and PTPN1 (also known as PTP-1B) are phosphatases that negatively regulate multiple cytokine signaling pathways and T cell receptor (TCR) signaling pathways. They inhibit inflammation by dephosphorylation of JAK and STAT family members, and reduce T-cell sensitivity to antigens by phosphorylation of LCK and FYN. PTPN2 deletion was found to increase the number of activated cytotoxic CD8+T cells in the tumor, improve antigen presentation and sensitivity to IFNγ, and thus enhance tumor sensitivity to CD8+T cells. Given the critical role of PTPN2/N1 in tumor and immune cells and its highly conserved active sites, researchers are developing PTPN2/N1 inhibitors. Currently, there are several PTPN2/N1 inhibitors, such as ABBV-CLS-579 and ABBV-CLS-484 (AC484). AC484 is an oral PTPN2/N1 active site inhibitor that enhances the response to interferon and promotes the activation and function of immune cell subsets. In a PD-1-resistant mouse model, AC484 monotherapy showed significant antitumor effects. Currently, a Phase 1 clinical trial of AC484 is underway to evaluate its efficacy alone or in combination with PD-1 inhibitors or VEGFR tyrosine kinase inhibitors (TKI) in the treatment of advanced or metastatic solid tumors. In addition, using Chemistry42, its generating-AI platform, Insili has also developed a novel PTPN2/N1 inhibitor that has drug-like properties, good oral bioavailability in vivo, and strong in vivo anti-tumor activity, demonstrating nanoscale inhibitory efficacy.

Phase 1ImmunotherapyLicense out/in

05 Oct 2023

·www.fiercebiotech.com

AbbVie and Calico immunotherapy boosts PD-1 response and tackles T cell exhaustion in mice

Besides demonstrating that it’s possible to target a phosphatase, the drug may also provoke the pharmaceutical industry to look beyond biologics for immunotherapy. A small molecule from AbbVie and Calico Life Sciences currently in early-stage clinical trials for solid tumors appears to improve the response to PD-1 inhibitors in mice with solid tumors. It also incurs a survival benefit when used on its own. In the results of a study published Oct. 4 in Nature, researchers from AbbVie, Calico and the Broad Institute at Harvard and MIT reported that mice with pancreatic, breast and metastatic cancer who were treated with an orally-administered small molecule, ABBV-CLS-484, alongside a PD-1 inhibitor outlived controls and had slower tumor growth. Mice that received the drug by itself had a smaller but still statistically significant survival benefit. Importantly, ABBV-CLS-484 also appeared to reduce T cell exhaustion in mice and reinvigorate exhausted human T cells, a sign that the drug may be able to stave off a major pathway of resistance for immunotherapies. “Resistance to PD-1 blockade is a major problem in oncology, as the majority of patients show primary resistance to [immune checkpoint blockade],” study co-lead Robert Manguso, Ph.D., of the Broad Institute, told Fierce Biotech Research in an email. “Even among responders, the majority of patients will develop adaptive or secondary resistance. We need new immunotherapies and combinations to improve overall response rates and treat resistant tumors.” ABBV-CLS-484 inhibits the activity of PTPN1 and PTPN2, both types of enzymes known as protein tyrosine phosphatases. Typically, they act as immune checkpoints by interfering with molecules along JAK/STAT signaling pathways, crucial elements of inflammation. This is helpful for keeping the immune system under control when it’s warding off pathogens, but not so much when it needs all hands on deck to destroy malignant cells, as Manguso explained. Inhibiting PTPN1 and PTPN2 unleashes that portion of the immune response, giving the body another weapon in its anticancer arsenal. Until recently, though, fighting cancer this way was wishful thinking. Protein tyrosine phosphatases like PTPN1 and PTPN2 were dismissed as “undruggable” targets for a number of reasons, one of which was an electrical problem, so to speak: Since the binding site was positively charged, it would only bind to negatively charged molecules—which usually can’t cross the outer membrane to get into the cell. Previous attempts to develop phosphatase inhibitors that could overcome this had failed. Still, the case for targeting PTPN1 and PTPN2 was growing. The results of CRISPR screening, published by Manguso’s lab in 2017, suggested that PTPN2 could improve responses to immunotherapy. Around the same time, work from other labs that suggested targeting PTPN1 and PTPN2 together could have a one-two punch of making T cells more effective against cancer while also sensitizing tumor cells to immunotherapy. “We knew that drugging a phosphatase would be challenging,” Manguso recalled. His lab partnered with AbbVie and Calico to find a solution, which ultimately came in the form of ABBV-CLS-484.“The medicinal chemistry lab at AbbVie did groundbreaking work on this project, and their belief in the promise of the target and the culture of optimism around it were big drivers of the eventual success,” Manguso said. Besides demonstrating that it’s possible to target a phosphatase—and that doing so can potentially both make immunotherapy more effective and overcome a major source of resistance—the drug may also provoke the pharmaceutical industry to look beyond biologics for immunotherapy, Manguso noted. Small molecules have more flexible dosing options, lower production costs and are easier to distribute and store, he said. “The development of small molecule immunotherapies could help this type of treatment reach even more patients in need of better treatment options,” Manguso said. ABBV-CLS-484 is a product of AbbVie’s ongoing partnership with Calico to find therapies for age-related diseases. The companies first signed a deal in 2014 where each party could co-invest up to $1.5 billion, with an original investment of $250,000 each and the possibility of an additional $500,000 each. They extended it twice since, adding another $1 billion each time. Editor's note: This article has been updated to clarify the details of the deal between AbbVie and Calico.

ImmunotherapyClinical Result

05 Oct 2023

·www.prnewswire.com

Nature Publishes Discovery and Preclinical Results for ABBV-CLS-484, a Potential First-in-Class PTPN2/N1 Inhibitor in Cancer Immunotherapy

NORTH CHICAGO, Ill. and SOUTH SAN FRANCISCO, Calif., Oct. 4, 2023 /PRNewswire/ -- AbbVie (NYSE: ABBV), the Broad Institute of MIT and Harvard, and Calico Life Sciences 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. The findings, based on research conducted by AbbVie in collaboration with the Broad Institute and Calico, support the development of ABBV-CLS-484 as a promising new strategy for cancer immunotherapy. Titled "The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity," the paper highlights the novel structural insights and design that led to the discovery of ABBV-CLS-484 and its dual mechanism of action that targets tumor cells and suppresses their growth, as well as promotes the activation of several immune cell types to increase their anti-tumor activity.1 Researchers at the Broad previously identified protein tyrosine phosphatase non-receptor type 2 (PTPN2) and its closely related paralog PTPN1 as potential targets for cancer immunotherapy through an in vivo CRISPR screen.2 However, this challenging target class had previously been deemed "undruggable". AbbVie researchers overcame the challenges and discovered the dual PTPN2/N1 inhibitor, ABBV-CLS-484, through structure-based drug design and optimization of drug-like properties. Discovery scientists at AbbVie, the Broad, and Calico further uncovered the biology and mechanism of action of ABBV-CLS-484. 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. Through in vivo studies and single cell transcriptional profiling of tumor-infiltrating lymphocytes from ABBV-CLS-484 treated mice, the team revealed that ABBV-CLS-484 inflames the tumor microenvironment and promotes NK and CD8+ T-cell function. In T cells, mechanistically, ABBV-CLS-484 induces epigenetic and metabolic changes resulting in a unique functional state causing increased cytotoxicity and reduced T-cell exhaustion and dysfunction. "Immunotherapies like PD-1 blockade have revolutionized cancer treatment; however, many patients do not respond well to them, and a significant unmet need remains," said Christina Baumgartner, Ph.D., co-first author and senior principal research scientist, AbbVie. "Through the extraordinary efforts of AbbVie's medicinal chemistry team to drug the undruggable, we now have a potential first-in-class PTPN2/N1 inhibitor. We're excited to share its biology and mechanism of action, and look forward to further evaluating it in the clinic." "This study is a powerful demonstration of how collaboration can bring together diverse expertise to advance our understanding of disease biology and lead to discoveries that support new treatment strategies for people living with cancer," said Marcia Paddock, M.D., Ph.D., co-author and director of oncology new target development at Calico. "We are proud to be working with both AbbVie and the Broad Institute and look forward to sharing additional progress from our clinical studies of this novel immunotherapy." ABBV-CLS-484 is the first active-site phosphatase inhibitor to enter clinical evaluation as a cancer therapy and is currently in an AbbVie and Calico-led Phase 1 clinical trial in solid tumors (NCT04777994). "This is an unprecedented opportunity to evaluate how immune responses work," said Robert Manguso, Ph.D., co-senior author on the study, associate member at the Broad, and assistant professor at the Massachusetts General Hospital Center for Cancer Research and Harvard Medical School. "The ability to further explore this signaling pathway in clinical studies is really important." About AbbVie AbbVie's mission is to discover and deliver innovative medicines and solutions that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas – immunology, oncology, neuroscience, and eye care – and products and services in our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on LinkedIn, Facebook, Instagram, X (formerly Twitter), and YouTube.

ImmunotherapyPhase 1Pre-Clinical Data

100 Deals associated with Osunprotafib

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	United States	Calico LLC	09 Mar 2021
Advanced Malignant Solid Neoplasm	Phase 1	Japan	Calico LLC	09 Mar 2021
Advanced Malignant Solid Neoplasm	Phase 1	France	Calico LLC	09 Mar 2021
Advanced Malignant Solid Neoplasm	Phase 1	Israel	Calico LLC	09 Mar 2021
Advanced Malignant Solid Neoplasm	Phase 1	South Korea	Calico LLC	09 Mar 2021
Advanced Malignant Solid Neoplasm	Phase 1	Spain	Calico LLC	09 Mar 2021
Anaplastic Large-Cell Lymphoma	Preclinical	China	Jiangsu Provincial People's Hospital	08 Dec 2024

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