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1403-A PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumor immunity
  1. Hakimeh Ebrahimi-Nik1,2,3,
  2. Christina K Baumgartner4,
  3. Arvin Iracheta-Vellve5,
  4. Keith M Hamel4,
  5. Kira Olander6,
  6. Thomas GR Davis6,
  7. Kathleen A McGuire4,
  8. Geoff T Halvorsen4,
  9. Omar I Avila6,
  10. Chirag Patel7,
  11. Sarah Kim6,
  12. Ashwin V Kammula6,
  13. Audrey J Muscato6,
  14. Kyle Halliwill8,
  15. Prasanthi Geda9,
  16. Kelly Klinge4,
  17. Zhaoming Xiong4,
  18. Ryan Duggan4,
  19. Liang Mu4,
  20. Mitchell D Yeary6,
  21. James C Patti6,
  22. Tyler M Balon6,
  23. Rebecca Mathew10,
  24. Carey Backus10,
  25. Domenick Kennedy4,
  26. Angeline Chen4,
  27. Kenton Longenecker4,
  28. Joseph Klahn11,
  29. Cara Hrusch4,
  30. Navasona Krishnan4,
  31. Charles W Hutchins4,
  32. Jacqueline Aguado4,
  33. Marinka Bulic4,
  34. Payal Tiwari6,
  35. Kayla J Colvin6,
  36. Cun Lan Chuong6,
  37. Ian C Kohnle6,
  38. Matthew G Rees6,
  39. Andrew Boghossian6,
  40. Melissa Ronan6,
  41. Jennifer A Roth6,
  42. Meng-Ju Wu6,
  43. Debattama R Sen3,
  44. Gabriel K Griffin6,
  45. Nabeel El-Bardeesy3,
  46. Patricia Trusk4,
  47. Meng Sun7,
  48. Yue Liu7,
  49. Joshua H Decker4,
  50. Yi Yang4,
  51. Stacey Fossey4,
  52. Wei Qiu4,
  53. Qi Sun4,
  54. Marcia N Paddock7,
  55. Elliot P Farney4,
  56. Clay Beauregard7,
  57. Jennifer M Frost4,
  58. Kathleen B Yates3,6,
  59. Philip R Kym4 and
  60. Robert T Manguso3,6
  1. 1Somerville, MA, USA
  2. 2Ohio State University Comprehensive Cancer Center and Pelotonia Institute for Immuno-Oncology, Columbus, OH, USA
  3. 3Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
  4. 4AbbVie Inc., North Chicago, IL, USA
  5. 5AstraZeneca, Wellesley, MA, USA
  6. 6Broad Institute of MIT and Harvard, Cambridge, MA, USA
  7. 7Calico Life Sciences, South San Francisco, CA, USA
  8. 8AbbVie, San Bruno, CA, USA
  9. 9Bristol Myers Squibb, Summit, NJ, USA
  10. 10AbbVie Inc., South San Franscisco, CA, USA
  11. 11AbbVie, Elk Grove Village, IL, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Immune checkpoint blockade is effective for a subset of patients across many cancers, but most patients are refractory to current immunotherapies and new approaches are needed to overcome resistance.1 2 The protein tyrosine phosphatase PTPN2 and the closely related PTPN1 are central regulators of inflammation, and their genetic deletion in either tumor cells or host immune cells promotes anti-tumor immunity.3–6 However, phosphatases are challenging drug targets and in particular, the active site has been considered undruggable. Here, we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2/N1 active site inhibitor.

Methods In this study, we characterize AC484 and evaluate its effects in vitro and in vivo. We conduct in vitro experiments to investigate the interferon response and the activation and function of various immune cell subsets in response to AC484. We employ murine cancer models resistant to PD-1 blockade and assess the anti-tumor efficacy of AC484 monotherapy in these models. Additionally, through single-cell transcriptional profiling of tumor-infiltrating immune cells, we examine the transcriptional and functional effects of AC484 treatment, with a focus on CD8+ T cells.

Results AC484 treatment demonstrates the ability to amplify the response to interferon and enhance the activation and function of multiple immune cell subsets in vitro. In murine cancer models resistant to PD-1 blockade, monotherapy AC484 treatment generates robust anti-tumor immunity. Transcriptomic and functional analyses of tumor-infiltrating immune cells reveal that AC484 treatment elicits broad effects on myeloid and lymphoid compartments, particularly influencing CD8+ T cells. Surprisingly, we find that AC484 treatment induces a unique transcriptional state in CD8+ T cells mediated by enhanced JAK-STAT signaling, whereby T cells display a highly cytotoxic effector profile, increased memory signatures, and reduced exhaustion and dysfunction.

Conclusions Our results demonstrate that oral administration of small molecule inhibitors of PTPN2/N1 can induce potent anti-tumor immunity. PTPN2/N1 inhibitors offer a promising new strategy for cancer immunotherapy and are currently being evaluated clinically in patients with advanced solid tumors (NCT04777994). 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.


  1. Hugo W, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2017;168:542.

  2. Fares CM, Van Allen EM, Drake CG, Allison JP, Hu-Lieskovan S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book. 2019;39:147–164.

  3. Manguso RT, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547:413–418.

  4. Wiede F, et al. PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. EMBO J. 2020;39:e103637.

  5. LaFleur MW, et al. PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity. Nat. Immunol. 2019;20:1335–1347.

  6. Flosbach M, et al. PTPN2 deficiency enhances programmed T cell expansion and survival capacity of activated T cells. Cell Rep. 2020;32:107957.

Ethics Approval The protocol, under which human blood samples were acquired, was approved by and is reviewed on an annual basis by WCG IRB (Puyallup, Washington). WCG IRB is in full compliance with the Good Clinical Practices as defined under the U.S. Food and Drug Administration (FDA) Regulations, U.S. Department of Health and Human Services (HHS) regulations and the International Conference on Harmonisation (ICH) Guidelines. All human research participants signed informed consent forms. All animal studies at AbbVie, were reviewed and approved by AbbVie’s Institutional Animal Care and Use Committee and in compliance with the NIH Guide for Care and Use of Laboratory Animals guidelines. Animal studies were conducted in an AAALAC accredited program where veterinary care and oversight was provided to ensure appropriate animal care. All in vivo studies conducted at the Broad Institute were approved by the Broad Institute IACUC committee and mice were housed in a specific-pathogen free facility. All in vivo studies at Calico were conducted according to protocols approved by the Calico Institutional Animal Care and Use Committee.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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