SCIENCE

Resolvin E1 is a BLT1 agonist that promotes immune homeostasis

A novel approach targeting the BLT1 receptor

Biased Agonism of RvE1 and LTB4 at BLT1

  • Role of BLT1 in Human Health: BLT1, a key G protein-coupled receptor (GPCR) involved in regulating innate and adaptive immune responses, has two naturally-occurring ligands, RvE1 and LTB4. that have distinct biological outcomes, attributed to "biased agonism", a feature of many GPCRs. 1-3

  • LTB4 at BLT1: LTB4 activation of BLT1 plays a critical role in triggering early inflammatory responses for host defense. However, when this pathway remains unchecked, it can contribute to the progression of chronic diseases and cancer. This has motivated development of anti-inflammatory drugs focused on inhibiting LTB4 synthesis or blocking the BLT1 receptor. However, these efforts have had limited success, in part due to the essential and complex role of BLT1 in immune regulation. 4-8

  • RvE1 at BLT1: RvE1 promotes immune homeostasis by stimulating clearance of cellular debris and microbes from inflamed tissue, a process called phagocytosis. RvE1 acting through BLT1 also promotes tissue repair and competes with LTB4 at BLT1 to reduce its pro-inflammatory effects. This multi-faceted mechanism offers unique therapeutic potential in chronic diseases like IBD and cancer. 9-21

Inflammatory bowel disease

TP-317 has shown promising results in preclinical models of IBD, demonstrating multiple beneficial effects on intestinal health and immune function. This pro-resolution, barrier-protective mechanism distinguishes TP-317 from approved IBD therapies.

TP-317 Mechanism of Action in IBD

Promotes barrier integrity, a critical goal in IBD management to limit entry of pathogenic substances from the gut that exacerbate inflammation 10-13

Induces phagocytosis (clearance) of immune cell debris and microbes from inflamed tissue that perpetuate chronic inflammation if left uncleared 14

Downregulates inflammatory cytokines that are key drivers of the inflammatory cascade in IBD 9

Limits migration of immune cells from the microvasculature into the intestinal mucosa that drive inflammation 15-19

Solid tumor cancers

Harnessing the body’s natural defense to fight cancer must meet two pre-requisites. First, T-cells can function as cytotoxic T-cells with the ability to detect and kill tumor cells only when primed with tumor antigens presented by innate immune cells. Second, tumors cells must present their antigens to enable detection by cytotoxic T-cells. These pre-requisites are currently not effectively addressed by approved therapies including immune checkpoint inhibitors.

TP-317 enhances anti-tumor immunity by stimulating macrophages and dendritic cells to clear tumor debris from the tumor environment and to utilize the tumor material ingested in this process to present tumor antigens to T-cells. TP-317 also enhances presentation of antigens by the tumor cells themselves. This multi-faceted mechanism turns “immune cold” tumors into “immune hot” tumors and distinguishes TP-317’s ability to augment anti-tumor immunity. 13, 20-24

TP-317 Mechanism of Action in Solid Tumors

References

  1. Merlin J, Park J, Vandekolk TH, Fabb SA, Allinne J, Summers RJ, Langmead CJ, Riddy DM. Multipathway In Vitro Pharmacological Characterization of Specialized Proresolving G Protein-Coupled Receptors. Mol Pharmacol. 2022 Apr;101(4):246-256.

  2.  Rankovic Z, Brust TF, Bohn LM. Biased agonism: An emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett. 2016 Jan 15;26(2):241-250.

  3.  Hodavance SY, Gareri C, Torok RD, Rockman HA. G Protein-coupled Receptor Biased Agonism. J Cardiovasc Pharmacol. 2016 Mar;67(3):193-202.

  4.  Yokomizo T, Shimizu T. The leukotriene B4 receptors BLT1 and BLT2 as potential therapeutic targets. Immunol Rev. 2023 Aug;317(1):30-41.

  5. Subramanian BC, Majumdar R, Parent CA. The role of the LTB4-BLT1 axis in chemotactic gradient sensing and directed leukocyte migration. Semin Immunol. 2017 Oct;33:16-29.

  6. Tong WG, Ding XZ, Hennig R, Witt RC, Standop J, Pour PM, Adrian TE. Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Clin Cancer Res. 2002 Oct;8(10):3232-42

  7.  Kalinkin AI, Sigin VO, Kuznetsova EB, Ignatova EO, Vinogradov II, Vinogradov MI, Vinogradov IY, Zaletaev DV, Nemtsova MV, Kutsev SI, Tanas AS, Strelnikov VV. Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors. Int J Mol Sci. 2023 Dec 11;24(24):17343.

  8.  Ihara A, Wada K, Yoneda M, Fujisawa N, Takahashi H, Nakajima A. Blockade of leukotriene B4 signaling pathway induces apoptosis and suppresses cell proliferation in colon cancer. J Pharmacol Sci. 2007 Jan;103(1):24-32.

  9. Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol. 2007 Mar 15;178(6):3912-7.

  10. Hayashi S, Muraleedharan CK, Oku M, Tomar S, Hogan SP, Quiros M, Parkos CA, Nusrat A. Intestinal epithelial BLT1 promotes mucosal repair. JCI Insight. 2022 Dec 8;7(23):e162392.

  11. Quiros M, Feier D, Birkl D, Agarwal R, Zhou DW, García AJ, Parkos CA, Nusrat A. Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing. Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9477-9482.

  12. Yang M, Lippestad M, Hodges RR, Fjærvoll HK, Fjærvoll KA, Bair JA, Utheim TP, Serhan CN, Dartt DA. RvE1 uses the LTB4 receptor BLT1 to increase [Ca2+]i and stimulate mucin secretion in cultured rat and human conjunctival goblet cells. Ocul Surf. 2020 Jul;18(3):470-482.

  13. Bodduluri SR, Mathis S, Maturu P, Krishnan E, Satpathy SR, Chilton PM, Mitchell TC, Lira S, Locati M, Mantovani A, Jala VR, Haribabu B. Mast Cell-Dependent CD8+ T-cell Recruitment Mediates Immune Surveillance of Intestinal Tumors in ApcMin/+ Mice. Cancer Immunol Res. 2018 Mar;6(3):332-347.

  14. El Kebir D, Gjorstrup P, Filep JG. Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation. Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14983-8.

  15. Aoki H, Hisada T, Ishizuka T, Utsugi M, Ono A, Koga Y, Sunaga N, Nakakura T, Okajima F, Dobashi K, Mori M. Protective effect of resolvin E1 on the development of asthmatic airway inflammation. Biochem Biophys Res Commun. 2010 Sep 10;400(1):128-33.

  16. Oner F, Alvarez C, Yaghmoor W, Stephens D, Hasturk H, Firatli E, Kantarci A. Resolvin E1 Regulates Th17 Function and T Cell Activation. Front Immunol. 2021 Mar 17;12:637983.

  17. Perez-Hernandez J, Chiurchiù V, Perruche S, You S. Regulation of T-Cell Immune Responses by Pro-Resolving Lipid Mediators. Front Immunol. 2021 Nov 16;12:768133.

  18. Sawada Y, Honda T, Nakamizo S, Otsuka A, Ogawa N, Kobayashi Y, Nakamura M, Kabashima K. Resolvin E1 attenuates murine psoriatic dermatitis. Sci Rep. 2018 Aug 8;8(1):11873.

  19. Sawada Y, Honda T, Hanakawa S, Nakamizo S, Murata T, Ueharaguchi-Tanada Y, Ono S, Amano W, Nakajima S, Egawa G, Tanizaki H, Otsuka A, Kitoh A, Dainichi T, Ogawa N, Kobayashi Y, Yokomizo T, Arita M, Nakamura M, Miyachi Y, Kabashima K. Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses. J Exp Med. 2015 Oct 19;212(11):1921-30.

  20. Kantarci A, Kansal S, Hasturk H, Stephens D, Van Dyke TE. Resolvin E1 Reduces Tumor Growth in a Xenograft Model of Lung Cancer. Am J Pathol. 2022 Oct;192(10):1470-1484.

  21. Panigrahy D, Gartung A, Yang J, Yang H, Gilligan MM, Sulciner ML, Bhasin SS, Bielenberg DR, Chang J, Schmidt BA, Piwowarski J, Fishbein A, Soler-Ferran D, Sparks MA, Staffa SJ, Sukhatme V, Hammock BD, Kieran MW, Huang S, Bhasin M, Serhan CN, Sukhatme VP. Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases. J Clin Invest. 2019 Jun 17;129(7):2964-2979.

  22. Chheda ZS, Sharma RK, Jala VR, Luster AD, Haribabu B. Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors. J Immunol. 2016 Sep 1;197(5):2016-26.

  23. Jala VR, Maturu P, Bodduluri SR, Krishnan E, Mathis S, Subbarao K, Wang M, Jenson AB, Proctor ML, Rouchka EC, Knight R, Haribabu B. Leukotriene B4-receptor-1 mediated host response shapes gut microbiota and controls colon tumor progression. Oncoimmunology. 2017 Aug 10;6(12):e1361593.

  24. Islam SA, Thomas SY, Hess C, Medoff BD, Means TK, Brander C, Lilly CM, Tager AM, Luster AD. The leukotriene B4 lipid chemoattractant receptor BLT1 defines antigen-primed T cells in humans. Blood. 2006 Jan 15;107(2):444-53.