Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy

PLoS ONE

Volumn 12, Issue 7, 2017, Pages

  Charych, Deborah ^a   Khalili, Samira ^a   Dixit, Vidula ^a   Kirk, Peter ^a   Chang, Thomas ^a   Langowski, John ^a   Rubas, Werner ^a   Doberstein, Stephen K ^a   Eldon, Michael ^a   Hoch, Ute ^a   Zalevsky, Jonathan ^a  

^a NEKTAR THERAPEUTICS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALDESLEUKIN; CD8 ANTIGEN; CYTOKINE RECEPTOR ANTAGONIST; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 2 RECEPTOR BETA; INTERLEUKIN 2 RECEPTOR GAMMA; MACROGOL; NKTR 214; UNCLASSIFIED DRUG; IL2RG PROTEIN, MOUSE; MACROGOL DERIVATIVE; NKTR-214; PRODRUG; STAT5 PROTEIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; BINDING KINETICS; BREAST CANCER; CANCER IMMUNOTHERAPY; CANCER INHIBITION; CD8+ T LYMPHOCYTE; CONTROLLED STUDY; DRUG CONJUGATION; DRUG ELIMINATION; DRUG HALF LIFE; DRUG PROTEIN BINDING; DRUG RECEPTOR BINDING; DRUG RELEASE; DRUG TOLERABILITY; FEMALE; IN VITRO STUDY; IN VIVO STUDY; MAXIMUM PLASMA CONCENTRATION; MEAN RESIDENCE TIME; MOLECULAR MECHANICS; MOUSE; MULTIPLE CYCLE TREATMENT; NONHUMAN; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; T LYMPHOCYTE ACTIVATION; TIME TO MAXIMUM PLASMA CONCENTRATION; TUMOR MICROENVIRONMENT; AGONISTS; ALGORITHM; ALLOTRANSPLANTATION; ANALOGS AND DERIVATIVES; ANIMAL; BAGG ALBINO MOUSE; C3H MOUSE; C57BL MOUSE; DRUG EFFECTS; IMMUNOLOGY; IMMUNOTHERAPY; KINETICS; METABOLISM; NEOPLASMS; PHOSPHORYLATION; PROCEDURES; THEORETICAL MODEL; TUMOR CELL LINE;

ALGORITHMS; ANIMALS; CD8-POSITIVE T-LYMPHOCYTES; CELL LINE, TUMOR; DRUG LIBERATION; FEMALE; IMMUNOTHERAPY; INTERLEUKIN RECEPTOR COMMON GAMMA SUBUNIT; INTERLEUKIN-2; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; INTERLEUKIN-2 RECEPTOR BETA SUBUNIT; KINETICS; MICE, INBRED BALB C; MICE, INBRED C3H; MICE, INBRED C57BL; MODELS, THEORETICAL; NEOPLASMS; PHOSPHORYLATION; POLYETHYLENE GLYCOLS; PRODRUGS; RECEPTORS, INTERLEUKIN-2; STAT5 TRANSCRIPTION FACTOR; T-LYMPHOCYTES, REGULATORY; TRANSPLANTATION, HOMOLOGOUS; TUMOR MICROENVIRONMENT;

EID: 85021846979     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0179431     Document Type: Article

References (40)

1. McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. J Clin Oncol. 2016; 34(8):833–42. https://doi.org/10.1200/JCO.2015.63.7421 PMID: 26755520.
2. Sznol M, Longo DL. Release the Hounds! Activating the T-Cell Response to Cancer. The New England journal of medicine. 2015; 372(4):374–5. https://doi.org/10.1056/NEJMe1413488 PMID: 25482238.
3. McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly JD, Smith DC, et al. Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J Clin Oncol. 2015; 33(18):2013–20. https://doi.org/10.1200/JCO.2014.58.1041 PMID: 25800770; PubMed Central PMCID: PMCPMC4517051.
4. Assal A, Kaner J, Pendurti G, Zang X. Emerging targets in cancer immunotherapy: beyond CTLA-4 and PD-1. Immunotherapy. 2015; 7(11):1169–86. https://doi.org/10.2217/imt.15.78 PMID: 26567614.
5. Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators. Frontiers in immunology. 2015; 6:418. https://doi.org/10.3389/fimmu.2015.00418 PMID: 26347741; PubMed Central PMCID: PMCPMC4544156.
6. Luheshi NM, Coates-Ulrichsen J, Harper J, Mullins S, Sulikowski MG, Martin P, et al. Transformation of the tumour microenvironment by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse orthotopic pancreatic tumour model. Oncotarget. 2016; 7(14):18508–20. https://doi.org/10.18632/oncotarget.7610 PMID: 26918344; PubMed Central PMCID: PMCPMC4951305.
7. Lipiainen T, Peltoniemi M, Sarkhel S, Yrjonen T, Vuorela H, Urtti A, et al. Formulation and stability of cytokine therapeutics. Journal of pharmaceutical sciences. 2015; 104(2):307–26. https://doi.org/10.1002/jps.24243 PMID: 25492409.
8. Schein CH. The shape of the messenger: using protein structure information to design novel cytokine-based therapeutics. Curr Pharm Des. 2002; 8(24):2113–29. PMID: 12369857.
9. Sim GC, Radvanyi L. The IL-2 Cytokine Family in Cancer Immunotherapy. Cytokine & Growth Factor Reviews. 2014. https://doi.org/10.1016/j.cytogfr.2014.07.018 PMID: 25200249
10. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005; 23(1):133–41. https://doi.org/10.1200/JCO.2005.03.206 PMID: 15625368.
11. Payne R, Glenn L, Hoen H, Richards B, Smith JW 2nd, Lufkin R, et al. Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program. J Immunother Cancer. 2014; 2:13. Epub 2014/05/24. https://doi.org/10.1186/ 2051-1426-2-13 PMID: 24855563; PubMed Central PMCID: PMCPmc4030280.
12. Alexandrescu DT, Maddukuri P, Wiernik PH, Dutcher JP. Thrombotic thrombocytopenic purpura/hemo-lytic uremic syndrome associated with high-dose interleukin-2 for the treatment of metastatic melanoma. J Immunother. 2005; 28(2):144–7. PMID: 15725958.
13. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nature reviews Immunology. 2012; 12(3):180–90. https://doi.org/10.1038/nri3156 PMID: 22343569.
14. Dutcher J. Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma. Oncology (Williston Park). 2002; 16(11 Suppl 13):4–10. PMID: 12469934.
15. Letourneau S, van Leeuwen EM, Krieg C, Martin C, Pantaleo G, Sprent J, et al. IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25. Proc Natl Acad Sci U S A. 2010; 107(5):2171–6. https://doi.org/10.1073/pnas.0909384107 PMID: 20133862; PubMed Central PMCID: PMC2836659.
16. Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, et al. NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. Clin Cancer Res. 2016; 22(3):680–90. https://doi.org/10.1158/1078-0432.CCR-15-1631 PMID: 26832745.
17. https://www.drugbank.ca/drugs/DB00041. Aldesleukin. DrugBank. (DB00041 (BTD00082, BIOD00082)):DB00041 (BTD82, BIOD82). DB00041 (BTD00082, BIOD00082).
18. Leon K, Garcia-Martinez K, Carmenate T. Mathematical Models of the Impact of IL2 Modulation Therapies on T Cell Dynamics. Frontiers in immunology. 2013; 4:439. https://doi.org/10.3389/fimmu.2013.00439 PMID: 24376444; PubMed Central PMCID: PMCPMC3858650.
19. Busse D, de la Rosa M, Hobiger K, Thurley K, Flossdorf M, Scheffold A, et al. Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107(7):3058–63. https://doi.org/10.1073/pnas.0812851107 PMID: 20133667; PubMed Central PMCID: PMCPMC2840293.
20. Feinerman O, Jentsch G, Tkach KE, Coward JW, Hathorn MM, Sneddon MW, et al. Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response. Mol Syst Biol. 2010; 6:437. https://doi.org/10.1038/msb.2010.90 PMID: 21119631; PubMed Central PMCID: PMCPMC3010113.
21. Garcia-Martinez K, Leon K. Modeling the role of IL2 in the interplay between CD4+ helper and regulatory T cells: studying the impact of IL2 modulation therapies. International immunology. 2012; 24 (7):427–46. https://doi.org/10.1093/intimm/dxr120 PMID: 22371423.
22. Shanafelt AB, Lin Y, Shanafelt MC, Forte CP, Dubois-Stringfellow N, Carter C, et al. A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo. Nature biotechnology. 2000; 18(11):1197–202. https://doi.org/10.1038/81199 PMID: 11062441.
23. Taniguchi T, Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell. 1993; 73(1):5–8. PMID: 8462103.
24. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA. Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006; 103(8):2788–93. https://doi.org/10.1073/pnas.0511161103 PMID: 16477002; PubMed Central PMCID: PMCPMC1413841.
25. Wang X, Rickert M, Garcia KC. Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science. 2005; 310(5751):1159–63. https://doi.org/10.1126/science.1117893 PMID: 16293754.
26. Wu Z, Johnson KW, Choi Y, Ciardelli TL. Ligand binding analysis of soluble interleukin-2 receptor complexes by surface plasmon resonance. The Journal of biological chemistry. 1995; 270(27):16045–51. PMID: 7608166.
27. Myszka DG, Arulanantham PR, Sana T, Wu Z, Morton TA, Ciardelli TL. Kinetic analysis of ligand binding to interleukin-2 receptor complexes created on an optical biosensor surface. Protein science: a publication of the Protein Society. 1996; 5(12):2468–78. https://doi.org/10.1002/pro.5560051209 PMID: 8976555; PubMed Central PMCID: PMC2143301.
28. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA. Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103(8):2788–93. https://doi.org/10.1073/pnas.0511161103 PMID: 16477002
29. Rickert M, Boulanger MJ, Goriatcheva N, Garcia KC. Compensatory energetic mechanisms mediating the assembly of signaling complexes between interleukin-2 and its alpha, beta, and gamma(c) receptors. J Mol Biol. 2004; 339(5):1115–28. https://doi.org/10.1016/j.jmb.2004.04.038 PMID: 15178252.
30. Konigsberg PJ, Godtel R, Kissel T, Richer LL. The development of IL-2 conjugated liposomes for therapeutic purposes. Biochimica et biophysica acta. 1998; 1370(2):243–51. PMID: 9545572.
31. Bos GW, Jacobs JJ, Koten JW, Van Tomme S, Veldhuis T, van Nostrum CF, et al. In situ crosslinked biodegradable hydrogels loaded with IL-2 are effective tools for local IL-2 therapy. Eur J Pharm Sci. 2004; 21(4):561–7. https://doi.org/10.1016/j.ejps.2003.12.007 PMID: 14998588.
32. Craiu A, Barouch DH, Zheng XX, Kuroda MJ, Schmitz JE, Lifton MA, et al. An IL-2/Ig fusion protein influences CD4+ T lymphocytes in naive and simian immunodeficiency virus-infected Rhesus monkeys. AIDS Res Hum Retroviruses. 2001; 17(10):873–86. https://doi.org/10.1089/088922201750290005 PMID: 11461674.
33. Penichet ML, Harvill ET, Morrison SL. Antibody-IL-2 fusion proteins: a novel strategy for immune protection. Hum Antibodies. 1997; 8(3):106–18. PMID: 9322080.
34. Zhang L, Zhang J, Shi Q, editors. Abstract A6: RNAseq and immune profiling analysis of syngeneic mouse models treated with immune checkpoint inhibitors enable biomarker discovery and model selection for cancer immunotherapy. Molecular Cancer Therapeutics; 2015.
35. Zhang L, Zhang J, Shi Q. Abstract A6: RNAseq and immune profiling analysis of syngeneic mouse models treated with immune checkpoint inhibitors enable biomarker discovery and model selection for cancer immunotherapy. Molecular Cancer Therapeutics. 2015; 14(12 Supplement 2):A6–A. https://doi.org/10.1158/1535-7163.targ-15-a6
36. Samlowski WE, McGregor JR, Jurek M, Baudys M, Zentner GM, Fowers KD. ReGels Polymer-based Delivery of Interleukin-2 as a Cancer Treatment. Journal of immunotherapy. 2006; 29(5):524–35. https://doi.org/10.1097/01.cji.0000211306.05869.25 PMID: 16971808
37. Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, et al. Exploiting a natural conformational switch to engineer an interleukin-2’superkine’. Nature. 2012; 484(7395):529–33. https://doi.org/10.1038/nature10975 PMID: 22446627; PubMed Central PMCID: PMC3338870.
38. Kalia V, Sarkar S, Subramaniam S, Haining WN, Smith KA, Ahmed R. Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity. 2010; 32(1):91–103. https://doi.org/10.1016/j.immuni.2009.11.010 PMID: 20096608.
39. Fishburn CS. The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. Journal of pharmaceutical sciences. 2008; 97(10):4167–83. https://doi.org/10.1002/jps.21278 PMID: 18200508.
40. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP 3rd, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. The New England journal of medicine. 2011; 365(22):2055–66. https://doi.org/10.1056/NEJMoa1108188 PMID: 22129252; PubMed Central PMCID: PMC3727432.