Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy

References

• Häffner AC, Garbe C, Burg G, Büttner P, Orfanos CE, Rassner G, The prognosis of primary and metastasising melanoma. An evaluation of the TNM classification in 2,495 patients. Br J Cancer. 1992;66(5):856–15. doi:https://doi.org/10.1038/bjc.1992.373.
   PubMed Web of Science ®Google Scholar
• Smith FO, Downey SG, Klapper JA, Yang JC, Sherry RM, Royal RE, Kammula US, Hughes MS, Restifo NP, Levy CL, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14(17):5610–5618. doi:https://doi.org/10.1158/1078-0432.Ccr-08-0116.
   PubMed Web of Science ®Google Scholar
• Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–2116. doi:https://doi.org/10.1200/jco.1999.17.7.2105.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE, Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. Jama. 1994;271(12):907–913. doi:10.1001/jama.1994.03510360033032.
   PubMed Web of Science ®Google Scholar
• Jeal W, Goa KL. Aldesleukin (recombinant interleukin-2): a review of its pharmacological properties, clinical efficacy and tolerability in patients with renal cell carcinoma. BioDrugs. 1997;7(4):285–317. doi:https://doi.org/10.2165/00063030-199707040-00005.
   PubMed Web of Science ®Google Scholar
• Kirchner GI, Franzke A, Buer J, Beil W, Probst‐Kepper M, Wittke F, Övermann K, Lassmann S, Hoffmann R, Kirchner H, et al. Pharmacokinetics of recombinant human interleukin-2 in advanced renal cell carcinoma patients following subcutaneous application. Br J Clin Pharmacol. 1998;46(1):5–10. doi:https://doi.org/10.1046/j.1365-2125.1998.00036.x.
   PubMed Web of Science ®Google Scholar
• Proleukin injection label. [Accessed 2023 May]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.pdf.
   Google Scholar
• Ohue Y, Nishikawa H. Regulatory T (treg) cells in cancer: can treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080–2089. doi:https://doi.org/10.1111/cas.14069.
   PubMed Web of Science ®Google Scholar
• Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity. 2010;33(2):153–65. doi:https://doi.org/10.1016/j.immuni.2010.08.004.
   PubMed Web of Science ®Google Scholar
• Ring AM, Lin J-X, Feng D, Mitra S, Rickert M, Bowman GR, Pande VS, Li P, Moraga I, Spolski R, et al. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat Immunol. 2012;13(12):1187–1195. doi:https://doi.org/10.1038/ni.2449.
   PubMed Web of Science ®Google Scholar
• Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res. 2015;3(3):219–227. doi:https://doi.org/10.1158/2326-6066.Cir-15-0009.
   PubMed Web of Science ®Google Scholar
• Spolski R, Li P, Leonard WJ. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 2018;18(10):648–659. doi:https://doi.org/10.1038/s41577-018-0046-y.
   PubMed Web of Science ®Google Scholar
• Arumugam P, Carroll KL, Berceli SA, Barnhill S, Wrenshall LE, Expression of a functional IL-2 receptor in vascular smooth muscle cells. J Immunol. 2019;202(3):694–703. doi:https://doi.org/10.4049/jimmunol.1701151.
   PubMed Web of Science ®Google Scholar
• Krieg C, Létourneau S, Pantaleo G, Boyman O, Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc Natl Acad Sci USA. 2010;107(26):11906–11. doi:https://doi.org/10.1073/pnas.1002569107.
   PubMed Web of Science ®Google Scholar
• Ahmadzadeh M, Rosenberg SA, IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood. 2006;107(6):2409–2414. doi:https://doi.org/10.1182/blood-2005-06-2399.
   PubMed Web of Science ®Google Scholar
• Sim GC, Martin-Orozco N, Jin L, Yang Y, Wu S, Washington E, Sanders D, Lacey C, Wang Y, Vence L, et al. IL-2 therapy promotes suppressive ICOS+ treg expansion in melanoma patients. J Clin Invest. 2014;124(1):99–110. doi:https://doi.org/10.1172/jci46266.
   PubMed Web of Science ®Google Scholar
• Sahin D, Arenas-Ramirez N, Rath M, Karakus U, Hümbelin M, van Gogh M, Borsig L, Boyman O. An IL-2-grafted antibody immunotherapy with potent efficacy against metastatic cancer. Nat Commun. 2020;11(1):6440. doi:https://doi.org/10.1038/s41467-020-20220-1.
   PubMed Web of Science ®Google Scholar
• Arenas-Ramirez N, Zou C, Popp S, Zingg D, Brannetti B, Wirth E, Calzascia T, Kovarik J, Sommer L, Zenke G, et al. Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2. Sci Transl Med. 2016;8(367):367ra166. doi:https://doi.org/10.1126/scitranslmed.aag3187.
   PubMed Web of Science ®Google Scholar
• Keller CW, Ruck T, McHugh D, Pfeuffer S, Gross CC, Korsukewitz C, Melzer N, Klotz L, Meuth SG, Münz C, et al. Impact of FcγR variants on the response to alemtuzumab in multiple sclerosis. Ann Clin Transl Neurol. 2019;6(12):2586–2594. doi:https://doi.org/10.1002/acn3.50935.
   PubMed Web of Science ®Google Scholar
• Spahr C, Shi SD, Lu HS. O-glycosylation of glycine-serine linkers in recombinant fc-fusion proteins: attachment of glycosaminoglycans and other intermediates with phosphorylation at the xylose sugar subunit. MAbs. 2014;6(4):904–914. doi:https://doi.org/10.4161/mabs.28763.
   PubMed Web of Science ®Google Scholar
• Wen D, Foley SF, Hronowski XL, Gu S, Meier W. Discovery and investigation of O-xylosylation in engineered proteins containing a (Ggggs)n linker. Anal Chem. 2013;85(9):4805–4812. doi:https://doi.org/10.1021/ac400596g.
   PubMed Web of Science ®Google Scholar
• Wolf B, Piksa M, Beley I, Patoux A, Besson T, Cordier V, Voedisch B, Schindler P, Stöllner D, Perrot L, et al. Therapeutic antibody glycosylation impacts antigen recognition and immunogenicity. Immunology. 2022;166(3):380–407. doi:https://doi.org/10.1111/imm.13481.
   PubMed Web of Science ®Google Scholar
• Au-Yeung BB, Smith GA, Mueller JL, Heyn CS, Jaszczak RG, Weiss A, Zikherman J. IL-2 modulates the TCR signaling threshold for CD8 but not CD4 T cell proliferation on a single-cell level. J Immunol. 2017;198(6):2445–2456. doi:https://doi.org/10.4049/jimmunol.1601453.
   PubMed Web of Science ®Google Scholar
• Robb RJ, Greene WC. Internalization of interleukin 2 is mediated by the beta chain of the high-affinity interleukin 2 receptor. J Exp Med. 1987;165(4):1201–1206. doi:https://doi.org/10.1084/jem.165.4.1201.
   PubMed Web of Science ®Google Scholar
• Gavin PG, Song N, Kim SR, Lipchik C, Johnson NL, Bandos H, Finnigan M, Rastogi P, Fehrenbacher L, Mamounas EP, et al. Association of polymorphisms in FCGR2A and FCGR3A with degree of trastuzumab benefit in the adjuvant treatment of ERBB2/HER2–positive breast cancer. JAMA Oncol. 2017;3(3):335–341. doi:https://doi.org/10.1001/jamaoncol.2016.4884.
   PubMed Web of Science ®Google Scholar
• Jacobs SA, Robidoux A, Abraham J, Pérez-Garcia JM, La Verde N, Orcutt JM, Cazzaniga ME, Piette F, Antolín S, Aguirre E, et al. NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2(+) breast cancer. Breast Cancer Res. 2019;21(1):133. doi:https://doi.org/10.1186/s13058-019-1196-y.
   PubMed Web of Science ®Google Scholar
• Hernandez R, Põder J, LaPorte KM, Malek TR. Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nat Rev Immunol. 2022;22(10):614–628. doi:https://doi.org/10.1038/s41577-022-00680-w.
   PubMed Web of Science ®Google Scholar
• Overwijk WW, Tagliaferri MA, Zalevsky J. Engineering IL-2 to give new life to T cell immunotherapy. Annu Rev Med. 2021;72(1):281–311. doi:https://doi.org/10.1146/annurev-med-073118-011031.
   PubMedGoogle Scholar
• Moynihan K, Pappas D, Sultan H, Park T, Kumar M, Lan R, Ni I, Chen J, Chin M, Schumacher T, et al. 1092 the CD8+ T cell selectivity of AB248 is essential for optimal anti-tumor activity and safety in nonclinical models. J Immunother Cancer. 2022;10:A1135–1135. doi:https://doi.org/10.1136/jitc-2022-SITC2022.1092.
   Web of Science ®Google Scholar
• Hsu EJ, Cao X, Moon B, Bae J, Sun Z, Liu Z, Fu Y-X. A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy. Nat Commun. 2021;12(1):2768. doi:https://doi.org/10.1038/s41467-021-22980-w.
   PubMed Web of Science ®Google Scholar
• Nirschl CJ, Brodkin HR, Hicklin DJ, Ismail N, Morris K, Seidel-Dugan C, Steiner P, Steuert Z, Sullivan JM, Tyagi E, et al. Discovery of a conditionally activated IL-2 that promotes antitumor immunity and induces tumor regression. Cancer Immunol Res. 2022;10(5):581–596. doi:https://doi.org/10.1158/2326-6066.Cir-21-0831.
   PubMed Web of Science ®Google Scholar
• Norville K, Skrombolas D, Ferry SL, Kearns N, Frelinger JG. A protease activatable interleukin-2 fusion protein engenders antitumor immune responses by interferon gamma-dependent and interferon gamma-Independent mechanisms. J Interferon Cytokine Res. 2022;42(7):316–328. doi:https://doi.org/10.1089/jir.2022.0043.
   PubMed Web of Science ®Google Scholar
• Ptacin JL, Caffaro CE, Ma L, San Jose Gall KM, Aerni HR, Acuff NV, Herman RW, Pavlova Y, Pena MJ, Chen DB, et al. An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism. Nat Commun. 2021;12(1):4785. doi:https://doi.org/10.1038/s41467-021-24987-9.
   PubMed Web of Science ®Google Scholar
• Sharma P, Goswami S, Raychaudhuri D, Siddiqui BA, Singh P, Nagarajan A, Liu J, Subudhi SK, Poon C, Gant KL, et al. Immune checkpoint therapy—current perspectives and future directions. Cell. 2023;186(8):1652–1669. doi:https://doi.org/10.1016/j.cell.2023.03.006.
   PubMed Web of Science ®Google Scholar
• Charych D, Khalili S, Dixit V, Kirk P, Chang T, Langowski J, Rubas W, Doberstein SK, Eldon M, Hoch U, et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLOS ONE. 2017;12(7):e0179431. doi:https://doi.org/10.1371/journal.pone.0179431.
   PubMed Web of Science ®Google Scholar
• Klein C, Waldhauer I, Nicolini VG, Freimoser-Grundschober A, Nayak T, Vugts DJ, Dunn C, Bolijn M, Benz J, Stihle M, et al. Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines. Oncoimmunology. 2017;6(3):e1277306. doi:https://doi.org/10.1080/2162402x.2016.1277306.
   PubMed Web of Science ®Google Scholar
• Ribba B, Boetsch C, Nayak T, Grimm HP, Charo J, Evers S, Klein C, Tessier J, Charoin JE, Phipps A, et al. Prediction of the optimal dosing regimen using a mathematical Model of tumor uptake for immunocytokine-based cancer immunotherapy. Clin Cancer Res. 2018;24(14):3325–3333. doi:https://doi.org/10.1158/1078-0432.Ccr-17-2953.
   PubMed Web of Science ®Google Scholar
• Lebbe C, Ravimohan S, Datta A, Chhibber A, Couselo EM, Pereira C, Sandhu S, Zhou M, Curti B, Khushalani N, et al. 1473 Mechanism of action of bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in patients with unresectable or metastatic melanoma from the phase 3 randomized open-label PIVOT IO-001 clinical trial. J Immunother Cancer. 2022;10:A1532. doi:https://doi.org/10.1136/jitc-2022-SITC2022.1473.
   Web of Science ®Google Scholar
• Gillies SD, Lo K-M, Burger C, Lan Y, Dahl T, Wong W-K. Improved circulating half-life and efficacy of an antibody-interleukin 2 immunocytokine based on reduced intracellular proteolysis. Clin Cancer Res. 2002;8(1):210–216.
   PubMed Web of Science ®Google Scholar
• Joerger M, Calvo E, Laubli H, Lopez J, Alonso G, Corral de la Fuente E, Hess D, König D, Sanchez Perez V, Bucher C, et al. Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors. J Immunother Cancer. 2023;11(11):e007784. doi:https://doi.org/10.1136/jitc-2023-007784.
   PubMedGoogle Scholar
• Diab A, Tannir NM, Bentebibel S-E, Hwu P, Papadimitrakopoulou V, Haymaker C, Kluger HM, Gettinger SN, Sznol M, Tykodi SS, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 2020;10(8):1158–1173. doi:https://doi.org/10.1158/2159-8290.Cd-19-1510.
   PubMed Web of Science ®Google Scholar