Tripokin: A multi-specific immunocytokine for cancer immunotherapy.
antibody–cytokine fusions
cancer immunotherapy
interleukin‐2
multi‐specific antibody
tumor necrosis factor
tumor targeting
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
23 Aug 2024
23 Aug 2024
Historique:
revised:
10
07
2024
received:
12
03
2024
accepted:
31
07
2024
medline:
23
8
2024
pubmed:
23
8
2024
entrez:
23
8
2024
Statut:
aheadofprint
Résumé
Antibodies that target the tumor microenvironment can be used to deliver pro-inflammatory payloads, such as cytokines. Cytokines are small proteins able to modulate the activity of the immune system, and antibody-cytokine fusion proteins have been tested in preclinical and clinical settings. In this study, we describe Tripokin, a novel multi-specific fusion protein that combines interleukin-2 and a single amino acid mutant of tumor necrosis factor. The two pro-inflammatory payloads were fused to the L19 antibody, a clinical-grade antibody against the extradomain B of fibronectin. The human payloads were used for clinical applications, while the corresponding murine cytokines were used for preclinical studies. The resulting fusion proteins were produced in mammalian cells and purified to homogeneity. The murine Tripokin product was well tolerated in tumor-bearing mice at three doses of 30 μg in a 2-day interval and promoted rapid tumor eradication in murine models, more efficiently than single-agent immunocytokines. Tripokin induced rapid tumor necrosis and stimulated a robust immune response, impacting innate and adaptive immune pathways. In addition, the combination with immune checkpoint inhibitors further boosted the therapeutic efficacy of our molecule. Tripokin represents a promising clinical candidate for the simultaneous delivery of interleukin-2 and tumor necrosis factor to neoplastic sites.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Innosuisse - Schweizerische Agentur für Innovationsförderung
ID : 36371.1 IP-LS
Informations de copyright
© 2024 UICC.
Références
Rosenberg SA. IL‐2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451‐5458.
Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high‐dose Interleukin‐2 identification of the antigens mediating response. Ann of Surg. 1998;228:307‐319.
Bright R, Coventry BJ, Eardley‐Harris N, Briggsw N. Clinical response rates from Interleukin‐2 therapy for metastatic melanoma over 30 years' experience: a meta‐analysis of 3312 patients [Internet]. J Immunother. 2017;40:21‐30.
Wiemann B, Starnes CO. Coley's toxins, tumor necrosis factor and cancer research: a historical perspective. Pharmacol Ther. 1994;64:529‐564.
Starnes CO. Coley's toxins in perspective. Nature. 1992;357:11‐12.
Eggermont AMM, Koops S, Li6nard D, et al. Isolated limb perfusion with high‐dose tumor necrosis factor‐alpha in combination with interferon‐gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial. J Clin Oncol. 1996;14:2653‐2665.
Eggermont AMM, de Wilt JHW, ten Hagen TLM. Current uses of isolated limb perfusion in the clinic and a model system for new strategies. Lancet Oncol. 2003;4:429‐437.
Gutbrodt KL, Neri D. Immunocytokines. Immunocytokines. Vol 1. MDPI; 2012:70‐87.
Sondel PM, Gillies SD. Immunocytokines for cancer immunotherapy. In: Morse MA, Clay TM, Lyerly HK, eds. Handbook of Cancer Vaccines. Cancer Drug Discovery and Development. Humana Press; 2004:341‐358.
List T, Neri D. Immunocytokines: a review of molecules in clinical development for cancer therapy. Clin Pharmacol. 2013;5:29‐45.
Frey K, Schliemann C, Schwager K, Giavazzi R, Johannsen M, Neri D. The immunocytokine F8‐IL2 improves the therapeutic performance of sunitinib in a mouse model of renal cell carcinoma. J Urol. 2010;184(6):2540‐2548.
Puca E, Probst P, Stringhini M, et al. The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors. Int J Cancer. 2020;146(9):2518‐2530.
Schliemann C, Hemmerle T, Berdel AF, et al. Dose escalation and expansion phase I studies with the tumour‐targeting antibody‐tumour necrosis factor fusion protein L19TNF plus doxorubicin in patients with advanced tumours, including sarcomas. Eur J Cancer. 2021;1(150):143‐154.
Weide B, Eigentler T, Catania C, et al. A phase II study of the L19IL2 immunocytokine in combination with dacarbazine in advanced metastatic melanoma patients. Cancer Immunol Immunother. 2019;68(9):1547‐1559.
Danielli R, Patuzzo R, Di Giacomo AM, et al. Intralesional administration of L19‐IL2/L19‐TNF in stage III or stage IVM1a melanoma patients: results of a phase II study. Cancer Immunol Immunother. 2015;64(8):999‐1009.
Berdel AF, Ruhnke L, Angenendt L, et al. Using stroma‐anchoring cytokines to augment ADCC: a phase 1 trial of F16IL2 and BI 836858 for posttransplant AML relapse. Blood Adv. 2022;6(12):3684‐3696.
Look T, Puca E, Bühler M, et al. Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell–dependent regression of glioblastoma. Sci Transl Med. 2023;15(697):eadf2281.
Weide B, Eigentler TK, Pflugfelder A, et al. Intralesional treatment of stage III metastatic melanoma patients with L19–IL2 results in sustained clinical and systemic immunologic responses. Cancer Immunol Res. 2014;2(7):668‐678.
Eigentler TK, Weide B, de Braud F, et al. A dose‐escalation and signal‐generating study of the Immunocytokine L19‐IL2 in combination with Dacarbazine for the therapy of patients with metastatic melanoma. Clin Cancer Res. 2011;17(24):7732‐7742.
Schwager K, Hemmerle T, Aebischer D, Neri D. The immunocytokine L19‐IL2 eradicates cancer when used in combination with CTLA‐4 blockade or with L19‐TNF. J Investig Dermatol. 2013;133(3):751‐758.
Balza E, Carnemolla B, Mortara L, et al. Therapy‐induced antitumor vaccination in neuroblastomas by the combined targeting of IL‐2 and TNFα. Int J Cancer. 2010;127(1):101‐110.
Gillies SD, Lan Y, Brunkhorst B, Wong WK, Li Y, Lo KM. Bi‐functional cytokine fusion proteins for gene therapy and antibody‐targeted treatment of cancer. Cancer Immunol Immunother. 2002;51(8):449‐460.
Halin C, Gafner V, Villani ME, et al. Synergistic Therapeutic Effects of a Tumor Targeting Antibody Fragment, Fused to Interleukin 12 and to Tumor Necrosis Factor 1 [Internet]. Cancer Res. 2003;63:3202‐3210.
De Luca R, Neri D. Potentiation of PD‐L1 blockade with a potency‐matched dual cytokine–antibody fusion protein leads to cancer eradication in BALB/c‐derived tumors but not in other mouse strains. Cancer Immunol Immunother. 2018;67(9):1381‐1391.
De Luca R, Kachel P, Kropivsek K, Snijder B, Manz MG, Neri D. A novel dual‐cytokine‐antibody fusion protein for the treatment of CD38‐positive malignancies. Protein Eng Des Sel. 2018;31(5):173‐179.
De Luca R, Soltermann A, Pretto F, et al. Potency‐matched dual cytokine–antibody fusion proteins for cancer therapy. Mol Cancer Ther. 2017;16(11):2442‐2451.
De Luca R, Gouyou B, Ongaro T, et al. A novel fully‐human potency‐matched dual cytokine‐antibody fusion protein targets carbonic anhydrase IX in renal cell carcinomas. Front Oncol. 2019;9:1228.
Saks S, Rosenblum M. Recombinant human TNF‐alpha: preclinical studies and results from early clinical trials. Immunol Ser. 1992;56:567‐587.
Pini A, Viti F, Santucci A, et al. Design and use of a phage display library: antibodies with subnanomolar affinity against a marker of angiogenesis eluted from a two‐dimensional gel. J Biol Chem. 1998;273(34):21769‐21776.
Van Ostade X, Tavernier1 J, Prange2 T, et al. Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis. EMBO J. 1991;10:827‐836.
Schneider CA, Rasband WS, Eliceiri KW. NIH image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671‐675.
Probst P, Kopp J, Oxenius A, et al. Sarcoma eradication by doxorubicin and targeted TNF relies upon CD8+ T‐cell recognition of a retroviral antigen. Cancer Res. 2017;77(13):3644‐3654.
Schliemann C, Wiedmer A, Pedretti M, Szczepanowski M, Klapper W, Neri D. Three clinical‐stage tumor targeting antibodies reveal differential expression of oncofetal fibronectin and tenascin‐C isoforms in human lymphoma. Leuk Res. 2009;33(12):1718‐1722.
Bruijnen STG, Chandrupatla DMSH, Giovanonni L, et al. F8‐IL10: a new potential Antirheumatic drug evaluated by a PET‐guided translational approach. Mol Pharm. 2019;16(1):273‐281.
Nadal L, Peissert F, Elsayed A, et al. Generation and in vivo validation of an IL‐12 fusion protein based on a novel anti‐human FAP monoclonal antibody. J Immunother Cancer. 2022;10(9):e005282.
Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin‐induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975;72(9):3666‐3670.
Feinberg B, Kurzrock R, Talpaz M, Blick M, Saks S, Gutterman JU. A phase I trial of intravenously‐administered recombinant tumor necrosis factor‐alpha in cancer patients. J Clin Oncol. 1988;6:1328‐1334.
Algire GH, Legallais FY, Anderson BF. Vascular reactions of normal and malignant tissues in vivo. V. The rôle of hypotension in the action of a bacterial polysaccharide on tumors. J Natl Cancer Inst. 1952;12(6):1279‐1295.
Runbeck E, Crescioli S, Karagiannis SN, Papa S. Utilizing immunocytokines for cancer therapy. Antibodies (Basel). 2021;10:10.
Gout DY, Groen LS, van Egmond M. The present and future of immunocytokines for cancer treatment. Cell Mol Life Sci. 2022;79:509.
Dakhel S, Ongaro T, Gouyou B, et al. Targeted enhancement of the therapeutic window of L19‐TNF by transient and selective inhibition of RIPK1‐signaling cascade. Oncotarget. 2019;10(62):6678‐6690.
Rotta G, Gilardoni E, Ravazza D, et al. A novel strategy to generate immunocytokines with activity‐on‐demand using small molecule inhibitors. EMBO Mol Med. 2024;16(4):904‐926.
Thurber GM, Schmidt MM, Wittrup KD. Antibody tumor penetration: transport opposed by systemic and antigen‐mediated clearance. Adv Drug Deliv Rev. 2008;60(12):1421‐1434.
Yang S, Xie C, Chen Y, et al. Differential roles of TNFα‐TNFR1 and TNFα‐TNFR2 in the differentiation and function of CD4+Foxp3+ induced Treg cells in vitro and in vivo periphery in autoimmune diseases. Cell Death Dis. 2019;10(1):27.
Khawli LA, Miller GK, Epstein AL. Effect of seven new vasoactive immunoconjugates on the enhancement of monoclonal antibody uptake in tumors. Cancer. 1994;73(3 Suppl):824‐831.
Folli S, Épèlegrin A, Chalandon Y, et al. Tumor‐necrosis factor can enhance radio‐antibody uptake in human colon carcinoma xenografts by increasing vascular permeability. Int J Cancer. 1993;53(5):829‐836.
Jorgovanovic D, Song M, Wang L, Zhang Y. Roles of IFN‐γ in tumor progression and regression: a review. Biomark Res. 2020;8(1):49.
Di Nitto C, Gilardoni E, Mock J, et al. An engineered IFNγ‐antibody fusion protein with improved tumor‐homing properties. Pharmaceutics. 2023;15(2):377.