Top

Published in:

01-12-2006 | Original Article

Target-selective activation of a TNF prodrug by urokinase-type plasminogen activator (uPA) mediated proteolytic processing at the cell surface

Authors: Jeannette Gerspach, Julia Németh, Sabine Münkel, Harald Wajant, Klaus Pfizenmaier

Published in: Cancer Immunology, Immunotherapy | Issue 12/2006

Abstract

We have previously developed TNF prodrugs comprised of a N-terminal scFv targeting, a TNF effector and a C-terminal TNFR1-derived inhibitor module linked to TNF via a MMP-2 motif containing peptide, allowing activation by MMP-2-expressing tumor cells. To overcome the known heterogeneity of matrix metalloprotease expression, we developed TNF prodrugs that become processed by other tumor and/or stroma-associated proteases. These TNF prodrugs comprise either an uPA-selective or a dual uPA-MMP-2-specific linker which displayed efficient, target-dependent and cleavage sequence-specific activation by the corresponding tumor cell-expressed proteases. Selective pharmacologic inhibition of endogenous uPA and MMP-2 confirm independent prodrug processing by these two model proteases and indicate the functional superiority of a prodrug containing a multi-specific protease linker. Processing optimised TNF prodrugs should increase the proportion of active therapeutic within the targeted tissue and thus potentially enhance tumor response rate.

Andreasen PA, Kjoller L, Christensen L, Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72:1PubMedCrossRef

Andreasen PA, Egelund R, Petersen HH (2000) The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 57:25PubMedCrossRef

Bauer S, Adrian N, Williamson B, Panousis C, Fadle N, Smerd J, Fettah I, Scott AM, Pfreundschuh M, Renner C (2004) Targeted bioactivity of membrane-anchored TNF by an antibody-derived TNF fusion protein. J Immunol 172:3930PubMed

Blasi F, Carmeliet P (2002) uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 3:932PubMedCrossRef

Borsi L, Balza E, Carnemolla B, Sassi F, Castellani P, Berndt A, Kosmehl H, Biro A, Siri A, Orecchia P, Grassi J, Neri D, Zardi L (2003) Selective targeted delivery of TNFalpha to tumor blood vessels. Blood 102:4384PubMedCrossRef

Bremer E, Samplonius DF, van Genne L, Dijkstra MH, Kroesen BJ, de Leij LF, Helfrich W (2005) Simultaneous inhibition of epidermal growth factor receptor (EGFR) signaling and enhanced activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis induction by an scFv:sTRAIL fusion protein with specificity for human EGFR. J Biol Chem 280:10025PubMedCrossRef

Bryde S, Grunwald I, Hammer A, Krippner-Heidenreich A, Schiestel T, Brunner H, Tovar GE, Pfizenmaier K, Scheurich P (2005) Tumor necrosis factor (TNF)-functionalized nanostructured particles for the stimulation of membrane TNF-specific cell responses. Bioconjug Chem 16:1459PubMedCrossRef

Cha SS, Kim JS, Cho HS, Shin NK, Jeong W, Shin HC, Kim YJ, Hahn JH, Oh BH (1998) High resolution crystal structure of a human tumor necrosis factor-alpha mutant with low systemic toxicity. J Biol Chem 273:2153PubMedCrossRef

Corti A (2004) Strategies for improving the anti-neoplastic activity of TNF by tumor targeting. Methods Mol Med 98:247PubMed

10.

Curnis F, Sacchi A, Borgna L, Magni F, Gasparri A, Corti A (2000) Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat Biotechnol 18:1185PubMedCrossRef

11.

Curnis F, Sacchi A, Corti A (2002) Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Invest 110:475PubMed

12.

Curnis F, Gasparri A, Sacchi A, Longhi R, Corti A (2004) Coupling tumor necrosis factor-alpha with alphaV integrin ligands improves its antineoplastic activity. Cancer Res 64:565PubMedCrossRef

13.

Duffy MJ, Maguire TM, McDermott EW, O’Higgins N (1999) Urokinase plasminogen activator: a prognostic marker in multiple types of cancer. J Surg Oncol 71:130PubMedCrossRef

14.

Duffy MJ, Maguire TM, Hill A, McDermott E, O’Higgins N (2000) Metalloproteinases: role in breast carcinogenesis, invasion and metastasis. Breast Cancer Res 2:252PubMedCrossRef

15.

Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161PubMedCrossRef

16.

Eggermont AM, ten Hagen TL (2001) Isolated limb perfusion for extremity soft-tissue sarcomas, in-transit metastases, and other unresectable tumors: credits, debits, and future perspectives. Curr Oncol Rep 3:359PubMedCrossRef

17.

Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876PubMedCrossRef

18.

Garin-Chesa P, Old LJ, Rettig WJ (1990) Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA 87:7235PubMedCrossRef

19.

Gerspach J, Muller D, Munkel S, Selchow O, Nemeth J, Noack M, Petrul H, Menrad A, Wajant H, Pfizenmaier K (2006) Restoration of membrane TNF-like activity by cell surface targeting and matrix metalloproteinase-mediated processing of a TNF prodrug. Cell Death Differ 13:273PubMedCrossRef

20.

Ginestra A, Monea S, Seghezzi G, Dolo V, Nagase H, Mignatti P, Vittorelli ML (1997) Urokinase plasminogen activator and gelatinases are associated with membrane vesicles shed by human HT1080 fibrosarcoma cells. J Biol Chem 272:17216PubMedCrossRef

21.

Grell M, Douni E, Wajant H, Lohden M, Clauss M, Maxeiner B, Georgopoulos S, Lesslauer W, Kollias G, Pfizenmaier K, Scheurich P (1995) The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83:793PubMedCrossRef

22.

Heppner KJ, Matrisian LM, Jensen RA, Rodgers WH (1996) Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol 149:273PubMed

23.

Hofmann UB, Westphal JR, van Muijen GN, Ruiter DJ (2000) Matrix metalloproteinases in human melanoma. J Invest Dermatol 115:337PubMedCrossRef

24.

Kamada H, Tsutsumi Y, Yamamoto Y, Kihira T, Kaneda Y, Mu Y, Kodaira H, Tsunoda SI, Nakagawa S, Mayumi T (2000) Antitumor activity of tumor necrosis factor-alpha conjugated with polyvinylpyrrolidone on solid tumors in mice. Cancer Res 60:6416PubMed

25.

Ke SH, Coombs GS, Tachias K, Corey DR, Madison EL (1997) Optimal subsite occupancy and design of a selective inhibitor of urokinase. J Biol Chem 272:20456PubMedCrossRef

26.

Kuroda K, Miyata K, Fujita F, Koike M, Fujita M, Nomura M, Nakagawa S, Tsutsumi Y, Kawagoe T, Mitsuishi Y, Mayumi T (2000) Human tumor necrosis factor-alpha mutant RGD-V29 (F4614) shows potent antitumor activity and reduced toxicity against human tumor xenografted nude mice. Cancer Lett 159:33PubMedCrossRef

27.

Lafleur MA, Tester AM, Thompson EW (2003) Selective involvement of TIMP-2 in the second activational cleavage of pro-MMP-2: refinement of the pro-MMP-2 activation mechanism. FEBS Lett 553:457PubMedCrossRef

28.

Laug WE, Wang K, Mundi R, Rideout W III, Kruithof EK, Bogenmann E (1992) Clonal variation of expression of the genes coding for plasminogen activators, their inhibitors and the urokinase receptor in HT1080 sarcoma cells. Int J Cancer 52:298PubMedCrossRef

29.

Liabakk NB, Talbot I, Smith RA, Wilkinson K, Balkwill F (1996) Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res 56:190PubMed

30.

Lim YT, Sugiura Y, Laug WE, Sun B, Garcia A, DeClerck YA (1996) Independent regulation of matrix metalloproteinases and plasminogen activators in human fibrosarcoma cells. J Cell Physiol 167:333PubMedCrossRef

31.

Liu S, Bugge TH, Leppla SH (2001) Targeting of tumor cells by cell surface urokinase plasminogen activator-dependent anthrax toxin. J Biol Chem 276:17976PubMedCrossRef

32.

Look MP, van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Ferno M, Eppenberger-Castori S, Sweep CG, Ulm K, Peyrat JP, Martin PM, Magdelenat H, Brunner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WE, Blankenstein MA, Broet P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LV, Klijn JG, O’Higgins N, Eppenberger U, Janicke F, Schmitt M, Foekens JA (2002) Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 94:116PubMed

33.

Lu F, Chen ZM, Liu QH, Chen CQ (2001) A novel human tumor necrosis factor alpha mutant showed potent antitumor activity and reduced toxicity in vivo. Acta Pharmacol Sin 22:619PubMed

34.

Maquoi E, Frankenne F, Noel A, Krell HW, Grams F, Foidart JM (2000) Type IV collagen induces matrix metalloproteinase 2 activation in HT1080 fibrosarcoma cells. Exp Cell Res 261:348PubMedCrossRef

35.

Mueller H (1998) Tumor necrosis factor as an antineoplastic agent: pitfalls and promises. Cell Mol Life Sci 54:1291PubMedCrossRef

36.

Ohba K, Miyata Y, Kanda S, Koga S, Hayashi T, Kanetake H (2005) Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: correlation with tumor associated macrophage and prognosis. J Urol 174:461PubMedCrossRef

37.

Pyke C, Kristensen P, Ralfkiaer E, Grondahl-Hansen J, Eriksen J, Blasi F, Dano K (1991) Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas. Am J Pathol 138:1059PubMed

38.

Samel D, Muller D, Gerspach J, Assohou-Luty C, Sass G, Tiegs G, Pfizenmaier K, Wajant H (2003) Generation of a FasL-based proapoptotic fusion protein devoid of systemic toxicity due to cell-surface antigen-restricted activation. J Biol Chem 278:32077PubMedCrossRef

39.

Schmalfeldt B, Prechtel D, Harting K, Spathe K, Rutke S, Konik E, Fridman R, Berger U, Schmitt M, Kuhn W, Lengyel E (2001) Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer. Clin Cancer Res 7:2396PubMed

40.

Stanton H, Gavrilovic J, Atkinson SJ, d’Ortho MP, Yamada KM, Zardi L, Murphy G (1998) The activation of ProMMP-2 (gelatinase A) by HT1080 fibrosarcoma cells is promoted by culture on a fibronectin substrate and is concomitant with an increase in processing of MT1-MMP (MMP-14) to a 45 kDa form. J Cell Sci 111(Pt 18):2789PubMed

41.

Torng PL, Mao TL, Chan WY, Huang SC, Lin CT (2004) Prognostic significance of stromal metalloproteinase-2 in ovarian adenocarcinoma and its relation to carcinoma progression. Gynecol Oncol 92:559PubMedCrossRef

42.

Turk BE, Huang LL, Piro ET, Cantley LC (2001) Determination of protease cleavage site motifs using mixture-based oriented peptide libraries. Nat Biotechnol 19:661PubMedCrossRef

43.

Wajant H, Moosmayer D, Wuest T, Bartke T, Gerlach E, Schonherr U, Peters N, Scheurich P, Pfizenmaier K (2001) Differential activation of TRAIL-R1 and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative. Oncogene 20:4101PubMedCrossRef

44.

Wajant H, Gerspach J, Pfizenmaier K (2005) Tumor therapeutics by design: targeting and activation of death receptors. Cytokine Growth Factor Rev 16:55PubMedCrossRef

45.

Wuest T, Gerlach E, Banerjee D, Gerspach J, Moosmayer D, Pfizenmaier K (2002) TNF-Selectokine: a novel prodrug generated for tumor targeting and site-specific activation of tumor necrosis factor. Oncogene 21:4257PubMedCrossRef

46.

Yamamoto Y, Tsutsumi Y, Yoshioka Y, Nishibata T, Kobayashi K, Okamoto T, Mukai Y, Shimizu T, Nakagawa S, Nagata S, Mayumi T (2003) Site-specific PEGylation of a lysine-deficient TNF-alpha with full bioactivity. Nat Biotechnol 21:546PubMedCrossRef

47.

Yamashita K, Tanaka Y, Mimori K, Inoue H, Mori M (2004) Differential expression of MMP and uPA systems and prognostic relevance of their expression in esophageal squamous cell carcinoma. Int J Cancer 110:201PubMedCrossRef

48.

Yoshioka Y, Tsutsumi Y, Ikemizu S, Yamamoto Y, Shibata H, Nishibata T, Mukai Y, Okamoto T, Taniai M, Kawamura M, Abe Y, Nakagawa S, Nagata S, Yamagata Y, Mayumi T (2004) Optimal site-specific PEGylation of mutant TNF-alpha improves its antitumor potency. Biochem Biophys Res Commun 315:808PubMedCrossRef

Title: Target-selective activation of a TNF prodrug by urokinase-type plasminogen activator (uPA) mediated proteolytic processing at the cell surface
Authors: Jeannette Gerspach
Julia Németh
Sabine Münkel
Harald Wajant
Klaus Pfizenmaier
Publication date: 01-12-2006
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 12/2006
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-006-0162-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 12/2006

Macrophage inflammatory protein (MIP)1α and MIP1β differentially regulate release of inflammatory cytokines and generation of tumoricidal monocytes in malignancy

STEAP, a prostate tumor antigen, is a target of human CD8+ T cells

Endoglin (CD105) is a target for an oral DNA vaccine against breast cancer

A mechanistic study of immune system activation by fusion of antigens with the ligand-binding domain of CTLA4

Antitumor effects of a xenogeneic survivin bone marrow derived dendritic cell vaccine against murine GL261 gliomas

Survival benefit associated with human anti-mouse antibody (HAMA) in patients with B-cell malignancies

Keynote webinar | Spotlight on antibody–drug conjugates in cancer