{ "types" : { "Bookmark" : { "pluralLabel" : "Bookmarks" }, "Publication" : { "pluralLabel" : "Publications" }, "GoldStandardPublication" : { "pluralLabel" : "GoldStandardPublications" }, "GoldStandardBookmark" : { "pluralLabel" : "GoldStandardBookmarks" }, "Tag" : { "pluralLabel" : "Tags" }, "User" : { "pluralLabel" : "Users" }, "Group" : { "pluralLabel" : "Groups" }, "Sphere" : { "pluralLabel" : "Spheres" } }, "properties" : { "count" : { "valueType" : "number" }, "date" : { "valueType" : "date" }, "changeDate" : { "valueType" : "date" }, "url" : { "valueType" : "url" }, "id" : { "valueType" : "url" }, "tags" : { "valueType" : "item" }, "user" : { "valueType" : "item" } }, "items" : [ { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2902f92a970fd0144df28117e499b6b53/pumaizi", "tags" : [ "2019","izi","mueller","kontermann" ], "intraHash" : "902f92a970fd0144df28117e499b6b53", "interHash" : "65f020c3d61c6b5ef58b99b3e7710154", "label" : "IL-15-based trifunctional antibody-fusion proteins with costimulatory TNF-superfamily ligands in the single-chain format for cancer immunotherapy", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Molecular Cancer Therapeutics", "year": "2019", "url": "http://www.ncbi.nlm.nih.gov/pubmed/31040163", "author": [ "Nadine Beha","Markus Harder","Sarah Ring","Roland E. Kontermann","Dafne Müller" ], "authors": [ {"first" : "Nadine", "last" : "Beha"}, {"first" : "Markus", "last" : "Harder"}, {"first" : "Sarah", "last" : "Ring"}, {"first" : "Roland E.", "last" : "Kontermann"}, {"first" : "Dafne", "last" : "Müller"} ], "pages": "molcanther.1204.2018", "pmid" : "31040163", "issn" : "1535-7163", "doi" : "10.1158/1535-7163.MCT-18-1204", "bibtexKey": "Beha2019" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2a690ea4ac41d4782cd472f2b1ccba483/pumaizi", "tags" : [ "2006","izi","mueller","pfizenmaier" ], "intraHash" : "a690ea4ac41d4782cd472f2b1ccba483", "interHash" : "e4e1715ccda9122c01b0b79aaecba98b", "label" : "Restoration of membrane TNF-like activity by cell surface targeting and matrix metalloproteinase-mediated processing of a TNF prodrug", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Cell Death and Differentiation", "year": "2006", "url": "https://www.ncbi.nlm.nih.gov/pubmed/16052236", "author": [ "J. Gerspach","D. Müller","S. Münkel","O. Selchow","J. Nemeth","M. Noack","H. Petrul","A. Menrad","H. Wajant","Klaus Pfizenmaier" ], "authors": [ {"first" : "J.", "last" : "Gerspach"}, {"first" : "D.", "last" : "Müller"}, {"first" : "S.", "last" : "Münkel"}, {"first" : "O.", "last" : "Selchow"}, {"first" : "J.", "last" : "Nemeth"}, {"first" : "M.", "last" : "Noack"}, {"first" : "H.", "last" : "Petrul"}, {"first" : "A.", "last" : "Menrad"}, {"first" : "H.", "last" : "Wajant"}, {"first" : "Klaus", "last" : "Pfizenmaier"} ], "volume": "13","number": "2","pages": "273--284","abstract": "Tumor necrosis factor (TNF) prodrugs are fusion proteins comprised of an N-terminal single-chain antibody variable fragment (scFv) targeting a TNF effector and a C-terminal TNF receptor (TNFR)1-derived inhibitor module. Introduction of matrix metalloproteinase (MMP)-2 recognition motifs between TNF and the TNFR1 fragment allowed activation by recombinant MMP-2 and MMP-expressing HT1080 cells. Processing by endogeneous MMPs required specific membrane binding of the TNF prodrug via the targeting scFv, ensuring strictly antigen-dependent activation. Interestingly, TNF bioactivity of the processed prodrug was approximately 1000-fold higher upon scFv-mediated targeting, and signaled juxtatropic cell death also to antigen-negative cells. Microscopical analyses of TNFR2 clustering and TNF receptor-associated factor 2 recruitment at contact sites to adjacent cells revealed the formation of stable TNFR complexes by target-bound, processed prodrug, resembling the increased signal capacity of natural, membrane-expressed TNF. MMP-2-sensitive TNF prodrugs represent novel cytokine-based reagents for targeted cancer therapy, which should be exploitable for MMP-overexpressing tumors.", "isbn" : "1350-9047 (Print)\n1350-9047 (Linking)", "pmid" : "16052236", "issn" : "13509047", "doi" : "10.1038/sj.cdd.4401735", "bibtexKey": "Gerspach2006" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2edbd788fd201dd0630411444af9e9443/pumaizi", "tags" : [ "izi","mueller","2022" ], "intraHash" : "edbd788fd201dd0630411444af9e9443", "interHash" : "e9c83893becce83f42e9cda697c2ca5b", "label" : "Optimized CD19/CD22/CD3 antibody", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Blood", "year": "2022", "url": "https://doi.org/10.1182/blood.2022018081", "author": [ "Dafne Müller" ], "authors": [ {"first" : "Dafne", "last" : "Müller"} ], "volume": "140","number": "16","pages": "1750-1751", "eprint" : "https://ashpublications.org/blood/article-pdf/140/16/1750/1927465/blood\\_bld-2022-018081-c-main.pdf", "issn" : "0006-4971", "doi" : "10.1182/blood.2022018081", "bibtexKey": "10.1182/blood.2022018081" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2610be9f2a99c444d8e87723bfc9c8c2b/pumaizi", "tags" : [ "izi","2014","mueller","kontermann" ], "intraHash" : "610be9f2a99c444d8e87723bfc9c8c2b", "interHash" : "69aef0d5f4b721d9e4420fb21018c1c8", "label" : "Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Molecular Cancer Therapeutics", "year": "2014", "url": "http://mct.aacrjournals.org/cgi/doi/10.1158/1535-7163.MCT-13-0282", "author": [ "V. Kermer","N. Hornig","M. Harder","A. Bondarieva","R. E. Kontermann","D. Muller" ], "authors": [ {"first" : "V.", "last" : "Kermer"}, {"first" : "N.", "last" : "Hornig"}, {"first" : "M.", "last" : "Harder"}, {"first" : "A.", "last" : "Bondarieva"}, {"first" : "R. E.", "last" : "Kontermann"}, {"first" : "D.", "last" : "Muller"} ], "volume": "13","number": "1","pages": "112--121","abstract": "Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common gamma-chain (gammac) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15Ralpha chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD\\_IL-15\\_scFv\\_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv\\_RD\\_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-gamma release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy.", "isbn" : "1538-8514 (Electronic)$\\backslash$r1535-7163 (Linking)", "pmid" : "24198185", "eprint" : "1512.00567", "issn" : "1535-7163", "archiveprefix" : "arXiv", "arxivid" : "1512.00567", "doi" : "10.1158/1535-7163.MCT-13-0282", "bibtexKey": "Kermer2014" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/28995fa8be5ca46ba345de1c24a26348b/pumaizi", "tags" : [ "izi","2025","mueller" ], "intraHash" : "8995fa8be5ca46ba345de1c24a26348b", "interHash" : "d5a3262cb9bca224243f20d64b1bbbb1", "label" : "Trifunctional antibody-cytokine fusion protein formats for tumor-targeted combination of IL-15 with IL-7 or IL-21", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 4, "pub-type": "article", "journal": "Frontiers in Immunology", "year": "2025", "url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1498697", "author": [ "Annika M. Möller","Sarah Vettermann","Felix Baumann","Max Pütter","Dafne Müller" ], "authors": [ {"first" : "Annika M.", "last" : "Möller"}, {"first" : "Sarah", "last" : "Vettermann"}, {"first" : "Felix", "last" : "Baumann"}, {"first" : "Max", "last" : "Pütter"}, {"first" : "Dafne", "last" : "Müller"} ], "volume": "Volume 16 - 2025","abstract": "Cytokines from the common gamma chain receptor family, such as IL-15, IL-21 and IL-7, show promise for cancer immunotherapy and have been incorporated individually into the immunocytokine approach. However, their efficacy as monotherapy is limited. Here, we investigated the molecular design of tumor-directed trifunctional antibody-cytokine fusion proteins for a combinatorial approach of IL-15 with either IL-7 or IL-21. Various fusion proteins differing in antibody format, cytokine composition and arrangement were generated and cooperative cytokine activity assessed in solution and bound to target cells. Comparative analysis revealed that formats with cytokines positioned at the N- and C-termini of the antibody were more effective than those arranged in series. For the former design, cooperative effects were observed with the scFv-based (IL-15+IL-7) trifunctional fusion protein, primarily enhancing the proliferation of naive T cells, while the scFv/Fab-based (IL-15+IL-21) trifunctional fusion proteins enhanced IFN-y release and the cytotoxic potential of T cells. Combining cytokines in the two-in-one molecule approach was principally advantageous when bound to target cells. Greater potency in inducing JAK-STAT pathway activation highlighted the importance of cytokine colocalization for cooperative receptor activation. Compared to the Fab-based (IL-15+IL-21) format, the scFv-based (IL-15+IL-21) format displayed a tendency towards higher activity in targeted and lower activity in untargeted settings, emphasizing the targeted concept. Thus, this study underscores the importance of molecular design in developing trifunctional immunocytokines and identified the scFv-based trifunctional (IL-15+IL-21) fusion protein, with the antibody in the central position, as a particularly promising candidate for further drug development.", "issn" : "16643224", "bibtexKey": "moller2025trifunctional" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2d55fc50c1990a01d7035a48d29e09b69/pumaizi", "tags" : [ "2008","izi","mueller","kontermann" ], "intraHash" : "d55fc50c1990a01d7035a48d29e09b69", "interHash" : "b66204619f50db27333edd3e204114fb", "label" : "A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Journal of Immunotherapy", "year": "2008", "url": "https://www.ncbi.nlm.nih.gov/pubmed/18779748", "author": [ "Dafne Müller","Katharina Frey","Roland E. Kontermann" ], "authors": [ {"first" : "Dafne", "last" : "Müller"}, {"first" : "Katharina", "last" : "Frey"}, {"first" : "Roland E.", "last" : "Kontermann"} ], "volume": "31","number": "8","pages": "714--722","abstract": "Costimulation is an essential step in T-cell activation and hence, represents an important aspect in cancer immunotherapy. 4-1BB, a member of the tumor necrosis factor receptor family, has gained particular interest as a costimulatory molecule. Here, we investigated the potential of a targeted activation of 4-1BB-mediated costimulation at the tumor site by generating a recombinant antibody-cytokine fusion protein composed of a single-chain antibody fragment (scFv36) specific for the tumor stromal antigen fibroblast activation protein (FAP) and the extracellular domain of the 4-1BB ligand (4-1BBL). The scFv36-4-1BBL fusion protein is a homotrimeric molecule that binds specifically to FAP and the receptor 4-1BB. T-cell costimulation was demonstrated by interferon-gamma release of peripheral blood mononuclear cells cocultured with FAP-expressing HT1080 cells upon T-cell receptor triggering by monoclonal anti-CD3 antibody. Costimulatory activity of the scFv36-4-1BBL fusion protein was concentration dependent, ligand-specific, and substantially constrained to FAP-expressing target cell binding. Furthermore, scFv36-4-1BBL enhanced T-cell activation when the bispecific antibody scDb33CD3 (specific for FAP and CD3) was used as primary stimulus. Thus, target cell-dependent costimulation with scFv36-4-1BBL constitutes a new option to enhance T-cell activation by bispecific antibodies or antigen-dependent T-cell receptor triggering and should be useful to improve T cell-mediated antitumor responses.", "isbn" : "1537-4513 (Electronic)$\\backslash$r1524-9557 (Linking)", "pmid" : "18779748", "issn" : "15249557", "doi" : "10.1097/CJI.0b013e31818353e9", "bibtexKey": "Muller2008b" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2618f2a6edd21584d7d68074fd7bc6cf7/pumaizi", "tags" : [ "izi","2023","mueller" ], "intraHash" : "618f2a6edd21584d7d68074fd7bc6cf7", "interHash" : "0d5c0f7eee537915b99fedbcae326345", "label" : "Targeting Co-Stimulatory Receptors of the TNF Superfamily for Cancer Immunotherapy", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "BioDrugs", "year": "2023", "url": "https://doi.org/10.1007/s40259-022-00573-3", "author": [ "Dafne Müller" ], "authors": [ {"first" : "Dafne", "last" : "Müller"} ], "volume": "37","number": "1","pages": "21--33", "issn" : "1179-190X", "doi" : "10.1007/s40259-022-00573-3", "bibtexKey": "Müller2023" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/269bbcf3fa7906c44b6eecc00d362a62e/pumaizi", "tags" : [ "2008","izi","mueller","kontermann" ], "intraHash" : "69bbcf3fa7906c44b6eecc00d362a62e", "interHash" : "bcd2e5cf5d41ed877a04ca196828703e", "label" : "Murine endoglin-specific single-chain Fv fragments for the analysis of vascular targeting strategies in mice", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Journal of Immunological Methods", "year": "2008", "url": "https://www.ncbi.nlm.nih.gov/pubmed/18790696", "author": [ "Dafne Müller","Gerhard Trunk","Anke Sichelstiel","Kirstin A. Zettlitz","Miguel Quintanilla","Roland E. Kontermann" ], "authors": [ {"first" : "Dafne", "last" : "Müller"}, {"first" : "Gerhard", "last" : "Trunk"}, {"first" : "Anke", "last" : "Sichelstiel"}, {"first" : "Kirstin A.", "last" : "Zettlitz"}, {"first" : "Miguel", "last" : "Quintanilla"}, {"first" : "Roland E.", "last" : "Kontermann"} ], "volume": "339","number": "1","pages": "90--98","abstract": "Endoglin has been identified as a promising cell surface antigen for vascular targeting approaches in cancer therapy, e.g. employing antibody molecules as targeting moieties. However, in vivo analysis of such strategies in mouse models requires antibodies recognizing endoglin on mouse endothelial cells. Here we describe the isolation of single-chain Fv fragments (scFvs) from phage display libraries, which bind to the extracellular region of mouse endoglin. One of these clones, scFv mE12, showed strong (Kd= 11 nM) and selective binding to purified endoglin and also to the endoglin-expressing mouse endothelioma cell line eEnd.2. This antibody recognized a linear epitope located in the N-terminal region (aa 27-361) of endoglin. Cell binding was further increased by generating a bivalent scFv-Fc fusion protein composed of scFv mE12 and the human $\\gamma$1 Fc part. Moreover, scFv mE12 was endowed with an additional cysteine residue in the linker region and applied for the generation of anti-endoglin scFv immunoliposomes capable of selectively binding to endoglin-expressing cells. Thus, anti-mouse endoglin scFv mE12 should be useful to analyze vascular targeting strategies in mice. © 2008 Elsevier B.V. All rights reserved.", "isbn" : "0022-1759 (Print)$\\backslash$r0022-1759 (Linking)", "pmid" : "18790696", "issn" : "00221759", "doi" : "10.1016/j.jim.2008.08.008", "bibtexKey": "Muller2008c" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/226ec9346d1211c369b60826700f0e28a/pumaizi", "tags" : [ "2015","izi","mueller" ], "intraHash" : "26ec9346d1211c369b60826700f0e28a", "interHash" : "4c635a80f5a2ae7addb41ede79544fd5", "label" : "Antibody fusions with immunomodulatory proteins for cancer therapy", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Pharmacology and Therapeutics", "year": "2015", "url": "http://www.ncbi.nlm.nih.gov/pubmed/26145167", "author": [ "Dafne Müller" ], "authors": [ {"first" : "Dafne", "last" : "Müller"} ], "volume": "154","pages": "57--66","abstract": "The potential of immunomodulatory proteins, in particular cytokines, for cancer therapy is well recognized, but hampered by the toxicity associated with their systemic application. In order to address this problem, targeted delivery by antibody fusion proteins has been early proposed and their development intensively pursued over the last decade. Here, factors influencing the selection and modification of cytokines and antibody formats for this approach are being discussed, indicating current developments and translational advances in the field.", "pmid" : "26145167", "issn" : "1879016X", "doi" : "10.1016/j.pharmthera.2015.07.001", "bibtexKey": "Muller2015a" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/246f222ec350bb74563504beeb5e35e3c/pumaizi", "tags" : [ "izi","2012","mueller" ], "intraHash" : "46f222ec350bb74563504beeb5e35e3c", "interHash" : "87f34e82046f232b2219a0e17290e775", "label" : "Targeted cancer immunotherapy: Mimicking physiological trans-presentation of IL-15", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "OncoImmunology", "year": "2012", "url": "http://www.ncbi.nlm.nih.gov/pubmed/23170284", "author": [ "Dafne Müller" ], "authors": [ {"first" : "Dafne", "last" : "Müller"} ], "volume": "1","number": "7","pages": "1213--1214","abstract": "Under physiological conditions, the trans-presentation of interleukin-15 (IL-15) by the IL-15 receptor alpha on the cell surface allows to confine and tune the IL-15-mediated immune responses. Therefore, targeting strategies that mimic this situation at the tumor sites appear especially promising for anticancer immunotherapy.", "isbn" : "2162-4011 (Print)", "pmid" : "23170284", "issn" : "21624011", "doi" : "10.4161/onci.20824", "bibtexKey": "Muller2012" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/23793e7366c6eb28b539412cd0cf89239/pumaizi", "tags" : [ "2007","izi","mueller","kontermann" ], "intraHash" : "3793e7366c6eb28b539412cd0cf89239", "interHash" : "e897c4ac1c23d8623b963761ae81b802", "label" : "Improved pharmacokinetics of recombinant bispecific antibody molecules by fusion to human serum albumin", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Journal of Biological Chemistry", "year": "2007", "url": "https://www.ncbi.nlm.nih.gov/pubmed/17347147", "author": [ "Dafne Müller","Anette Karle","Bettina Meißburger","Ines Höfig","Roland Stork","Roland E. Kontermann" ], "authors": [ {"first" : "Dafne", "last" : "Müller"}, {"first" : "Anette", "last" : "Karle"}, {"first" : "Bettina", "last" : "Meißburger"}, {"first" : "Ines", "last" : "Höfig"}, {"first" : "Roland", "last" : "Stork"}, {"first" : "Roland E.", "last" : "Kontermann"} ], "volume": "282","number": "17","pages": "12650--12660","abstract": "Recombinant bispecific antibodies such as tandem scFv molecules (taFv), diabodies (Db), or single chain diabodies (scDb) have shown to be able to retarget T lymphocytes to tumor cells, leading to their destruction. However, therapeutic efficacy is hampered by a short serum half-life of these small molecules having molecule masses of 50-60 kDa. Thus, improvement of the pharmacokinetic properties of small bispecific antibody formats is required to enhance efficacy in vivo. In this study, we generated several recombinant bispecific antibody-albumin fusion proteins and analyzed these molecules for biological activity and pharmacokinetic properties. Three recombinant antibody formats were produced by fusing two different scFv molecules, bispecific scDb or taFv molecules, respectively, to human serum albumin (HSA). These constructs (scFv(2)-HSA, scDb-HSA, taFv-HSA), directed against the tumor antigen carcinoembryonic antigen (CEA) and the T cell receptor complex molecule CD3, retained full binding capacity to both antigens compared with unfused scFv, scDb, and taFv molecules. Tumor antigen-specific retargeting and activation of T cells as monitored by interleukin-2 release was observed for scDb, scDb-HSA, taFv-HSA, and to a lesser extent for scFv(2)-HSA. T cell activation could be further enhanced by a target cell-specific costimulatory signal provided by a B7-DbCEA fusion protein. Furthermore, we could demonstrate that fusion to serum albumin strongly increases circulation time of recombinant bispecific antibodies. In addition, our comparative study indicates that single chain diabody-albumin fusion proteins seem to be the most promising format for further studying cytotoxic activities in vitro and in vivo.", "isbn" : "1265012660", "pmid" : "17347147", "issn" : "00219258", "doi" : "10.1074/jbc.M700820200", "bibtexKey": "Muller2007" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/250cf936f2051540a79a54a41e0098130/pumaizi", "tags" : [ "2007","izi","mueller","kontermann" ], "intraHash" : "50cf936f2051540a79a54a41e0098130", "interHash" : "c006c3d20cedb23ace3508f0b936a84f", "label" : "Recombinant bispecific antibodies for cellular cancer immunotherapy", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Current opinion in molecular therapeutics", "year": "2007", "url": "https://www.ncbi.nlm.nih.gov/pubmed/17694444", "author": [ "Dafne Müller","Roland E Kontermann" ], "authors": [ {"first" : "Dafne", "last" : "Müller"}, {"first" : "Roland E", "last" : "Kontermann"} ], "volume": "9","number": "4","pages": "319","abstract": "Bispecific antibodies recognizing two different antigens present on different cells have been developed for cellular cancer therapy in which cytotoxic effector cells are recruited to tumor cells. Initial studies with bispecific antibodies have not reached satisfactory clinical endpoints, mainly due to low efficacy, Fc-mediated side effects and immunogenicity. This has resulted in a declining interest in bispecific antibodies for cancer therapy. However, growing knowledge in effector cell biology and the implementation of antibody engineering technologies has led to a revival and the development of novel or improved strategies. Various recombinant bispecific antibodies have demonstrated efficacy in vitro andin vivo, with the first recombinant antibody molecule currently in clinical trials for the treatment of B-cell malignancies.", "isbn" : "1464-8431", "pmid" : "17694444", "issn" : "1464-8431", "bibtexKey": "Muller2007a" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/21ad0abdfa34f60051e142817cc0def4b/pumaizi", "tags" : [ "2009","izi","mueller","kontermann" ], "intraHash" : "1ad0abdfa34f60051e142817cc0def4b", "interHash" : "33f5d9a1d0eb2d8f3bb61290d5a0b433", "label" : "Targeting of Epidermal Growth Factor Receptor (EGFR)-Expressing Tumor Cells with Sterically Stabilized Affibody Liposomes (SAL)", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Bioconjugate Chemistry", "year": "2009", "url": "http://dx.doi.org/10.1021/bc900061v", "author": [ "Julia Beuttler","Miriam Rothdiener","Dafne Müller","Fredrik Y. Frejd","Roland E. Kontermann" ], "authors": [ {"first" : "Julia", "last" : "Beuttler"}, {"first" : "Miriam", "last" : "Rothdiener"}, {"first" : "Dafne", "last" : "Müller"}, {"first" : "Fredrik Y.", "last" : "Frejd"}, {"first" : "Roland E.", "last" : "Kontermann"} ], "volume": "20","number": "6","pages": "1201-1208","abstract": "Affibody molecules are small and stable antigen-binding molecules derived from the B domain of protein A. We applied a bivalent, high-affinity epidermal growth factor receptor (EGFR)-specific affibody molecule for the generation of targeted PEGylated liposomes. These sterically stabilized affibody liposomes (SAL) were produced by chemical coupling of the cysteine-modified affibody molecule to maleimide-PEG2000-DSPE and subsequent insertion into PEGylated liposomes. These SAL showed strong and selective binding to EGFR-expressing tumor cell lines. Binding was dependent on the amount of inserted affibody molecule−lipid conjugates and could be blocked by soluble EGF. Approximately 30\\% of binding activity was still retained after 6 days of incubation in human plasma at 37 °C. Binding of SAL to cells led to efficient internalization of the liposomes. Using mitoxantrone-loaded liposomes, we observed for SAL, compared to untargeted liposomes, an enhanced cytotoxicity toward EGFR-expressing cells. In summary, we show that SAL can be easily prepared from affibody molecules and thus may be suitable for the development of carrier systems for targeted delivery of drugs.", "eprint" : "http://dx.doi.org/10.1021/bc900061v", "doi" : "10.1021/bc900061v", "bibtexKey": "doi:10.1021/bc900061v" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/24645b225b773c4e58b2cc2eaff83a14a/pumaizi", "tags" : [ "izi","mueller","2010","kontermann" ], "intraHash" : "4645b225b773c4e58b2cc2eaff83a14a", "interHash" : "7a77c1cc96d80f128b5d9375bbcc8eb2", "label" : "Bispecific antibodies for cancer immunotherapy: Current perspectives", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "BioDrugs", "year": "2010", "url": "https://www.ncbi.nlm.nih.gov/pubmed/20199124", "author": [ "Dafne Müller","Roland E. Kontermann" ], "authors": [ {"first" : "Dafne", "last" : "Müller"}, {"first" : "Roland E.", "last" : "Kontermann"} ], "volume": "24","number": "2","pages": "89--98","abstract": "The concept of using bispecific antibodies to retarget immune effector cells for cancer therapy was conceived more than 20 years ago. However, initial clinical studies were rather disappointing mainly due to low efficacy, severe adverse effects and immunogenicity of the bispecific antibodies. A deeper understanding of effector cell biology and especially developments in the field of antibody engineering has led to the generation of new classes of bispecific antibodies capable of circumventing many of these obstacles. Furthermore, new applications were established for bispecific antibodies, such as pre-targeting strategies in radioimmunotherapy or dual targeting approaches in order to improve binding, selectivity, and efficacy. This review summarizes recent progress in the development of bispecific antibodies and describes some new concepts developed for cancer immunotherapy.", "isbn" : "1173-8804", "pmid" : "20199124", "issn" : "11738804", "doi" : "10.2165/11530960-000000000-00000", "bibtexKey": "Muller2010" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/204b158c77189f4d6387e185cf0856550/pumaizi", "tags" : [ "izi","mueller","2010","kontermann" ], "intraHash" : "04b158c77189f4d6387e185cf0856550", "interHash" : "8c5c1e9925ab2b81cf7bdb85979aa01f", "label" : "The effects of affinity and valency of an albumin-binding domain (ABD) on the half-life of a single-chain diabody-ABD fusion protein", "user" : "pumaizi", "description" : "", "date" : "2025-10-17 10:53:57", "changeDate" : "2025-10-17 10:53:57", "count" : 3, "pub-type": "article", "journal": "Protein Engineering, Design and Selection", "year": "2010", "url": "https://www.ncbi.nlm.nih.gov/pubmed/20817756", "author": [ "Jonas Hopp","Nora Hornig","Kirstin A. Zettlitz","Aline Schwarz","Nadine Fuß","Dafne Müller","Roland E. Kontermann" ], "authors": [ {"first" : "Jonas", "last" : "Hopp"}, {"first" : "Nora", "last" : "Hornig"}, {"first" : "Kirstin A.", "last" : "Zettlitz"}, {"first" : "Aline", "last" : "Schwarz"}, {"first" : "Nadine", "last" : "Fuß"}, {"first" : "Dafne", "last" : "Müller"}, {"first" : "Roland E.", "last" : "Kontermann"} ], "volume": "23","number": "11","pages": "827--834","abstract": "Fusion of small recombinant antibody fragments to an albumin-binding domain (ABD) from streptococcal protein G strongly extends their plasma half-life. This ABD binds with nanomolar affinity to human (HSA) and mouse serum albumin (MSA). It was speculated that an increase in albumin-binding affinity should lead to a further increase in half-life. In the present study, we analyzed the effects of affinity and valency of the ABD on the pharmacokinetic properties of a bispecific single-chain diabody (scDb), applied previously to investigate various half-life extension strategies. The scDb is directed against carcinoembryonic antigen (CEA) and CD3 capable of mediating T cell retargeting to tumor cells. Two scDb derivatives with increased (scDb-ABD-H) and decreased (scDb-ABD-L) affinity as well as an scDb molecule fused to two ABD (scDb-ABD(2)) were generated and produced in mammalian cells. The altered binding of these constructs to HSA and MSA was confirmed by ELISA and quartz crystal microbalance measurements. All constructs bound efficiently to CEA and CD3-positive cells and were able to activate T cells in a target cell-dependent manner, although T cell activation was reduced in the presence of serum albumin. All three derivatives showed a strongly increased half-life in mice as compared with scDb. Compared with the wild-type scDb-ABD, the half-life of scDb-ABD-H exhibited a prolonged half-life and scDb-ABD-L a reduced half-life, while the half-life scDb-ABD(2) was almost identical to that of scDb-ABD. However, these changes were only moderate, indicating that the half-life-extending property of the ABD in mice is only weakly influenced by affinity for serum albumin or valency of albumin binding.", "isbn" : "1741-0134 (Electronic)$\\backslash$n1741-0126 (Linking)", "pmid" : "20817756", "issn" : "17410126", "doi" : "10.1093/protein/gzq058", "bibtexKey": "Hopp2010" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/28995fa8be5ca46ba345de1c24a26348b/fabian", "tags" : [ "izi","2025","mueller" ], "intraHash" : "8995fa8be5ca46ba345de1c24a26348b", "interHash" : "d5a3262cb9bca224243f20d64b1bbbb1", "label" : "Trifunctional antibody-cytokine fusion protein formats for tumor-targeted combination of IL-15 with IL-7 or IL-21", "user" : "fabian", "description" : "", "date" : "2025-06-26 09:48:04", "changeDate" : "2025-06-26 09:48:04", "count" : 4, "pub-type": "article", "journal": "Frontiers in Immunology", "year": "2025", "url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1498697", "author": [ "Annika M. Möller","Sarah Vettermann","Felix Baumann","Max Pütter","Dafne Müller" ], "authors": [ {"first" : "Annika M.", "last" : "Möller"}, {"first" : "Sarah", "last" : "Vettermann"}, {"first" : "Felix", "last" : "Baumann"}, {"first" : "Max", "last" : "Pütter"}, {"first" : "Dafne", "last" : "Müller"} ], "volume": "Volume 16 - 2025","abstract": "Cytokines from the common gamma chain receptor family, such as IL-15, IL-21 and IL-7, show promise for cancer immunotherapy and have been incorporated individually into the immunocytokine approach. However, their efficacy as monotherapy is limited. Here, we investigated the molecular design of tumor-directed trifunctional antibody-cytokine fusion proteins for a combinatorial approach of IL-15 with either IL-7 or IL-21. Various fusion proteins differing in antibody format, cytokine composition and arrangement were generated and cooperative cytokine activity assessed in solution and bound to target cells. Comparative analysis revealed that formats with cytokines positioned at the N- and C-termini of the antibody were more effective than those arranged in series. For the former design, cooperative effects were observed with the scFv-based (IL-15+IL-7) trifunctional fusion protein, primarily enhancing the proliferation of naive T cells, while the scFv/Fab-based (IL-15+IL-21) trifunctional fusion proteins enhanced IFN-y release and the cytotoxic potential of T cells. Combining cytokines in the two-in-one molecule approach was principally advantageous when bound to target cells. Greater potency in inducing JAK-STAT pathway activation highlighted the importance of cytokine colocalization for cooperative receptor activation. Compared to the Fab-based (IL-15+IL-21) format, the scFv-based (IL-15+IL-21) format displayed a tendency towards higher activity in targeted and lower activity in untargeted settings, emphasizing the targeted concept. Thus, this study underscores the importance of molecular design in developing trifunctional immunocytokines and identified the scFv-based trifunctional (IL-15+IL-21) fusion protein, with the antibody in the central position, as a particularly promising candidate for further drug development.", "issn" : "16643224", "bibtexKey": "moller2025trifunctional" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/269bbcf3fa7906c44b6eecc00d362a62e/fabian", "tags" : [ "2008","izi","mueller","kontermann" ], "intraHash" : "69bbcf3fa7906c44b6eecc00d362a62e", "interHash" : "bcd2e5cf5d41ed877a04ca196828703e", "label" : "Murine endoglin-specific single-chain Fv fragments for the analysis of vascular targeting strategies in mice", "user" : "fabian", "description" : "", "date" : "2023-06-29 13:07:55", "changeDate" : "2023-06-29 13:07:55", "count" : 3, "pub-type": "article", "journal": "Journal of Immunological Methods", "year": "2008", "url": "https://www.ncbi.nlm.nih.gov/pubmed/18790696", "author": [ "Dafne Müller","Gerhard Trunk","Anke Sichelstiel","Kirstin A. Zettlitz","Miguel Quintanilla","Roland E. Kontermann" ], "authors": [ {"first" : "Dafne", "last" : "Müller"}, {"first" : "Gerhard", "last" : "Trunk"}, {"first" : "Anke", "last" : "Sichelstiel"}, {"first" : "Kirstin A.", "last" : "Zettlitz"}, {"first" : "Miguel", "last" : "Quintanilla"}, {"first" : "Roland E.", "last" : "Kontermann"} ], "volume": "339","number": "1","pages": "90--98","abstract": "Endoglin has been identified as a promising cell surface antigen for vascular targeting approaches in cancer therapy, e.g. employing antibody molecules as targeting moieties. However, in vivo analysis of such strategies in mouse models requires antibodies recognizing endoglin on mouse endothelial cells. Here we describe the isolation of single-chain Fv fragments (scFvs) from phage display libraries, which bind to the extracellular region of mouse endoglin. One of these clones, scFv mE12, showed strong (Kd= 11 nM) and selective binding to purified endoglin and also to the endoglin-expressing mouse endothelioma cell line eEnd.2. This antibody recognized a linear epitope located in the N-terminal region (aa 27-361) of endoglin. Cell binding was further increased by generating a bivalent scFv-Fc fusion protein composed of scFv mE12 and the human $\\gamma$1 Fc part. Moreover, scFv mE12 was endowed with an additional cysteine residue in the linker region and applied for the generation of anti-endoglin scFv immunoliposomes capable of selectively binding to endoglin-expressing cells. Thus, anti-mouse endoglin scFv mE12 should be useful to analyze vascular targeting strategies in mice. © 2008 Elsevier B.V. All rights reserved.", "isbn" : "0022-1759 (Print)$\\backslash$r0022-1759 (Linking)", "pmid" : "18790696", "issn" : "00221759", "doi" : "10.1016/j.jim.2008.08.008", "bibtexKey": "Muller2008c" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2610be9f2a99c444d8e87723bfc9c8c2b/fabian", "tags" : [ "izi","2014","mueller","kontermann" ], "intraHash" : "610be9f2a99c444d8e87723bfc9c8c2b", "interHash" : "69aef0d5f4b721d9e4420fb21018c1c8", "label" : "Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy", "user" : "fabian", "description" : "", "date" : "2023-06-29 13:07:55", "changeDate" : "2023-06-29 13:07:55", "count" : 3, "pub-type": "article", "journal": "Molecular Cancer Therapeutics", "year": "2014", "url": "http://mct.aacrjournals.org/cgi/doi/10.1158/1535-7163.MCT-13-0282", "author": [ "V. Kermer","N. Hornig","M. Harder","A. Bondarieva","R. E. Kontermann","D. Muller" ], "authors": [ {"first" : "V.", "last" : "Kermer"}, {"first" : "N.", "last" : "Hornig"}, {"first" : "M.", "last" : "Harder"}, {"first" : "A.", "last" : "Bondarieva"}, {"first" : "R. E.", "last" : "Kontermann"}, {"first" : "D.", "last" : "Muller"} ], "volume": "13","number": "1","pages": "112--121","abstract": "Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common gamma-chain (gammac) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15Ralpha chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD\\_IL-15\\_scFv\\_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv\\_RD\\_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-gamma release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy.", "isbn" : "1538-8514 (Electronic)$\\backslash$r1535-7163 (Linking)", "pmid" : "24198185", "eprint" : "1512.00567", "issn" : "1535-7163", "archiveprefix" : "arXiv", "arxivid" : "1512.00567", "doi" : "10.1158/1535-7163.MCT-13-0282", "bibtexKey": "Kermer2014" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/23793e7366c6eb28b539412cd0cf89239/fabian", "tags" : [ "2007","izi","mueller","kontermann" ], "intraHash" : "3793e7366c6eb28b539412cd0cf89239", "interHash" : "e897c4ac1c23d8623b963761ae81b802", "label" : "Improved pharmacokinetics of recombinant bispecific antibody molecules by fusion to human serum albumin", "user" : "fabian", "description" : "", "date" : "2023-06-29 13:07:55", "changeDate" : "2023-06-29 13:07:55", "count" : 3, "pub-type": "article", "journal": "Journal of Biological Chemistry", "year": "2007", "url": "https://www.ncbi.nlm.nih.gov/pubmed/17347147", "author": [ "Dafne Müller","Anette Karle","Bettina Meißburger","Ines Höfig","Roland Stork","Roland E. Kontermann" ], "authors": [ {"first" : "Dafne", "last" : "Müller"}, {"first" : "Anette", "last" : "Karle"}, {"first" : "Bettina", "last" : "Meißburger"}, {"first" : "Ines", "last" : "Höfig"}, {"first" : "Roland", "last" : "Stork"}, {"first" : "Roland E.", "last" : "Kontermann"} ], "volume": "282","number": "17","pages": "12650--12660","abstract": "Recombinant bispecific antibodies such as tandem scFv molecules (taFv), diabodies (Db), or single chain diabodies (scDb) have shown to be able to retarget T lymphocytes to tumor cells, leading to their destruction. However, therapeutic efficacy is hampered by a short serum half-life of these small molecules having molecule masses of 50-60 kDa. Thus, improvement of the pharmacokinetic properties of small bispecific antibody formats is required to enhance efficacy in vivo. In this study, we generated several recombinant bispecific antibody-albumin fusion proteins and analyzed these molecules for biological activity and pharmacokinetic properties. Three recombinant antibody formats were produced by fusing two different scFv molecules, bispecific scDb or taFv molecules, respectively, to human serum albumin (HSA). These constructs (scFv(2)-HSA, scDb-HSA, taFv-HSA), directed against the tumor antigen carcinoembryonic antigen (CEA) and the T cell receptor complex molecule CD3, retained full binding capacity to both antigens compared with unfused scFv, scDb, and taFv molecules. Tumor antigen-specific retargeting and activation of T cells as monitored by interleukin-2 release was observed for scDb, scDb-HSA, taFv-HSA, and to a lesser extent for scFv(2)-HSA. T cell activation could be further enhanced by a target cell-specific costimulatory signal provided by a B7-DbCEA fusion protein. Furthermore, we could demonstrate that fusion to serum albumin strongly increases circulation time of recombinant bispecific antibodies. In addition, our comparative study indicates that single chain diabody-albumin fusion proteins seem to be the most promising format for further studying cytotoxic activities in vitro and in vivo.", "isbn" : "1265012660", "pmid" : "17347147", "issn" : "00219258", "doi" : "10.1074/jbc.M700820200", "bibtexKey": "Muller2007" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2902f92a970fd0144df28117e499b6b53/fabian", "tags" : [ "2019","izi","mueller","kontermann" ], "intraHash" : "902f92a970fd0144df28117e499b6b53", "interHash" : "65f020c3d61c6b5ef58b99b3e7710154", "label" : "IL-15-based trifunctional antibody-fusion proteins with costimulatory TNF-superfamily ligands in the single-chain format for cancer immunotherapy", "user" : "fabian", "description" : "", "date" : "2023-06-29 13:07:55", "changeDate" : "2023-06-29 13:07:55", "count" : 3, "pub-type": "article", "journal": "Molecular Cancer Therapeutics", "year": "2019", "url": "http://www.ncbi.nlm.nih.gov/pubmed/31040163", "author": [ "Nadine Beha","Markus Harder","Sarah Ring","Roland E. Kontermann","Dafne Müller" ], "authors": [ {"first" : "Nadine", "last" : "Beha"}, {"first" : "Markus", "last" : "Harder"}, {"first" : "Sarah", "last" : "Ring"}, {"first" : "Roland E.", "last" : "Kontermann"}, {"first" : "Dafne", "last" : "Müller"} ], "pages": "molcanther.1204.2018", "pmid" : "31040163", "issn" : "1535-7163", "doi" : "10.1158/1535-7163.MCT-18-1204", "bibtexKey": "Beha2019" } ] }