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Prof. Dr. med. Jürgen Krauss
 
+49 6221 565922
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Antibody-based Immunotherapeutics

DKFZ
 
 
 

Our group/department has:

  • generated a collection of independently combinable IgG repertoires from B cells that have previously encountered tumor-related antigen(s) in the course of a humoral immune response. For this purpose B cell repertoires from 20 different tumor-draining lymph nodes of head and neck cancer patients have been employed for cloning 20 individual phage display libraries in the scFv antibody format (Diebolder et al., mAbs 2013). The LYmph Node Derived Antibody Library (LYNDAL) collection is the largest cancer patient immune library to date. From these libraries we have already successfully isolated human antibody fragments specifically binding to cancer-related antigens and immune modulating targets, which are currently further characterized in terms of biochemical, biophysical, and functional properties. Furthermore, the libraries are currently screened for binders to an extended panel of immune modulating and cancer testis antigens (collaboration Halama/Jäger). Selection for the latter group of antibodies will enable the development of highly cancer-specific chimeric antigen receptors (CARs) for engineered autologous T cell transfer approaches.
  • developed a humanized monoclonal antibody for the treatment of Herpes simplex virus (HSV) infections. Following the elucidation of a unique molecular mechanism on how this antibody prevents the virus from intruding into host cell membranes (Krawczyk et al. J Virol 2011) we demonstrated in preclinical models that due to its specific mode of action this compound is also highly active toward HSV strains being (multi)resistant toward standard antiviral chemotherapy (Krawczyk et al. Proc Natl Acad Sci USA 2013). As a consequence, the novel antibody for the first time provides a treatment option for also the most desperate clinical situation of drug resistant disease that frequently occurs in highly immuncompromised patients (e.g. >30% in allogeneic stem cell transplantation settings or HIV co-infection). Because the antibody has been considered to address a significant unmet medical need it has been listed as one of the most essential scientific finding in therapeutics in the 04/2013 issue of the Science-Business eXchange (SciBX) magazine. Patent protection for the antibody has been filed for Europe, USA, Canada, Brazil, China, Japan, and India.
  • generated a stability-engineered humanized antibody fragment in a diabody format for targeting the lymphoma- and leukemia-associated antigen CD22 (Krauss et al. 2008 Patent #7,456,260 B2). This compound has been produced in the milk of transgenic animals (Collaboration with Prof. Dr. Gottfried Brem, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Austria and Dr. Grosse-Hovest, Department of Immunology, Eberhard Karls University Tübingen) and is currently in advanced preclinical development as a novel radio-immunoconjugate for the treatment of lymphoma/leukemia (Collaboration with Prof. Dr. Uwe Haberkorn, Department of Nuclear Medicine, University Hospital Heidelberg & Clinical Cooperation Unit Nuclear Medicine, DKFZ).
  • optimized the biophysical properties of a humanized antibody fragment directed against the adenocarcinoma antigen MUC1 (Patent #WO2001/007690 A1).
  • in collaboration with Prof. Dr. R. Kontermann (Institute of Cell Biology and Immunology, University of Stuttgart) developed a dimeric immunofusion protein comprising a bivalent humanized anti-EGFR diabody and Ranpirnase, a ribonuclease from the leopard frog. We have shown that this compound confers high specific toxicity toward targeted tumor cells. This efficacy can be markedly increased by improving cytosolic substrate access through employment of viral fusion loop components. Following the demonstration that the in vitro activity also translates into efficacy in tumor xenografted mice the dimeric fusion protein could be translated as first-in-class compound into a phase I clinical trial in head and neck cancer patients.).

2011 – 2015

  • Weber T, Bötticher B, Mier W, Sauter M, Krämer S, Leotta K, Keller A, Schlegelmilch A, Grosse-Hovest L, Jäger D, Haberkorn U, Arndt MAE, Krauss J. High treatment efficacy by dual targeting of Burkitt’s lymphoma xenografted mice with a 177Lu-based CD22-specific radioimmunoconjugate and Rituximab. European Journal of Nuclear Medicine and Molecular Imaging 2015 in press. doi: 10.1007/s00259-015-3175-6

  • Kiesgen S, Arndt MA, Korber C, Arnold U, Weber T, Halama N, Keller A, Botticher B, Schlegelmilch A, Liebers N, Cremer M, Herold-Mende C, Dyckhoff G, Federspil PA, Jensen AD, Jager D, Kontermann RE, Mier W, Krauss J. An EGF receptor targeting Ranpirnase-diabody fusion protein mediates potent antitumour activity in vitro and in vivo. Cancer Lett. 2015 Feb 1;357(1):364-73. doi: 10.1016/j.canlet.2014.11.054

  • Kiesgen S, Liebers N, Cremer M, Arnold U, Weber T, Keller A, Herold-Mende C, Dyckhoff G, Jager D, Kontermann RE, Arndt MA, Krauss J. A fusogenic dengue virus-derived peptide enhances antitumor efficacy of an antibody-ribonuclease fusion protein targeting the EGF receptor. Protein Eng Des Sel. 2014 Oct;27(10):331-8. doi: 10.1093/protein/gzu040

  • Diebolder P, Keller A, Haase S, Schlegelmilch A, Kiefer JD, Karimi T, Weber T, Moldenhauer G, Kehm R, Eis-Hubinger AM, Jager D, Federspil PA, Herold-Mende C, Dyckhoff G, Kontermann RE, Arndt MA, Krauss J. Generation of "LYmph Node Derived Antibody Libraries" (LYNDAL) for selecting fully human antibody fragments with therapeutic potential. MAbs. 2014 Jan-Feb;6(1):130-42. doi: 10.4161/mabs.27236

  • Krawczyk A, Arndt MA, Grosse-Hovest L, Weichert W, Giebel B, Dittmer U, Hengel H, Jager D, Schneweis KE, Eis-Hubinger AM, Roggendorf M, Krauss J. Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody. Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6760-5. doi: 10.1073/pnas.1220019110
  • „Entwicklung eines chimären Antigen-Rezeptors (CAR) zur adoptiven T-Zell-Therapie von Lymphomen und Leukämien“. Kooperationsprojekt mit Universitätsklinik Köln (Prof. H. Abken) & Universität Erlangen (Prof. L. Nitschke). Deutsche José Carreras Leukämie-Stiftung – DJCLS R14/20

  • „Development of selective chimeric antigen receptors (CAR) for the adoptive T-cell therapy of malignant tumors“. Safety CARs. Private Sponsor.