Antikörper- und zellbasierte Immuntherapeutika

• generated a collection of independently combinable IgG repertoires from B cells that have previously encountered tumor-related antigens 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.
• We 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 immunocompromised 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. The antibody was successfully tested in a phase I clinical trial on healthy volunteers by Heidelberg Immunotherapeutics GmbH and the results showed an excellent safety profile.
• 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.
• engineered CD22-specific CARs with different backbones and analyzed their in vitro and in vivo properties. The most potent CAR candidate will be brought forward towards clinical application.

• Stock S, Übelhart R, Schubert ML, Fan F, He B. Hoffmann JM, Wang L, Wang S, Gong W, Neuber B, Hückelhoven-Krauss A, Gern U, Christ C, Hexel M, Schmidt P, Krauss J, Jäger D, Müller-Tidow C, Dreger P, Schmitt M, Sellner L. Idelalisib for optimized CD19-specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients. Int J Cancer 2019 Sep 1;145(5):1312-1324. doi: 10.1002/ijc.32201. Epub 2019 Feb 28.
• Liebers N, Holland-Letz T, Welschof M, Høgset A, Jäger D, Arndt MAE, Krauss J. Highly efficient destruction of squamous carcinoma cells of the head and neck by photochemical internalization of Ranpirnase. J Exp Ther Oncol. 2017 Nov;12(2):113-120.
• Weber T, Bötticher B, Arndt MA, Mier W, Sauter M, Exner E, Keller A, Krämer S, Leotta K, Wischnjow A, Grosse-Hovest L, Strumberg D, Jäger D, Gröne HJ, Haberkorn U, Brem G, Krauss J. Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model. Cancer Lett. 2016 Oct 28;381(2):296-304. doi: 10.1016/j.canlet.2016.08.007. Epub 2016 Aug 11.
• Weber T, Mavratzas A, Kiesgen S, Haase S, Bötticher B, Exner E, Mier W, Grosse-Hovest L, Jäger D, Arndt MA, Krauss J. A humanized anti-CD22-Onconase antibody-drug conjugate mediates highly potent destruction of targeted tumor cells. J Immunol Res. 2015;2015:561814. doi: 10.1155/2015/561814. Epub 2015 Oct 28.
• 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) gegen CD22 zur adoptiven T-Zell-Therapie von B-Zell-Lymphomen und –Leukämien“. Kooperationsprojekt mit dem Regensburger Centrum für Interventionelle Immunologie (Prof. Hinrich Abken) & Universität Erlangen (Prof. Lars Nitschke). Deutsche Krebshilfe
• „Development of selective chimeric antigen receptors (CAR) for the adoptive T-cell therapy of malignant tumors“. Safety CARs. Private Sponsor.

Gruppenleiter:
Prof. Dr. med. Jürgen Krauss
juergen.krauss@nct-heidelberg.de

Dr. rer.nat Rudolf Übelhart
rudolf.uebelhart@nct-heidelberg.de

Doktorandin:
Lisa Noll (cand. rer.nat)
lisa1.noll@med.uni-heidelberg.de

Technische Assistenten:
Christiane Christ
Christiane.christ@med.uni-heidelberg.de

Monika Hexel
Monika.hexel@med.uni-heidelberg.de

Mathias Utz
M.utz@dkfz-heidelberg.de