Research Report 2000 - MDC

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Cytotoxic T cell targeting by bispecific antibodies and chimeric T cell receptors Anja Löffler, Jan Schwenkenbecher, Ralf Bargou in cooperation with Bernd Groner (Frankfurt), Zelig Eshhar (Israel), and Gert Riethmüller (München) Cytotoxic lysis by T cells requires specific binding of the T-cell receptor complex to antigenic peptides presented by MHC molecules. Bispecific antibodies can bypass this requirement by targeting T lymphocytes to cells that express an antigen recognized by a monoclonal antibody. Using a recombinant bispecific single-chain antibody (CD19 x CD3) we have been able to induce rapid and highly effective lymphoma cell cytotoxicity by unstimulated T cells. In collaboration with G. Riethmüller we are planning a phase I study for the treatment of lymphoma patients. Currently, we are trying to establish the same strategy for the treatment of multiple myeloma patients using a novel plasma cellspecific surface antigen as a target structure. Tumor cell-targeting can also be achieved by chimeric T-cell receptors, whereby the cytoplasmic part of the ζ-chain of the T-cell receptor/CD3 complex is fused to a recombinant single chain antibody. Using retroviral vectors, we have achieved high transfer rates and stable surface expression of chimeric T-cell receptors with different specificities in T cells. A clinical phase-I trial in patients with metastatic breast cancer is planned. Cell-biologic features of acute leukemias Wolf-Dieter Ludwig, Christian Wuchter, Richard Ratei, Leonid Karawajew Acute lymphoblastic (ALL) and acute myeloid leukemias (AML) exhibit a high degree of genotypic diversity. Recently, significant associations between immunophenotypic and genotypic features have been described that in the near future might contribute to the development of individually adjusted treatment strategies. In the last few years, we have characterized the expression and function of molecules involved in apoptosis regulation and chemosensitivity modulation in 104 T-lineage ALL and AML subtypes. Spontaneous apoptosis, cytokine responsiveness and expression of apoptosis-regulating Bcl-2 and Bax proteins have been analyzed in leukemic blasts from T-ALL patients. IL-7, in contrast to IL-4 and IL-2, is a highly efficient inhibitor of apoptosis and this correlates with the expression levels of the IL-7 receptor (α-chain as well as upregulation of Bcl-2 protein expression. In a large series of T-ALL samples (n=130), in vitro IL-7 responsiveness is associated with cortical/mature immunophenotype and better in vivo early cytoreduction. This suggests that IL-7 responsiveness might have potential prognostic relevance as a surrogate marker reflecting differential survival factor dependence, apoptosis regulation and treatment response in T lineage ALL. Resistance to chemotherapy-induced apoptosis and multiple-drug-resistance (MDR) activity, mainly mediated by the efflux pump P-glycoprotein (P-gp), contribute to the failure of chemotherapy in hematologic malignancies. In a large series of adult de novo AML patients, the most immature AML cells exhibited a significantly lower CD95 (Fas/APO- 1) expression, CD95 sensitivity and extent of spontaneous apoptosis in vitro as well as a significantly higher Bcl-2 expression and P-gp function, compared with more mature AML blasts. Several functional parameters, including high P-gp function, low spontaneous apoptosis in vitro, high Bcl-2 expression and low CD95 sensitivity, have been found to be predictive of a poor response to induction chemotherapy in adult de novo AML. Prospective studies monitoring apoptosis-related parameters during chemotherapy in cytogenetically defined risk groups are in progress.
Selected Publications Sturm, I., Köhne, C.H., Wolff, G., Petrowsky, H., Hillebrand, T., Hauptmann S., Lorenz M., Dörken, B., and Daniel, P.T. (1999) Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative prognostic factor in patients with resected liver metastases. J. Clin. Oncol. 17, 1364-1374. Rickers, A., Beyaert, R., Vandenabeele, P., Dörken, B., and Bommert, K. (1999). Cleavage of transkription factor SP1 by caspases during anti-IgM-induced B Cell apoptosis. Eur. J. Biochem. 261, 269- 274. Löffler, A., Kufer, P., Lutterbüse, R., Zettl, F., Daniel, P.T., Schwenkenbecher, J.M., Riethmüller, G., Dörken, B., and Bargou, R. (<strong>2000</strong>) A recombinant bispecific single chain antibody CD19xCD3 induces rapid and high lymphoma directed T cell cytotoxicity. Blood, in press. Jundt, F., Anagnostopoulos, I., Bommert, K., Emmerich, F., Müller, G., Foss, H.-D., Royer, H.-D., Stein, H., and Dörken B. (1999) Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils. Blood 94, 2065-2071. Emmerich, F., Meiser, M., Hummel, M., Demel, G., Foss, H.-D., Jundt, F., Mathas, S., Krappmann, D., Scheidereit, C., Stein, H., and Dörken, B. (1999) Overexpression of I kappa B alpha without inhibition of NF-κB acitivity and mutations in the I kappa B alpha gene in Reed-Sternberg cells. Blood 94, 3129-3134. Ludwig, W.D., Rieder, H., Bartram, C.R., Heinze, B., Schwartz, S., Gassmann, W., Löffler, H., Hossfeld, D., Heil, G., Handt, S., Heyll, A., Diedrich, H., Fischer, K., Weiss, A., Völkers, B., Aydemir, Ü., Fonatsch, C., Gökbuget, N., Thiel, E., and Hoelzer, D. (1998) Immunophenotypic and genotypic features, clinical characteristics, and treatment outcome of adult Pro-B acute lymphoblastic leukemia: Results of the german multicenter trials GMALL 03/87 and 04/89. Blood 92, 1898- 1909. Structure of the Group Group leader Prof. Dr. Bernd Dörken Scientists Prof. Dr. Wolf-Dieter Ludwig Dr. Ralf Bargou Dr. Kurt Bommert Dr. Sophie Cayeux Dr. Peter Daniel Dr. Florian Emmerich Dr. Franziska Jundt Dr. Leonid Karawajew Dr. Ida-Johanna Körner Dr. Markus Mapara Dr. Stefan Mathas Dr. Gerhard Wolff Dr. Christian Wuchter Dr. Isrid Sturm Graduate and undergraduate students Dirk Höhnemann Freya Riechert Silke Ritschel Sebastian Theuring Antje Haefker Niels Peters Patric Seibert Anja Löffler Jan Schwenkenbecher Ulrike Steinhusen Technical assistants Kati Hildebrandt Andrea Katzer Kerstin Krüger Ina Krukenberg Sylvia Metzner Ute Nitschke 105
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Research Report 2000 Covers the Per
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Molecular Therapy Molecular and Dev
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The quantum theory, that provided a
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Introduction Clinical Research The
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Genome Research in Berlin- Brandenb
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External Evaluation Over the period
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Congresses In the years reported, t
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Awards A number of prestigious priz
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Genetics, Bioinformatics and Struct
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disorders. Various MDC groups have
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Steen R.G., Kwitek-Black A.E., Glen
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Selected Publications Binas, B., Da
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Technology transfer Based on the fu
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Selected Publications Müller, D.N.
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Selected Publications Hennies, H.C.
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Somatic genetic alterations in brea
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Clinical and Molecular Genetics of
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Selected Publications Toka, H.R., B
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Lbx1, c-met and the control of cell
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Selected Publications Moore, A., Mc
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Selected Publications Herz, J., Wil
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We aim to study the genetic epidemi
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Nucleation Nucleation as a pre-requ
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Selected Publications Damaschun, G.
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Selected Publications Yuan, T., Wal
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stability. By determining the struc
Page 53 and 54: Role of Protein Dynamics in Enzyme
Page 55 and 56: Modeling Nucleic Acid Structure and
Page 57 and 58: Conformation, Stability and Interac
Page 59 and 60: Protein Structure Analysis and Prot
Page 61 and 62: Cell Growth and Differentiation 61
Page 63 and 64: dendritic cells (DC). Adoptive tran
Page 65 and 66: developmental pathway that may invo
Page 67 and 68: Regulation of Transcription in Mamm
Page 69 and 70: Differentiation and Growth Control
Page 71 and 72: Cell cycle-dependent transcriptiona
Page 73 and 74: Cell Cycle Regulation Hans-Dieter R
Page 75 and 76: Epithelial Differentiation, Invasio
Page 77 and 78: Selected Publications Hartmann, G.,
Page 79 and 80: Selected Publications Behrens, J.,
Page 81 and 82: Selected Publications Karsten, U.,
Page 83 and 84: Depressed contractility in human he
Page 85 and 86: Understanding calcium handling prot
Page 87 and 88: VSMCs. We have cloned and character
Page 89 and 90: Surgical Oncology Peter M. Schlag T
Page 91 and 92: Ubiquitin System and Endoplasmic Re
Page 93 and 94: P450 Cytochromes and the Endoplasmi
Page 95 and 96: Vascular Biology Hermann Haller Thi
Page 97 and 98: Selected Publications Gollasch, M.,
Page 99 and 100: Electron Microscopy Members of the
Page 101 and 102: Molecular Therapy 101
Page 103: Hematology, Oncology and Tumor Immu
Page 107 and 108: Selected Publications Westermann, J
Page 109 and 110: fractions. The hematopoietic potent
Page 111 and 112: Interaction of pharmacologically ac
Page 113 and 114: Molecular Basis of Congestive Heart
Page 115 and 116: Selected Publications Schneider, G.
Page 117 and 118: different murine and human tumor ce
Page 119 and 120: Molecular and Cell Biology of Hemat
Page 121 and 122: Phospholipids Dietrich Arndt Cytoto
Page 123 and 124: Regulation and Deregulation of Cell
Page 125 and 126: Evolution, Regulation and Genetic A
Page 127 and 128: Molecular and Developmental Neurosc
Page 129 and 130: Cellular Neurosciences Helmut Kette
Page 131 and 132: Growth Factor and Regeneration Gary
Page 133 and 134: Synapse Formation and Function Fran
Page 135 and 136: Developmental Neurobiology Fritz G.
Page 137 and 138: Selected Publications Volkmer, H.,
Page 139 and 140: Structure and Organization 139
Page 141 and 142: Prof. Dr. Hans Meyer President of t
Page 143 and 144: Supporting Divisions Safety The div
Page 145 and 146: Press and Public Relations Research
Page 147 and 148: Purchasing and Materials Management
Page 149 and 150: Computing The computing group of th
Page 151 and 152: Awards Thomas Biederer Boehringer-M
Page 153 and 154: Index A Abdul, Yetunde 90 Aguirre-A
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H Haase, Hannelore 85, 97, 100, 142
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Q Qin, Zhihai 107, 117 Quass, Petra
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Board of Trustees Chair Wolf-Michae
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