Previous and Current Research
Our major goals are to develop and optimize novel tools for retargeting of immune effector cells. These tools are helpful for modulation of wanted and unwanted immune responses including for (i) activation of the immune system against tumor or virus infected cells, (ii) destruction of autoreactive cells in an antigen specific manner, and (iii) modulation of immune responses including the induction of antigen-specific tolerance. Aside of conventional bispecific antibodies and antigen specific chimeric antigen receptors (CARs) for retargeting of T cells e. g. to prostate cancer or leukemic cells we have developed a novel and unique modular cell targeting system allowing us to target any kind of antigen. The modular system bases on replacable target modules which can be combined with either bispecific universal effector modules or a universal CAR. Both effector strategies can also be used for an inducible targeting strategy. Effector and target modules together form a novel platform which allows us to engage target cells (e.g. tumor cells, virus infected cells) directly with immune effector cells. T cell engagement is mediated via CD3, NK cells are engaged via activating receptors such as ULBP2. Blood dendritic cells (DCs) are targeted via a unique sugar structure on their surface. In case of DCs the targeting system does not only deliver an antigen cargo but also the genetic information for maturation of the DCs. Alternatively, effector cells can be transduced with either an antigen specific or our unique universal CAR. Effector cells armed with universal CARs are indifferent to healthy tissues and can reversibly be armed with targeting modules to any kind of antigen. The cross-linkage of effector and target cell will activate the effector cell. Currently, we have developed targeting strategies for surface molecules on leukemic cells (e.g. CD19, CD33, CD133) or prostate cancer (PSCA, PSMA) or a universibly applicable inducible surface target antigen.
Future Projects and Goals
Two of our conventional bispecific abs (CD3-CD33 and CD3-PSCA) are presently on the way to be translated into the clinic. In parallel, we are going to finish the preclinical work for our modular mono- or multispecific targeting systems. Furthermore, we develop and functionally characterize novel additional targeting molecules that will be included into the system. Moreover, knock in animal models for syngeneic studies and allowing us to isolate transgenic armed effector cells are developed in order to show proof of concept for the diverse applicability of our modular targeting systems including for tumor diseases, autoimmune diseases, GvHD, transplantation/rejection as well as viral infections.
Arndt, C., Feldmann, A., von Bonin, M., Cartellieri, M., Ewen, E.-M., Koristka, S., Michalk, I., Stamova, S., Berndt, N., Hermsdorf, A., Bornhäuser, M., Ehninger, G., Schmitz, M. and Bachmann, M.
Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: Description of a novel modular targeting system.Leukemia, in press. (IP 10,2). (2013)
Arndt, C., von Bonin, M., Cartellieri, M., Feldmann, A., Koristka, S., Michalk, I., Stamova, S., Bornhäuser, M., Ehninger, G. and Bachmann, M.
Redirection of T cells with a first fully humanized bispecific CD33-CD3 antibody efficiently eliminates AML blasts without harming hematopoietic stem cells.Leukemia, doi: 10.1038/leu.2013.18. [Epub ahead of print] (IP 10,2). (2013)
Koristka, S., Cartellieri, M., Arndt, C., Bippes, C.C., Feldmann, A., Michalk, I., Wiefel, K., Stamova, S., Schmitz, M., Ehninger, G., Bornhäuser, M. and Bachmann, M.
The nuclear antigeen La: An inducible target for retargeting of human regulatory T cells for the treatment of GvHD?J. Autoimmunity 42, 105-16. DOI: 10.1016/j.jaut.2013.01.002 (Epub 2013 Jan 22) (IP 7,4). (2013)
Thieme, S., Gyárfás, T., Richter, C., Özhan-Kizil, G., Fu, J., Alexopoulou, D., Muders, M.H., Michalk, I., Jakob, C., Dahl, A., Klink, B., Bandoła, J., Bachmann, M., Schröck, E., Buchholz, F., Stewart, A.F., Weidinger, G., Anastassiadis, K. and Brenner, S.
The histone demethylase UTX regulates stem cell migration and hematopoiesis.Blood, 121, 2462-2473 DOI: 10.1182/blood-2012-08-452003. (Epub 2013 Jan 30) (IP 9,9). (2013)
Kloss C. C., Condomines, M., Cartellieri, M., Bachmann, M. and Sadelain, M.
Combinatorial antigen-recognition with balanced signaling ensures selective tumor eradication by engineered T cells.Nature Biotechnology, doi:10.1038/nbt.2459. (IP 23,3). (2013)