Development of UniCAR TMs for targeting of FAP positive cells
Based on the UniCAR platform technology we aim to develop novel immunotheranostic approaches for e.g. tumor, cardio-vascular and infectious diseases. In general, the human fibroblast activation protein (FAP) that is particularly expressed by cells in the tumor microenvironment represents an attractive target. Our main task involves the development of UniCAR target modules (TMs) against this antigen. These will be biochemically evaluated and functionally tested in combination with UniCAR T cells using 2D and 3D models. Thereby we can gain insight into the suitability of the novel anti-FAP TMs for imaging and treatment of tumors.
Radionuclide and labeling development for targeted theranostics
UniCAR target modules (TMs) against human fibroblast activation protein (FAP) will be equipped with radioactive chelating entities (chelators) to enable positron emission tomography (PET), single-photon emission computing tomography (SPECT) or therapeutic applications such as radioimmunotherapy with electron- or alpha-emitters. For this purpose, we develop robust chelators with efficient, mild and fast radiolabeling kinetics for a variety of radiometal ions to allow rapid complexation at mild conditions. In particular, this involves the further development of our in-house chelators based on bispidines and sarcophagines. Particular attention is paid to radiometal-labeled molecules for simultaneous nuclear and optical imaging. Concerning the latter, the clinical potential of such probes, especially for fluorescence-guided surgery, is assessed.
Optimization of tumor theranostics by usage of bio(nano)materials
We aim to employ functionalized nanomaterials including transition metal clusters as support frameworks for the development of theragnostic complexes with extended half-lives. Such complexes will consist of UniCAR target modules (TMs) against human fibroblast activation protein (FAP) and will confer with the labeling for imaging, (re)targeting and radiosensitization. Accordingly, we will build on the existing capabilities in the area by adapting our synthetic routes to produce homo- and hetero-metallic clusters containing chemical elements with a high atomic number (high Z elements). We will drive forward the development of such nanomaterials as biocompatible motifs to deliver a selection of radionuclides for targeted radioimmunotherapy and for multimodal molecular imaging.
Preclinical evaluation and clinical translation
A series of different anti-FAP (fibroblast activation protein) UniCAR target modules (TMs) and conjugated derivatives will be created which will be based on either recombinant antibody derivatives or small molecules. They will be modified for either directly labeling or indirectly labeling or be conjugated with nanoparticles (NPs). These TMs will be functionally evaluated in experimental tumor mouse models. In addition, they will be analyzed using a heart disease model. Furthermore, they will be used for imaging after labeling e.g. with positron emitters including Ga-68, Cu-64 or Zr-89. In addition, the radiopharmaceuticals armed with the β–emitters Cu-67 and Lu-177 or with the α-emitters Bi-213 and Ac-225 will be evaluated in the respective disease model. An iterative work circle between the four work packages will be established to ensure an optimized final preclinical product which leads finally to the initiation of production and documentation of GMP grade material. In addition, we will start to establish all the required functional and release assays as well as the documentation for a clinical translation.