AGBA. BIOGEN

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Examinando AGBA. BIOGEN por Autor "Arndt, Claudia"

Mostrando 1 - 3 de 3
  • Publicación
    Acceso abierto
    A theranostic PSMA ligand for PET imaging and retargeting of T cells expressing the universal chimeric antigen receptor UniCAR
    (Taylor & Francis Group, 2019-09-07) Arndt, Claudia; Feldmann, Anja; Koristka, Stefanie; Schäfer, Martin; Bergmann, Ralf; Mitwasi, Nicola; Berndt, Nicole; Bachmann, Dominik; Kegler, Alexandra; Schmitz, Marc; Puentes-Cala, Edinson; Soto, Javier-Andrés; Ehninger, Gerhard; Pietzsch, Jens; Liolios, Christos; Wunderlich, Gerd; Kotzerke, Jörg; Kopka, Klaus; Bachmann, Michael; Taylor & Francis Group
    Chimeric antigen receptor (CAR) T cells have shown impressive therapeutic potential. Due to the lack of direct control mechanisms, therapy-related adverse reactions including cytokine release- and tumor lysis syndrome can even become life-threatening. In case of target antigen expression on non-malignant cells, CAR T cells can also attack healthy tissues. To overcome such side effects, we have established a modular CAR platform termed UniCAR: UniCAR T cells per se are inert as they recognize a peptide epitope (UniCAR epitope) that is not accessible on the surface of living cells. Bifunctional adapter molecules termed target modules (TM) can cross-link UniCAR T cells with target cells. In the absence of TMs, UniCAR T cells automatically turn off. Until now, all UniCAR TMs were constructed by fusion of the UniCAR epitope to an antibody domain. To open up the wide field of low-molecular-weight compounds for retargeting of UniCAR T cells to tumor cells, and to follow in parallel the progress of UniCAR T cell therapy by PET imaging we challenged the idea to convert a PET tracer into a UniCAR-TM. For proof of concept, we selected the clinically used PET tracer PSMA-11, which binds to the prostate-specific membrane antigen overexpressed in prostate carcinoma. Here we show that fusion of the UniCAR epitope to PSMA-11 results in a low-molecular-weight theranostic compound that can be used for both retargeting of UniCAR T cells to tumor cells, and for non-invasive PET imaging and thus represents a member of a novel class of theranostics.
  • Publicación
    Acceso abierto
    An oligo-His-tag of a targeting module does not influence its biodistribution and the retargeting capabilities of UniCAR T cells
    (2019-07-29) Jureczek, Justyna; Bergmann, Ralf; Berndt, Nicole; Koristka, Stefanie; Kegler, Alexandra; Puentes-Cala, Edinson; Soto, Javier-Andrés; Arndt, Claudia; Bachmann, Michael; Feldmann, Anja
    Recently, we established the controllable modular UniCAR platform technology to advance the efficacy and safety of CAR T cell therapy. The UniCAR system is composed of (i) target modules (TMs) and (ii) UniCAR armed T cells. TMs are bispecific molecules that are able to bind to the tumor cell surface and simultaneously to UniCAR T cells. For interaction with UniCAR T cells, TMs contain a peptide epitope sequence which is recognised by UniCAR T cells. So far, a series of TMs against a variety of tumor targets including against the prostate stem cell antigen (PSCA) were constructed and functionally characterised. In order to facilitate their purification all these TMs are expressed as recombinant proteins equipped with an oligo-His-tag. The aim of the here presented manuscript was to learn whether or not the oligo-His-tag of the TM influences the UniCAR system. For this purpose, we constructed TMs against PSCA equipped with or lacking an oligo-His-tag. Both TMs were compared side by side including for functionality and biodistribution. According to our data, an oligo-His-tag of a UniCAR TM has only little if any effect on its binding affinity, in vitro and in vivo killing capability and in vivo biodistribution.
  • Publicación
    Acceso abierto
    Nanosensors in clinical development of CAR-T cell immunotherapy
    (2022-06-15) Nguyen-Le, Trang Anh; Bartsch, Tabea; Wodtke, Robert; Brandt, Florian; Arndt, Claudia; Feldman, Anja; Sandoval-Bojorquez, Diana Isabel; Roig, Arnau Perez; Ibarlucea, Bergoi; Lee, Seungho; Chan-Ki, Baek; Cuniberti, Gianaurelio; Bergmann, Ralf; Puentes-Cala, Edinson; Soto, Javier Andres; Kurien, Biji T.; Bachmann, Michael; Larysa, Baraban; BIOGEN
    Immunotherapy using CAR-T cells is a new technological paradigm for cancer treatment. To avoid severe side effects and tumor escape variants observed for conventional CAR-T cells approach, adaptor CAR technologies are under development, where intermediate target modules redirect immune cells against cancer. In this work, silicon nanowire field-effect transistors are used to develop target modules for an optimized CAR-T cell operation. Focusing on a library of seven variants of E5B9 peptide that is used as CAR targeting epitope, we performed multiplexed binding tests using nanosensor chips. These peptides had been immobilized onto the sensor to compare the transistor signals upon titration with anti-La 5B9 antibodies. The correlation of binding affinities and sensor sensitivities enabled a selection of candidates for the interaction between CAR and target modules. An extremely low detection limit was observed for the sensor, down to femtomolar concentration, outperforming the current assay of the same purpose. Finally, the CAR T-cells redirection capability of selected peptides in target modules was proven successful in an in-vitro cytotoxicity assay. Our results open the perspective for the nanosensors to go beyond the early diagnostics in clinical cancer research towards developing and monitoring immunotherapeutic treatment, where the quantitative analysis with the standard techniques is limited.