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Generation of an artificial human B cell line test system using Transpo-mAb (TM) technology to evaluate the therapeutic efficacy of novel antigen-specific fusion proteins

: Klose, D.; Woitok, M.; Niesen, J.; Beerli, R.R.; Grawunder, U.; Fischer, R.; Barth, S.; Fendel, R.; Nachreiner, T.

Volltext ()

PLoS one. Online journal 12 (2017), Nr.7, Art. e0180305, 21 S.
ISSN: 1932-6203
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer IME ()

The antigen-specific targeting of autoreactive B cells via their unique B cell receptors (BCRs) is a novel and promising alternative to the systemic suppression of humoral immunity. We generated and characterized cytolytic fusion proteins based on an existing immunotoxin comprising tetanus toxoid fragment C (TTC) as the targeting component and the modified Pseudomonas aeruginosa exotoxin A (ETA') as the cytotoxic component. The immunotoxin was reconfigured to replace ETA' with either the granzyme B mutant R201K or MAPTau as human effector domains. The novel cytolytic fusion proteins were characterized with a recombinant human lymphocytic cell line developed using Transpo-mAb (TM) technology. Genes encoding a chimeric TTC-reactive immunoglobulin G were successfully integrated into the genome of the precursor B cell line REH so that the cells could present TTC-reactive BCRs on their surface. These cells were used to investigate the specific cytotoxicity of GrB(R201K)-TTC and TTC-MAPTau, revealing that the serpin proteinase inhibitor 9-resistant granzyme B R201K mutant induced apoptosis specifically in the lymphocytic cell line. Our data confirm that antigen-based fusion proteins containing granzyme B (R201K) are suitable candidates for the depletion of autoreactive B cells.