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Titel: Integration of the B-Cell Receptor Antigen Neurabin-I/SAMD14 Into an Antibody Format as New Therapeutic Approach for the Treatment of Primary CNS Lymphoma
VerfasserIn: Bewarder, Moritz
Kiefer, Maximilian
Moelle, Clara
Goerens, Lisa
Stilgenbauer, Stephan
Christofyllakis, Konstantinos
Kaddu-Mulindwa, Dominic
Fadle, Natalie
Regitz, Evi
Neumann, Frank
Hoth, Markus
Preuss, Klaus-Dieter
Pfreundschuh, Michael
Thurner, Lorenz
Sprache: Englisch
Titel: Frontiers in Oncology
Bandnummer: 10
Verlag/Plattform: Frontiers
Erscheinungsjahr: 2020
Freie Schlagwörter: B-cell receptor antigens
primary central nervous system lymphoma
neurabin-I/SAMD14
BAR-body
auto-antigens
DDC-Sachgruppe: 610 Medizin, Gesundheit
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Recently, neurabin-I and SAMD14 have been described as the autoantigenic target of approximately 66% of B-cell receptors (BCRs) of primary central nervous system lymphomas (PCNSL). Neurabin-I and SAMD14 share a highly homologous SAM domain that becomes immunogenic after atypical hyper-N-glycosylation (SAMD14 at ASN339 and neurabin-I at ASN1277). This post-translational modification of neurabin-I and SAMD14 seems to lead to a chronic immune reaction with B-cell receptor activation contributing to lymphoma genesis of PCNSLs. The selective tropism of PCNSL to the CNS corresponds well to the neurabin-I and SAMD14 protein expression pattern. When conjugated to Pseudomonas Exotoxin A (ETA´), the PCNSL reactive epitope exerts cytotoxic effects on lymphoma cells expressing a SAMD14/neurabin-I reactive BCR. Thus, the reactive epitopes of SAMD14/neurabin-I might be useful to establish additional therapeutic strategies against PCNSL. To test this possibility, we integrated the PCNSLreactive epitope of SAMD14/neurabin-I into a heavy-chain-only Fab antibody format in substitution of the variable region. Specific binding of the prokaryotically produced SAMD14/neurabin-I Fab-antibody to lymphoma cells and their internalization were determined by flow cytometry. Since no established EBV-negative PCNSL cell line exists, we used the ABC-DLBCL cell lines OCI-Ly3 and U2932, which were transfected to express a SAMD14/neurabin-I reactive BCR. The SAMD14/neurabin-I Fab antibody bound specifically to DLBCL cells expressing a BCR with reactivity to SAMD14/neurabin-I and not to unmanipulated DLBCL cell lines. Eukaryotically produced full-length IgG antibodies are well established as immunotherapy format. Therefore, the PCNSLreactive epitope of SAMD14/neurabin-I was cloned into a full-length IgG1 format replacing the variable domains of the light and heavy chains. The IgG1-format SAMD14/neurabin-I construct was found to specifically bind to target lymphoma cells expressing a SAMD14/neurabin-I reactive B cell receptor. In addition, it induced dosedependent relative cytotoxicity against these lymphoma cells when incubated with PBMCs. Control DLBCL cells are not affected at any tested concentration. When integrated into the Fab-format and IgG1-format, the PCNSL-reactive epitope of SAMD14/neurabin-I functions as B-cell receptor Antigen for Reverse targeting (BAR). In particular, the IgG1-format BAR-body approach represents a very attractive therapeutic format for the treatment of PCNSLs, considering its specificity against SAMD14/neurabin-I reactive BCRs and the well-known pharmacodynamic properties of IgG antibodies.
DOI der Erstveröffentlichung: 10.3389/fonc.2020.580364
URL der Erstveröffentlichung: https://doi.org/10.3389/fonc.2020.580364
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-424892
hdl:20.500.11880/38131
http://dx.doi.org/10.22028/D291-42489
ISSN: 2234-943X
Datum des Eintrags: 30-Jul-2024
Bezeichnung des in Beziehung stehenden Objekts: Supplementary Material
In Beziehung stehendes Objekt: https://www.frontiersin.org/api/v3/articles/580364/file/Table_1.DOCX/580364_supplementary-materials_tables_1_docx/1?isPublishedV2=false
Fakultät: M - Medizinische Fakultät
Fachrichtung: M - Biophysik
M - Innere Medizin
Professur: M - Prof. Dr. Markus Hoth
M - Prof. Dr. Stephan Stilgenbauer
M - Dr. med. Lorenz Thurner
M - Keiner Professur zugeordnet
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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