TY  - JOUR
A1  - Rasche, Leo
A1  - Duell, Johannes
A1  - Morgner, Charlotte
A1  - Chatterjee, Manik
A1  - Hensel, Frank
A1  - Rosenwald, Andreas
A1  - Einsele, Hermann
A1  - Topp, Max S.
A1  - Brändlein, Stephanie
T1  - The Natural Human IgM Antibody PAT-SM6 Induces Apoptosis in Primary Human Multiple Myeloma Cells by Targeting Heat Shock Protein GRP78
JF  - PLoS ONE
N2  - In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM.
KW  - cytotoxicity
KW  - apoptosis
KW  - immunohistochemistry techniques
KW  - enzyme-linked immunoassays
KW  - multiple myeloma
KW  - cell staining
KW  - cell binding
KW  - complement system
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130125
VL  - 8
IS  - 5
ER  - 
TY  - JOUR
A1  - Leich, E.
A1  - Weißbach, S.
A1  - Klein, H.-U.
A1  - Grieb, T.
A1  - Pischimarov, J.
A1  - Stühmer, T.
A1  - Chatterjee, M.
A1  - Steinbrunn, T.
A1  - Langer, C.
A1  - Eilers, M.
A1  - Knop, S.
A1  - Einsele, H.
A1  - Bargou, R.
A1  - Rosenwald, A.
T1  - Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules
JF  - Blood Cancer Journal
N2  - Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.
KW  - multiple myeloma
KW  - somatic mutations
KW  - whole-exome sequencing
KW  - adhesion
KW  - receptor tyrosine kinases
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128663
VL  - 3
IS  - e102
ER  -