title: The natural human IgM antibody PAT-SM6 induces apoptosis in primary human multiple myeloma cells by targeting heat shock protein GRP78.
abstract: 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.
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Leo
authors.initials: L
authors.lastname: Rasche
authors.forename: Johannes
authors.initials: J
authors.lastname: Duell
authors.forename: Charlotte
authors.initials: C
authors.lastname: Morgner
authors.forename: Manik
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Frank
authors.initials: F
authors.lastname: Hensel
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Max S
authors.initials: MS
authors.lastname: Topp
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brändlein
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003167:Complement Activation / Q000187:drug effects; D015922:Complement C1q / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology*; D007150:Immunohistochemistry; D009101:Multiple Myeloma / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D015203:Reproducibility of Results
chemical_list: D000911:Antibodies, Monoclonal; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007075:Immunoglobulin M; D015922:Complement C1q