The natural human IgM antibody PAT-SM6 induces apoptosis in primary human multiple myeloma cells by targeting heat shock protein GRP78

PLoS One. 2013 May 7;8(5):e63414. doi: 10.1371/journal.pone.0063414. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Apoptosis / drug effects*
  • Bone Marrow / drug effects
  • Bone Marrow / pathology
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Complement Activation / drug effects
  • Complement C1q / metabolism
  • Endoplasmic Reticulum Chaperone BiP
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Heat-Shock Proteins / antagonists & inhibitors*
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunoglobulin M / pharmacology*
  • Immunohistochemistry
  • Multiple Myeloma / pathology*
  • Protein Binding / drug effects
  • Reproducibility of Results

Substances

  • Antibodies, Monoclonal
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Immunoglobulin M
  • Complement C1q

Grant support

LR was supported by IZKF Wuerzburg Erstantragstellerprogramm (Projekt Z-3/15) and the Deutsche Forschungsgemeinschaft (DFG) (KFO 216). This work was supported by research funding from Patrys Ltd, Australia, a company currently conducting clinical trials of PAT-SM6 as a potential anti-cancer treatment. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.