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Clinical Trial
. 2015 Mar;100(3):377-84.
doi: 10.3324/haematol.2014.117945. Epub 2015 Jan 30.

GRP78-directed immunotherapy in relapsed or refractory multiple myeloma - results from a phase 1 trial with the monoclonal immunoglobulin M antibody PAT-SM6

Leo Rasche  1 , Johannes Duell  1 , Inês C Castro  2 , Valentina Dubljevic  3 , Manik Chatterjee  1 , Stefan Knop  1 , Frank Hensel  2 , Andreas Rosenwald  4 , Hermann Einsele  1 , Max S Topp  1 , Stephanie Brändlein  5
Affiliations
Clinical Trial

GRP78-directed immunotherapy in relapsed or refractory multiple myeloma - results from a phase 1 trial with the monoclonal immunoglobulin M antibody PAT-SM6

Leo Rasche et al. Haematologica. 2015 Mar.

Abstract

The primary objective of this phase 1 study was to evaluate the safety and tolerability of the anti-glucose regulated protein 78 monoclonal immunoglobulin M antibody PAT-SM6 in subjects with relapsed or refractory multiple myeloma. Twelve heavily pretreated patients received four intravenous infusions of PAT-SM6 at doses of 0.3, 1, 3, and 6 mg/kg within 2 weeks. Efficacy, pharmacokinetics and immunogenicity were followed up until the end of the trial (day 36). In addition, immune cell patterns in peripheral blood were assessed by flow cytometry and glucose regulated protein 78 expression status was evaluated in bone marrow specimens by immunohistochemistry and flow cytometry at screening. All doses administered were found to be safe and well tolerated; the maximum tolerated dose was not reached. The most common treatment emergent adverse event was leukopenia (grades 1 and 2) in eight out of the 12 multiple myeloma patients. Pharmacokinetic analysis demonstrated dose-proportional increases in drug serum concentration. The terminal half-life ranged from 5.86 to 8.41 h, the apparent volume of distribution ranged from 101 to 150 mL/kg, and clearance ranged from 8.11 to 16.1 mL/h/kg. All patients showed glucose regulated protein 78 surface expression on multiple myeloma cells. Four out of the 12 patients (33.3 %) had stable disease, according to the International Myeloma Working Group criteria, after PAT-SM6 treatment across the doses 1, 3 and 6 mg/kg. In summary, single-agent PAT-SM6 was well tolerated with modest clinical activity in relapsed or refractory multiple myeloma. Further trials exploring the combination of PAT-SM6 with existing myeloma therapies are planned.

Trial registration: clinicaltrials.gov identifier: NCT01727778.

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Figures

Figure 1.
Figure 1.
Study design. Len: lenalidomide; BTZ: bortezomib; anti-ID: anti-idiotype antibody specific for PAT-SM6. PK: pharmacokinetic.
Figure 2.
Figure 2.
Pharmakokinetics: mean serum concentration profiles of PAT-SM6 for dose days 1 and 10 by dose level (linear). There is a minimal accumulation over the dosing period, with similar serum concentrations and pharmacokinetic parameters on day 1 and day 10. For the majority of subjects, the maximal concentration occurred at 1.5 h (end of infusion).
Figure 3.
Figure 3.
Changes in M-protein from baseline to end of the trial. Bars represent percentage changes in M-protein from baseline to day 36/end of the trial. Four patients experienced stable disease according to the IMWG criteria.
Figure 4.
Figure 4.
PAT-SM6 target binding (A) Immunohistochemical staining with PAT-SM6 on paraffin-fixed sections of MM patients and flow cytometry analysis on MM cells from bone marrow. Tumor biopsies from patients with MM were collected, fixed in formalin and embedded in paraffin. Positive control: anti-CD138; isotype control: unrelated human IgM. PAT-SM6 specifically stained multiple myeloma cells (magnification x 100). Images were captured using a Leica DM BL microscope, a Leica ICC HD digital camera and Leica LAS EZ V2.1.0 software. MM cells obtained from bone marrow were analyzed by flow cytometry for PAT-SM6 cell surface binding. PAT-SM6 displayed binding to the cell surface of MM cells. The isotype control (gray histogram) was unrelated human IgM antibody. (B) Detection of PAT-SM6 on circulating MM cells. Before and after dosing, patients’ blood was collected and circulating MM cells were purified using CD138 magnetic beads. PAT-SM6 binding was confirmed using an anti-idiotype antibody specific for PAT-SM6 (anti-ID) by confocal microscopy (Leica DMRE/ UV microscope). In the post-treatment sample, red stained MM cells indicate the presence of PAT-SM6. Anti-CD138 was used as a positive control for MM cells (green).
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