title: GRP78-directed immunotherapy in relapsed or refractory multiple myeloma - results from a phase 1 trial with the monoclonal immunoglobulin M antibody PAT-SM6.
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.
  
  
  BACKGROUND
  clinicaltrials.gov identifier: NCT01727778.
authors: Department of Internal Medicine II, University Hospital Würzburg, Germany.
authors: Leo
authors: L
authors: Rasche
authors: Department of Internal Medicine II, University Hospital Würzburg, Germany.
authors: Johannes
authors: J
authors: Duell
authors: Patrys GmbH, Würzburg, Germany.
authors: Inês C
authors: IC
authors: Castro
authors: Patrys Ltd., Melbourne, Australia.
authors: Valentina
authors: V
authors: Dubljevic
authors: Department of Internal Medicine II, University Hospital Würzburg, Germany.
authors: Manik
authors: M
authors: Chatterjee
authors: Department of Internal Medicine II, University Hospital Würzburg, Germany.
authors: Stefan
authors: S
authors: Knop
authors: Patrys GmbH, Würzburg, Germany.
authors: Frank
authors: F
authors: Hensel
authors: Institute of Pathology, University of Würzburg, Germany, and Comprehensive Cancer Center Mainfranken, Germany.
authors: Andreas
authors: A
authors: Rosenwald
authors: Department of Internal Medicine II, University Hospital Würzburg, Germany.
authors: Hermann
authors: H
authors: Einsele
authors: Department of Internal Medicine II, University Hospital Würzburg, Germany.
authors: Max S
authors: MS
authors: Topp
authors: Institute of Pathology, University of Würzburg, Germany, and Comprehensive Cancer Center Mainfranken, Germany stephanie.braendlein@uni-wuerzburg.de.
authors: Stephanie
authors: S
authors: Brändlein
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015870:Gene Expression; D006207:Half-Life; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D007075:Immunoglobulin M / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D007262:Infusions, Intravenous; D007970:Leukopenia / Q000209:etiology / Q000473:pathology; D008297:Male; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012008:Recurrence
chemical_list: D000911:Antibodies, Monoclonal; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007075:Immunoglobulin M
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