title: A transplant "immunome" screening platform defines a targetable epitope fingerprint of multiple myeloma.
abstract: Multiple myeloma (MM) is a hematological cancer for which immune-based treatments are currently in development. Many of these rely on the identification of highly disease-specific, strongly and stably expressed antigens. Here, we profiled the myeloma B-cell immunome both to explore its predictive role in the context of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and to identify novel immunotherapeutic targets. We used random peptide phage display, reverse immunization, and next-generation sequencing-assisted antibody phage display to establish a highly myeloma-specific epitope fingerprint targeted by B-cell responses of 18 patients in clinical remission. We found that allogeneic HSCT more efficiently allowed production of myeloma-specific antibodies compared with autologous HSCT and that a highly reactive epitope recognition signature correlated with superior response to treatment. Next, we performed myeloma cell surface screenings of phage-displayed patient transplant immunomes. Although some of the screenings yielded clear-cut surface binders, the majority of screenings did not, suggesting that many of the targeted antigens may in fact not be accessible to the B-cell immune system in untreated myeloma cells. This fit well with the identification of heat-shock proteins as a class of antigens that showed overall the broadest reactivity with myeloma patient sera after allogeneic HSCT and that may be significantly translocated to the cell surface upon treatment as a result of immunogenic cell death. Our data reveal a disease-specific epitope signature of MM that is predictive for response to treatment. Mining of transplant immunomes for strong myeloma surface binders may open up avenues for myeloma immunotherapy.
authors.affiliation: Department of Oncology and Hematology, Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Aneta
authors.initials: A
authors.lastname: Schieferdecker
authors.affiliation: Department of Oncology and Hematology, Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Anna
authors.initials: A
authors.lastname: Oberle
authors.affiliation: Department of Oncology and Hematology, Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thiele
authors.affiliation: Department of Oncology and Hematology, Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Fabian
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Department of Oncology and Hematology, Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Göthel
authors.affiliation: Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Technische Universität Braunschweig, Braunschweig, Germany; YUMAB GmbH, Braunschweig, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Miethe
authors.affiliation: Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Technische Universität Braunschweig, Braunschweig, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hust
authors.affiliation: Department of Oncology and Hematology, Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Friederike
authors.initials: F
authors.lastname: Braig
authors.affiliation: Department of Oncology and Hematology, Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Mareike
authors.initials: M
authors.lastname: Voigt
authors.affiliation: Department of Stem Cell Transplantation.
authors.forename: Ute-Marie
authors.initials: UM
authors.lastname: von Pein
authors.affiliation: Institute of Immunology, and.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Koch-Nolte
authors.affiliation: Institute of Immunology, and.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Haag
authors.affiliation: Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; and.
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Indenbirken
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; and.
authors.forename: Adam
authors.initials: A
authors.lastname: Grundhoff
authors.affiliation: Department of Oncology and Hematology, Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Stem Cell Transplantation, Department of Hematology and Oncology, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bacher
authors.affiliation: Department of Stem Cell Transplantation.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Kröger
authors.affiliation: Department of Oncology and Hematology, Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Mascha
authors.initials: M
authors.lastname: Binder
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D018604:Epitope Mapping / Q000379:methods*; D000939:Epitopes / Q000378:metabolism*; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D009194:Myeloma Proteins / Q000032:analysis / Q000302:isolation & purification; D019151:Peptide Library; D010449:Peptide Mapping / Q000379:methods; D020543:Proteome / Q000032:analysis / Q000276:immunology*; D019737:Transplants / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000939:Epitopes; D009194:Myeloma Proteins; D019151:Peptide Library; D020543:Proteome; C017551:myeloma immunoglobulins