LRPAP1 is a frequent proliferation-inducing antigen of BCRs of mantle cell lymphomas and can be used for specific therapeutic targeting

  • Leukemia. 2019 Jan;33(1):148-158. doi: 10.1038/s41375-018-0182-1.
Lorenz Thurner  1 ,  Sylvia Hartmann  2 ,  Natalie Fadle  3 ,  Maria Kemele  3 ,  Theresa Bock  3 ,  Moritz Bewarder  3 ,  Evi Regitz  3 ,  Frank Neumann  3 ,  Anna Nimmesgern  4 ,  Lutz von Müller  4 ,  Christiane Pott  5 ,  Yoo-Jin Kim  6 ,  Rainer Maria Bohle  6 ,  Mariusz Wasik  7 ,  Stephen J Schuster  7 ,  Martin-Leo Hansmann  2 ,  Klaus-Dieter Preuss  3 ,  Michael Pfreundschuh  3
Affiliations
  • 1. José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany. [email protected].
  • 2. Dr. Senckenberg Institute of Pathology, Goethe University Hospital, Frankfurt am Main, Germany.
  • 3. José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
  • 4. Institute of Medical Microbiology and Hygiene, Saarland University, Homburg/Saar, Germany.
  • 5. Second Department of Medicine, University Hospital Schleswig-Holstein, Kiel, Germany.
  • 6. Saarland University Medical School, Institute of Pathology, Homburg/Saar, Germany.
  • 7. Lymphoma Program, Abramson Cancer Center University of Pennsylvania, Philadelphia, PA, USA.
PMID: 29955130 DOI: 10.1038/s41375-018-0182-1
Abstract

The predominant usage of VH4-34 and V3-21 and reports of stereotyped CDR3s suggest a shared antigenic target of B-cell receptors (BCR) from mantle cell lymphomas (MCL). To identify the target antigens of MCL-BCRs, BCRs from 21 patients and seven MCL cell lines were recombinantly expressed and used for antigen screening. The BCRs from 8/21 patients and 2/7 MCL cell lines reacted specifically with the autoantigen low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1). High-titered and light chain-restricted anti-LRPAP1 serum antibodies were found in MCL patients, but not in controls. LRPAP1 induced proliferation by BCR pathway activation, while an LRPAP1-ETA' toxin-conjugate specifically killed MCL cells with LRPAP1-specific BCRs. Our results suggest a role of LRPAP1 in lymphomagenesis and maintenance of a considerable proportion of MCL cases by chronic autoantigenic stimulation, likely evolving from a chronic autoreactive B-cell response. Importantly, LRPAP1 can be used for a novel therapeutic approach that targets MCL with LRPAP1-reactive BCRs with high specificity.

Products