A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage display
- 12 November 2009
- journal article
- Published by American Society of Hematology in Blood
- Vol. 114 (20), 4494-4502
- https://doi.org/10.1182/blood-2009-05-222786
Abstract
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative treatment available for patients with B-cell chronic lymphocytic leukemia (B-CLL). Here, we show that post-alloHSCT antibody repertoires can be mined for the discovery of fully human monoclonal antibodies to B-CLL cell-surface antigens. Sera collected from B-CLL patients at defined times after alloHSCT showed selective binding to primary B-CLL cells. Pre-alloHSCT sera, donor sera, and control sera were negative. To identify post-alloHSCT serum antibodies and subsequently B-CLL cell-surface antigens they recognize, we generated a human antibody-binding fragment (Fab) library from post-alloHSCT peripheral blood mononuclear cells and selected it on primary B-CLL cells by phage display. A panel of Fab with B-CLL cell-surface reactivity was strongly enriched. Selection was dominated by highly homologous Fab predicted to bind the same antigen. One Fab was converted to immunoglobulin G1 and analyzed for reactivity with peripheral blood mononuclear cells from B-CLL patients and healthy volunteers. Cell-surface antigen expression was restricted to primary B cells and up-regulated in primary B-CLL cells. Mining post-alloHSCT antibody repertoires offers a novel route to discover fully human monoclonal antibodies and identify antigens of potential therapeutic relevance to B-CLL and possibly other cancers. Trials described herein were registered at www.clinicaltrials.gov as nos. NCT00055744 and NCT00003838.Keywords
This publication has 50 references indexed in Scilit:
- Stem Cell Transplantation in Chronic Lymphocytic LeukemiaTransplantation and Cellular Therapy, 2009
- Generation, Affinity Maturation, and Characterization of a Human Anti-Human NKG2D Monoclonal Antibody with Dual Antagonistic and Agonistic ActivityJournal of Molecular Biology, 2008
- SAGE analysis demonstrates increased expression of TOSO contributing to Fas-mediated resistance in CLLBlood, 2008
- Antibody Therapy for Chronic Lymphocytic LeukemiaSeminars in Hematology, 2008
- Graft-versus-leukemia in chronic lymphocytic leukemiaBone Marrow Transplantation, 2007
- Reduced Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation: Current PerspectivesTransplantation and Cellular Therapy, 2007
- Chimeric rabbit/human Fab and IgG specific for members of the Nogo-66 receptor family selected for species cross-reactivity with an improved phage display vectorJournal of Immunological Methods, 2006
- Receptor editing in lymphocyte development and central toleranceNature Reviews Immunology, 2006
- Graft-versus-Leukemia Target Antigens in Chronic Myelogenous Leukemia Are Expressed on Myeloid Progenitor CellsClinical Cancer Research, 2005
- Rabbit Immune Repertoires as Sources for Therapeutic Monoclonal Antibodies: The Impact of Kappa Allotype-correlated Variation in Cysteine Content on Antibody Libraries Selected by Phage DisplayJournal of Molecular Biology, 2002