Siglec-6 on Chronic Lymphocytic Leukemia Cells Is a Target for Post-Allogeneic Hematopoietic Stem Cell Transplantation Antibodies

Autor: Ina C. Wecken, Adrian Wiestner, Jo Soden, Jim Freeth, Brian C. Shaffer, Jing Chang, Christoph Rader, Sivasubramanian Baskar, Gustavo J. Martinez, Haiyong Peng, Matthew G. Cyr
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
medicine.drug_class
Chronic lymphocytic leukemia
medicine.medical_treatment
Immunology
Antigens
Differentiation
Myelomonocytic
Enzyme-Linked Immunosorbent Assay
Hematopoietic stem cell transplantation
Monoclonal antibody
Article
Cell Line
Flow cytometry
03 medical and health sciences
Antibody Repertoire
Antigen
Antigens
CD
Lectins
medicine
Humans
RNA
Small Interfering
biology
medicine.diagnostic_test
Hematopoietic Stem Cell Transplantation
Antibodies
Monoclonal
High-Throughput Nucleotide Sequencing
Flow Cytometry
medicine.disease
Leukemia
Lymphocytic
Chronic
B-Cell
Leukemia
030104 developmental biology
Tissue Array Analysis
Gene Knockdown Techniques
Leukocytes
Mononuclear
biology.protein
Cancer research
Antibody
Cell Surface Display Techniques
Immunoglobulin Heavy Chains
Zdroj: Cancer Immunology Research. 6:1008-1013
ISSN: 2326-6074
2326-6066
Popis: Although the 5-year survival rate of chronic lymphocytic leukemia (CLL) patients has risen to >80%, the only potentially curative treatment is allogeneic hematopoietic stem cell transplantation (alloHSCT). To identify possible new monoclonal antibody (mAb) drugs and targets for CLL, we previously developed a phage display–based human mAb platform to mine the antibody repertoire of patients who responded to alloHSCT. We had selected a group of highly homologous post-alloHSCT mAbs that bound to an unknown CLL cell surface antigen. Here, we show through next-generation sequencing of cDNAs encoding variable heavy-chain domains that these mAbs had a relative abundance of ∼0.1% in the post-alloHSCT antibody repertoire and were enriched ∼1,000-fold after three rounds of selection on primary CLL cells. Based on differential RNA-seq and a cell microarray screening technology for discovering human cell surface antigens, we now identify their antigen as Siglec-6. We verified this finding by flow cytometry, ELISA, siRNA knockdown, and surface plasmon resonance. Siglec-6 was broadly expressed in CLL and could be a potential target for antibody-based therapeutic interventions. Our study reaffirms the utility of post-alloHSCT antibody drug and target discovery. Cancer Immunol Res; 6(9); 1008–13. ©2018 AACR.
Databáze: OpenAIRE
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