Siglec-6 Identified as Drug Target for Chronic Lymphocytic Leukemia
Cell surface antigen Siglec-6 was broadly expressed in chronic lymphocytic leukemia after transplantation, suggesting a new potential drug target.
Cell surface antigen Siglec-6 was broadly expressed in chronic lymphocytic leukemia (CLL) post allogeneic hematopoietic stem cell transplantation (post-alloHSCT), suggesting a new potential target for antibody-based therapeutics.1 Although patients with CLL have a 5-year survival rate of more than 80%, alloHSCT is the only curative treatment and new monoclonal antibody drugs and targets are needed. The study findings were recently published in Cancer Immunology Research.
To identify a possible monoclonal antibody drug target, researchers first tapped into a platform they had previously developed to mine the antibody repertoire of patients who responded to alloHSCT and used a group of highly homologous monoclonal antibodies shown to bind to the same unknown CLL cell surface antigen.
Through next-generation sequencing of cDNAs encoding variable heavy-chain domains, the study authors wrote, they showed that these monoclonal antibodies had a relative abundance of approximately 0.1% in the post-alloHSCT antibody repertoire and were enriched approximately 1000-fold after 3 rounds of selection on primary CLL cells.
Using RNA-seq and cell microarray screening technology, the unknown CLL cell surface antigen was identified as Siglec-6. The identity of the antigen was confirmed using flow cytometry, ELISA, siRNA knockdown, and surface plasmon resonance experiments.
Siglec-6 is not expressed by hematopoietic stem cells; expression is believed to be limited to the placenta, mast cells, and exhausted B cells.
“Siglec-6 was broadly expressed in CLL and could be a potential target for antibody-based therapeutic interventions,” the study authors concluded. “Our study reaffirms the utility of post-alloHSCT antibody drug and target discovery.”
- Chang J, Peng H, Shaffer BC, et al. Siglec-6 on chronic lymphocytic leukemia cells is a target for post-allogeneic hematopoietic stem cell transplantation antibodies. Cancer Immunol Res. 2018;6:1008-1013. doi: 10.1158/2326-6066.CIR-18-0102