TLR9: CpG-conjugated 10 amino acid lytic peptides to treat TLR9+ MDS

This technology is a novel platform for selective delivery of therapeutics to neoplastic cells for the treatment of MDS and solid tumors that overexpress membrane TLR9. Surface TLR9 receptor expression is abundant in several tumor types compared to normal tissues, making it a prime candidate target for tumor selective payload delivery while sparing normal cells and systemic toxicities. MDS affects approximately 50,000 patients in the US annually with few effective treatment options without adverse side effects. Our targeted therapeutic delivery platform technology addresses a significant unmet medical need in the roughly $1B market for MDS therapeutics.


  • MDS is a stem cell malignancy that largely afflicts individuals >60 years of age and often progresses to acute myeloid leukemia (AML). The annual inciidence of MDS is 40-50,000 in the US according to Surveillance, Epidemiology and End Results (SEER) and Medicare records.
  • Few disease-specific treatment strategies exist for MDS patients due to lack of unique to the malignant clone.
    The most effective MDS and AML treatments also lead to many adverse systemic toxicities. For example, azanucleoside analogues are standard for MDS patients of varied genotypes and risk levels, but they can be associated with side effects such as nausea, cytopenias, pain, liver and kidney toxicity and increased risk of respiratory infections.
  • Lenalidomide (Revlimid; Celgene) is currently the only MDS selective therapy on the market and it is only indicated for use in del(5q) MDS patients, which accounts for just 30% of all MDS patients.
    The market for this subset of MDS patients is still significant, with Revlimid generating $400M in 2013 revenue from MDS patients in the US alone.
  • This CpG platform offers a strategy for targeted therapies for the majority of MDS patients and many solid tumors by exploiting the disease specific membrane expression of TLR9 in the malignant clone & neoplastic stem cells to deliver disease selective bioactive payloads.


A covalently linked multi-component, targeted therapeutic for the selective delivery of cytotoxic agents to malignant cells. The targeting moiety is a CpG linker, a native ligand for the TLR9 receptor, which upon binding directs the internalization of the therapeutic by malignant cells that display surface membrane expression of TLR9. This CpG oligonucleotide is conjugated to different payload combinations to achieve desired effects, such as lytic peptides to cause cell membrane lysis, toxic molecules to kill the targeted cells &/or siRNAs to synthetically sensitize the targeted cells to cytotoxic conjugates. The CpG-lytic peptide conjugate has been shown significantly reduce malignant cells in both a transgenic mouse MDS model & MDS patient samples. CpG conjugated with two siRNAs against the phosphatases PP2A-Ca and CDC25C, and lenalidomide produced ~45% cell death in vitro at a 2µg concentration of the CpG-siRNAs-lenalidomide conjugate.


Provisional patent application filed on 10/31/14 for Drs. Alan List and Sheng Wei


Charlie Shaw, PhD
Associate Director, Patents and Licensing