Bispecific aptamer for treating cancer
Inventors
Assignees
Augusta University • Augusta University Research Institute Inc
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Publication Number
US-11332747-B2
Publication Date
2022-05-17
Expiration Date
Abstract
Bispecific aptamers having a first end that specifically binds to a first tumor specific marker, tumor antigen, or viral protein and a second end that specifically binds to a second tumor specific marker, tumor antigen, or viral protein are provide. The bispecific aptamers can be used to treat cancer or virally infected cells. Generally, the bispecific aptamers bind to two surface proteins, preferably different proteins, on the same cell. In a preferred embodiment the bispecific aptamers bind to two different tumor markers, tumor antigens, tumor specific proteins and combinations thereof.
Core Innovation
The disclosed invention relates to bispecific aptamers that bind two targets on the same cell, including a first end that specifically binds to EpCAM and a second end that specifically binds to CD44. The approach is described for treating cancer cells and virally infected cells by targeting a tumor marker and a second tumor marker or related antigen on the cell surface. The disclosed target scope emphasizes using two cell-surface markers, antigens, or viral proteins on the same cell for dual binding activity.
A preferred embodiment includes a fused CD44-EpCAM RNA aptamer with a double stranded adaptor and unpaired base linkers, together with 2′-fluoro-modified nucleotides. The adaptor is described as 23 bp, and the unpaired base linkers are described as 2–3 unpaired base linkers plus the adaptor and fused aptamer structure. The 2′-fluoro modifications are described as improving circulation half-life/renal filtration, increasing dual binding, and enhancing serum stability.
The disclosed invention further relates to combining the bispecific aptamer with one or more siRNA that downregulate an oncogene, including oncogenes selected from a defined group. The disclosed results report inhibition of ovarian cancer cell viability, induction of apoptosis, and suppression of tumor/peritoneal metastasis in a xenograft model. The disclosed biodistribution is described as largely limited to tumor-bearing organs, with low apparent toxicity and no innate immune cytokine (IFNα/TNFα) elevation in PBMC assays.
Claims Coverage
The document includes two independent claims. Across these claims, the inventive features focus on a bispecific aptamer binding EpCAM and CD44 and combining that aptamer with siRNA to downregulate a selected oncogene, with a further independent claim directed to a composition including a pharmaceutically acceptable excipient.
EpCAM/CD44 bispecific aptamer binding ends
A bispecific aptamer comprising a first end that specifically binds to a first tumor specific marker and a second end that specifically binds to a second tumor specific marker, wherein the first tumor specific marker is EpCAM and the second tumor specific marker is CD44.
siRNA downregulating an oncogene encoded by a selected oncogene
The bispecific aptamer further comprising one or more siRNA that downregulate an oncogene, wherein the oncogene is encoded by an oncogene selected from the group consisting of ABL1, ABL2, AKT1, AKT2, ATF1, BCL11A, BCL2, BCL3, BCL6, BCR, BRAF, CARD11, CBLB, CBLC, CCND1, CCND2, CCND3, CDX2, CTNNB1, DDB2, DDIT3, DDX6, DEK, ELK4, ERBB2, ETV4, ETV6, EVI1, EWSR1, FEV, FGFR1, FGFR1OP, FGFR2, FUS, GOLGA5, GOPC, HMGA1, HMGA2, HRAS, IRF4, JUN, KIT, KRAS, LCK, LMO2, MAF, MAFB, MAML2, MDM2, MET, MITF, MPL, MYB, MYC, MYCL1, MYCN, NCOA4, NFKB2, NRAS, NTRK1, NUP214, PAX8, PDGFB, PIK3CA, PIM1, PLAG1, PPARG, PTPN11, RAF1, REL, RET, ROS1, SMO, SS18, TCL1A, TET2, TFG, MLL, TLX, TPR, and USP6.
EpCAM/CD44 bispecific aptamer plus siRNA formulation with pharmaceutically acceptable excipient
A composition comprising a bispecific aptamer having a first end that specifically binds to tumor specific marker EpCAM and a second end that specifically binds to tumor specific marker CD44 and further comprising one or more siRNA that downregulate an AKT1 oncogene and wherein the composition further comprises a pharmaceutically acceptable excipient.
Overall, the claims cover bispecific aptamers with EpCAM and CD44 binding ends, together with siRNA that downregulate a selected oncogene including AKT1, and a composition formulation that includes a pharmaceutically acceptable excipient.
Stated Advantages
Improves circulation half-life/renal filtration.
Increases dual binding.
Enhances serum stability.
Inhibits ovarian cancer cell viability.
Induces apoptosis.
Improves tumor/peritoneal metastasis suppression in a xenograft model.
Shows biodistribution largely limited to tumor-bearing organs.
Low apparent toxicity.
No innate immune cytokine (IFNα/TNFα) elevation in PBMC assays.
Documented Applications
Treating cancer cells, including targeting EpCAM and CD44 for ovarian cancer.
Suppressing tumor/peritoneal metastasis in a xenograft mouse model.
Treating virally infected cells by targeting two cell-surface markers, antigens, or viral proteins on the same cell.
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