The invention are therapeutic PD-1 DNA aptamers used to block PD-1 activity and enhance T-cell cytotoxicity against leukemias and solid tumors.
Stage of Development
In vitro data: Several aptamers were developed using SELEX technology against endogenous immunoprecipitated
PD-1 and they were found to have highly conserved regions using high throughput sequencing. Six PD-1 specific aptamers were then assessed for target validation using leukemic cell lysates (cell lines and primary patient samples) and were found to bind to the PD-1 in its native state. In vitro cytotoxicity T- cell assays demonstrated the ability of PD-1 aptamer to potently enhance T-cell response and cytokine production in Mixed Lymphocyte Reaction (MLR).
In vivo data: A PEGylated form of PD-1 DNA aptamer demonstrated the ability to block PD-1:PD-L1 interaction and significantly reduced the growth of HEL92.1.7 leukemic tumor cells in vivo in a humanized NSG mice with a potency equivalent to an antagonistic anti-PD-1 therapeutic agents. Tumor growth inhibition in humanized NSG mice treated with PD-1 DNA aptamer was 22.59% and comparable to PD-1 antibody over the control group.
Competitive Landscape
Cancer cells develop an extraordinary ability to escape the immune response by expressing proteins that alter immune checkpoints. Checkpoint inhibitors have become effective immunomodulators to promote cancer immunity and circumvent these effects. Recently, several therapeutic antibodies have been developed that target PD-1/PD-L1 axis to activate T-cell response against tumors in mice and humans and have been FDA approved. DNA aptamers mimic therapeutic antibodies that targets the PD-1/PD-L1 axis. High affinity DNA aptamers that selectively bind to
important proteins involved in cancer progression are emerging as a new class of drugs and diagnostic agents. DNA aptamers are alternatives to small-molecule and antibody-based drugs due to their high specificity to therapeutic protein targets and their amenability for easy modification to carry a toxic cargo to kill cancer cells in the body.
Competitive Advantage
- • DNA Aptamers with high affinity, specificity, and selectivity for PD-1
- • Exhibit higher tissue-penetrating potential due to their small size
- • The Aptamers are small, easy and inexpensive to make, have ambient stability and chemical amenability for various modifications and attachments
- • Useful as a therapeutic, diagnostic, or imaging agent
- • Tumor targets include leukemias as well as solid tumors expressing PD-1
- • Appear to have negligible immunogenicity in vivo
Intellectual Property
US Patent filed: September 6, 2017
