Antibody Carriers of CpG Oligodeoxynucleotides for Solid Tumor Immunotherapy Public Deposited

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  • March 19, 2019
Creator
  • Cheung, Roland
    • Affiliation: Eshelman School of Pharmacy
Abstract
  • The use of CpG oligodeoxynucleotide (ODN) TLR9 agonists for oncology therapy has been primarily limited to its use as an adjuvant in combination therapies. Successful anti-cancer therapy has been limited to the intratumoral and peritumoral routes of administration. Subcutaneous (SC) administration has showed promise, but results have been modest at best. For cancer monotherapy with CpG, we developed a delivery system utilizing an endogenous antibody as a carrier for CpG ODNs. Our system first involves conjugation of a small molecule 2,4-dinitrophenyl (DNP) hapten to CpG. Next, we immunize mice against the hapten such that a high titer of anti-DNP antibodies is maintained in the systemic circulation. Upon injection of DNP-CpG, an immune complex will be formed. Subsequently, the immune complex will be taken up by dendritic cells for CpG processing by TLR9 endosomal receptors. This system was shown to be effective in tumor growth inhibition in our animal model upon intravenous (IV) delivery of CpG ODNs, an administration route that has never shown to be effective. In the following investigations, we found that the SC route of administration exhibited great efficacy. Anti-tumor response was as good as IV delivery and showed an improvement over SC administration of underivatized CpG. Pharmacokinetic analysis suggests that increased half-life of CpG may play a role toward the therapeutic effect. In vitro studies suggest that our immune complex effectively activates dendritic cells and that this effect is possibly due to facilitated processing of the immune complexes via Fc receptor-mediated endocytosis and not due to the extent of CpG uptake. Based on collective results, we proposed mechanisms by which we were able to garner such a positive immunological response. Additional opportunities stemming from this work will certainly be of great value. The establishment of SC and IV formulations that exhibit desirable properties carries tremendous implications for the deliver of other therapeutic agents.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Pharmacy."
Advisor
  • Cho, Moo J.
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  • Chapel Hill, NC
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  • Open access
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