Importance of Avidity in Endogenous Drug Carrier: Antibody Carrier for CpG Oligonucleotides

摘要

In animal models, successful anti-cancer monotherapy with CpG oligodeoxynucleotide (ODN) has been limited to the intratumoral and peritumoral routes of administration. To overcome this limitation, we developed a delivery system utilizing an endogenous antibody as a carrier for CpG ODNs. When a 1:1 conjugate of 2,4-dinitrophenyl (DNP) to a CpG ODN was administered to tumor-bearing mice that were pre-immunized against DNP, intravenous (IV) administration successfully inhibited tumor growth. In the present studies, we reproduced the IV results and showed that a DNP derivative of a controlled ODN with scrambled nucleotide sequence failed in the same model. Perhaps more significantly, contralateral subcutaneous (SC) routes of administration also suppressed tumor growth. However, in a separate experiment, when the anti-DNP titer level was low, the anti-tumor effect was abolished, supporting the importance of the avidity involved in the complexation. With the low titer, a significant fraction of injected dose must have existed as unbound that is subject to rapid clearance. The present study justifies chemically crosslink immune complexes such that the CpG ODN cannot dissociate in the body after administration.