CONJUGATES OF DOUBLE-STRANDED OLIGONUCLEOTIDES WITH POLY(ETHYLENE GLYCOL) AND KEYHOLE LIMPET HEMOCYANIN: A MODEL FOR TREATING SYSTEMIC LUPUS ERYTHEMATOSUS.

Jones, David S.; Hachmann, John P.; Osgood, Stephen A.; Hayag, Merle S.; Barstad, Paul A.; Iverson, G. Michael; Coutts, Stephen M.

La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego, CA 92121

Two types of oligonucleotides were synthesized with linker groups attached at the 5'-end. Both were repeating dimers of deoxyribocytidine and deoxyriboadenosine. A 20-mer was prepd. with a thiol-contg. linker, masked as a disulfide, and a 50-mer was prepd. with a vicinal diol-contg. linker. A tetraiodo-acetylated poly(ethylene glycol) (PEG) deriv. was synthesized and reacted with the thiol-contg. 20-mer to provide an oligonucleotide PEG conjugate of precisely four oligonucleotides on each PEG carrier. The vicinal diol on the 50-mer was oxidized to an aldehyde and conjugated to keyhole limpet hemocyanin (KLH) to provide an oligonucleotide-KLH conjugate by reductive alkylation. The conjugates were annealed with complementary (TG)n strands. While the double-stranded oligonucleotide-KLH conjugate is an immunogen, eliciting the synthesis of antibodies against oligonucleotides, the PEG conjugate has the biol. property of specifically suppressing (tolerizing) B cells which make antibodies against the immunizing oligonucleotide.

Published in Bioconjugate Chemistry, 1994, 5.