Effects of Polynucleotides on Monkeys and Man

Abstract

Interest in the biological effects of nucleic acids as immune modulators developed about simultaneously and almost independently of the realization that some of the nucleic acids could act as interferon inducers. A symposium held in 1970 reported studies, dating from about 1967, on poly adenylic-polyuridylic acid (poly A·poly U) and poly inosinic-poly cytidylic acid as compounds that were able strongly to augment antibody responses in mice to some antigens and to restore immune competence to mice that had become immune compromised for a variety of reasons (1). It was not long after the discovery of interferon that a number of people became aware of the potential use of interferon as a broad spectrum antiviral agent in the treatment of human disease. However, until recently, with the development of DNA recombinant techniques for large scale production of human interferon, obtaining enough interferon to do valid clinical trials was extremely difficult to do. A number of non replicating entities were found that could cause the host (rodents in most studies) to produce interferon. In 1967 it was reported that the most effective of these was a synthetic double stranded RNA, polyino-sinic-polycytidylic acid, or polyI·polyC (2). This polynucleotide also was shown to be able to act as an immune adjuvant, acting to augment strongly the production of antibodies to a number of antigens, under conditions where interferon did not do so. Poly A-poly U also was a good immune adjuvant in mice, but induced the formation of only very small amounts of circulating interferon. PolyA·polyU was a good antitumor agent. It was tested much less extensively than polyI·polyC as an antiviral, but where tested was less effective (1).

PolyI·polyC proved to be only very slightly active in monkeys and chimpanzees (3). Clinical trials in man as an antitumor agent were very disappointing, because, while the material showed very little toxicity in man it induced the formation of only very low levels of interferon, and showed no antitumor action (4,5). This was later associated with the finding that there is present in primate serum a relatively high concentration of enzymes that hydrolize and inactivate polyI·polyC (6).

A derivative of polyI·polyC, made by complexing the ds RNA with polylysine and carboxymethylcellulose, called polyICLC proved much more resistant to hydrolysis than was polyI·polyC. It was able to induce the formation of large quantitites of interferon in monkeys, chimpanzees and humans (7). The remainder of this chapter will be devoted to an examination of studies that have been done with this stabilized derivative of polyI·polyC, called polyICLC, with polyA·polyU, and with another polynucleotide called Ampligen (8).

The material will be presented in three parts; 1) a brief summary of preclinical studies in rodents, 2) immune modulating effects in primates, including man, and 3) clinical studies.