Double-stranded ribonucleic acids with rugged physico-chemical structure and highly specific biologic activity

Inventors

Carter, William A. • Strayer, David R.

Assignees

AIM Immunotech Inc

Abstract

A novel form of Rugged dsRNA with a unique composition and physical characteristics was identified with high specificity of binding to TLR3, which conveys an important range of therapeutic opportunities. Unlike the previous known antiviral Ampligen® (poly I, poly C12,U) the new and improved form (poly I, poly C30,U) has a reduced tendency to form branched dsRNA which results in increased bioactivity due to an increased ability to bind TLR3 receptor. Pharmaceutical formulations containing the new nucleic acid as active ingredients and methods of treatment are also provided. The invention also provides a description of the physicochemical properties of this novel form of Rugged dsRNA and a method for its preparation in substantially pure form. DsRNAs acting thru TLR3 receptor activation are potent antiviral compounds as well as anticancer agents; also through secondary immunomodulation they can enhance the bioactivity of vaccines and also treat autoimmune disorders.

Core Innovation

The disclosed subject matter describes "rugged" double-stranded RNA (Rugged dsRNA) as an improved variant of Ampligen® (poly(I):poly(C12U)). Rugged dsRNA is characterized by reduced branching and increased resistance to thermal denaturation and ribonuclease digestion relative to unselected or unimproved Ampligen®.

Rugged dsRNA includes poly(I):poly(C30-35U), preferably poly(I):poly(C30U), where U substitutions occur approximately once per 30–35 cytidines. The Rugged dsRNA is described as forming a minimally active ~50 bp, unbranched, helical non-branching conformation that binds TLR3 with higher specificity and improved bioactivity versus unselected/unimproved Ampligen®.

Physicochemical characterization is emphasized to support the ruggedness concept, including circular dichroism (CD) and HPLC fractionation, where a distinctive ~5 min HPLC peak is reported. The disclosure also includes TLR3-dependent signaling, including IFN-α/β, IL-6, and IL-12, and discusses physicochemical and compositional ranges for size (30–300 kDa), approximate length (~50–500 bp), and helical turns (~4.7–6.7).

Claims Coverage

The provided independent claims define isolated dsRNA species with denaturation resistance under conditions that separate hybridized poly(riboinosinic acid) and poly(ribocytosinic acid) strands, with two inventive features.

Across the independent claims, the inventive scope is directed to isolated dsRNA that remains resistant to denaturation under strand-separating conditions, while structurally specifying a single strand containing unpaired uracil/guanine bases and a ribo(In)·ribo(C30-35U)n repeating-unit composition with n ranging from 40 to 500.

Stated Advantages

Documented Applications