Double-stranded ribonucleic acids with rugged physico-chemical structure and highly specific biologic activity
Inventors
Carter, William A. • Strayer, David
Assignees
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Publication Number
US-9315538-B2
Publication Date
2016-04-19
Expiration Date
Abstract
The invention relates to our discovery of a novel double-stranded ribonucleic acid (dsRNA) having specific biological activities, which includes acting as a selective agonist for activation of the Toll-like receptor 3. Its “rugged” molecular structure as measured by physico-chemical techniques is resistant to molecular unfolding (i.e., denaturation). This structure appears to be responsible for increased efficacy of dsRNA in therapeutic applications and improved biological activity (e.g., used as an immunoregulatory agent). Medicaments, processes for their manufacture, and methods for their use are provided herein.
Core Innovation
The invention relates to an isolated double-stranded ribonucleic acid (dsRNA) that is enzymatically active under thermal stress and is partially hybridized. The dsRNA has each strand with a defined molecular weight range and strand identity defined by poly(ribocytosinic uracilic acid) on one strand and poly(riboinosinic acid) on the opposite strand. The two strands do not base pair the position of the uracil base, while the two strands base pair the position of the cytosine base.
The invention further defines the dsRNA as having a strand length range and a duplex structure characterized by a defined number of helical turns. The specified base-pairing relationship is maintained, including the non-base-pairing of the uracil base position and the base pairing of the cytosine base position, together with partial hybridization. Additional forms are described that specify particular repeat/segment constructs using poly(ribocytosinic uracilic acid) and poly(riboinosinic acid) units.
The rugged partially hybridized dsRNA variant is described as a selective Toll-like receptor 3 (TLR3) agonist, and is resistant to denaturation/hydrolysis. The description states increased binding and biological efficacy, longer stability, and that the molecular species can be enriched by denaturing-selection to obtain a dominant HPLC peak species with characteristic CD signatures.
Claims Coverage
The independent claims define three related isolated, thermally stress-enzymatically active, partially hybridized dsRNA structures, each with specific strand composition and base-pairing constraints, and further supported by dependent refinements that specify structural construct variants and composition scope (one or more different dsRNAs).
Thermal-stress enzymatically active partially hybridized dsRNA with uracil non-base-pairing
An isolated dsRNA enzymatically active under thermal stress comprising each strand with a molecular weight of about 250 Kda to about 320 Kda, where a single strand is comprised of poly(ribocytosinic uracilic acid) and an opposite strand is comprised of poly(riboinosinic acid); the two strands do not base pair the position of the uracil base, the two strands base pair the position of the cytosine base, and the strands are partially hybridized.
Thermal-stress enzymatically active partially hybridized dsRNA with defined strand length and base-pairing constraints
An isolated dsRNA enzymatically active under thermal stress comprising each strand of a length from about 380 bases to about 450 bases, with one strand comprised of poly(ribocytosinic uracilic acid) and an opposite strand comprised of poly(riboinosinic acid); the two strands do not base pair the position of the uracil base, the two strands base pair the position of the cytosine base, and the strands are partially hybridized.
Thermal-stress enzymatically active partially hybridized dsRNA with helical-turn configuration
An isolated dsRNA enzymatically active under thermal stress comprising each strand with about 30 to 38 helical turns of duplexed RNA strands, with one strand comprised of poly(ribocytosinic uracilic acid) and the opposite strand comprised of poly(riboinosinic acid); the two strands do not base pair the position of the uracil base, the two strands base pair the position of the cytosine base, and the strands are partially hybridized.
Across the independent claims, the core inventive concept is an isolated, thermally stress-enzymatically active, partially hybridized dsRNA defined by uracil-position non-base-pairing, cytosine-position base-pairing, and specific structural parameters (molecular weight, strand length, or helical turns), with refinements that further specify repeat/segment forms and allow one or more different dsRNAs.
Stated Advantages
Resistant to denaturation/hydrolysis and described as more rugged molecular structure.
Increased binding/biological efficacy.
Longer stability versus unselected AMPLIGEN® (rintatolimod).
Enrichment by denaturing-selection to obtain a dominant HPLC peak species with characteristic CD signatures.
Described as a selective Toll-like receptor 3 (TLR3) agonist.
Documented Applications
Therapeutic use cases are described involving TLR3-mediated immune activation against infections.
Therapeutic use cases are described involving abnormal cell proliferation/cancer.
Therapeutic use cases are described for vaccination/adjuvant contexts.
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