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Publication Number
US-10934550-B2
Publication Date
2021-03-02
Expiration Date
Abstract
Immunogenic modulators and compositions comprising oligonucleotide agents capable of inhibiting suppression of immune response by reducing expression of one or more gene involved with an immune suppression mechanism.
Core Innovation
The invention relates to an immunotherapy platform using ex vivo engineered cells and immunogenic compositions that include self-deliverable RNAi (sdRNAi) oligonucleotides to suppress tumor immune resistance and immune suppression mechanisms. The platform uses an immune modulator comprising sdRNA that targets immune checkpoint pathways and other immunosuppressive regulators, with the intent that gene suppression reduces immune evasion mediated by those targets.
The document describes checkpoint-related targets including PD1 (PDCD1), CTLA4, LAG3, BTLA, KIR, B7-H3/B7-H4, and TGFBR2, as well as cytokine receptor and downstream signaling mechanisms, including IL10R/IL10RA, TGF-beta receptors, STAT3, and p38/MAPK14. The document also describes targeting apoptosis regulators including BAX, BAC, CASP8, and TP53 as part of the immune resistance suppression strategy.
The sdRNA is described with specific structural features including guide strand and passenger strand lengths, a double stranded region and a single stranded region, and chemical modifications including 5–9 phosphorothioate modifications and at least one 2′-O-methyl or 2′-fluoro modification, with optional hydrophobic or chemical modifications such as phosphorothioate and cholesterol or sterols. The composition includes engineered immune cells modified by the sdRNA to suppress immune-suppressive expression such as PD1 expression.
The document provides a rationale that reduced toxicity versus checkpoint inhibitor antibodies may be achieved by using sdRNAi and single-cell combination action. It also outlines sdRNA target-sequence selection using a proprietary sdRNA potency prediction algorithm and describes in vitro demonstrations of gene knockdown and checkpoint reduction in primary T-cells, NK and T-cell lines, together with ex vivo melanoma combination strategies and PBMC subset delivery.
Claims Coverage
The partial content provides two independent claims, covering an immune modulator as a chemically modified sdRNA with defined strand lengths, structural regions, and chemical modifications that targets a specified SEQ ID range and suppresses PD1 expression, and an immunogenic composition including immune cells modified by that sdRNA to suppress PD1 expression. Across the dependent claims referenced in the partial content, additional inventive features narrow quantitative inhibition, add further chemical modification entities, extend checkpoint targeting beyond PD1, and specify eligible immune cell types or production or transforming characteristics.
Chemically modified sdRNA with defined guide and passenger lengths and single- and double-stranded regions to suppress PD1
The sdRNA comprises a guide strand about 19–25 nucleotides long and a passenger strand about 10–19 nucleotides long, including a double stranded region and a single stranded region, wherein the single stranded region includes 5–9 phosphorothioate modifications, and wherein the sdRNA is chemically modified including at least one 2′-O-methyl modification or 2′-fluoro modification, the sdRNA targeting a sequence selected from SEQ ID NOs: 281-300 and being capable of suppressing expression of PD1.
Immunogenic composition with immune cells modified by PD1-suppressing sdRNA
The immunogenic composition comprises an sdRNA with the guide strand about 19–25 nucleotides long and passenger strand about 10–19 nucleotides long, including a double stranded region and a single stranded region, wherein the single stranded region includes 5–9 phosphorothioate modifications, and wherein the sdRNA is chemically modified including at least one 2′-O-methyl modification or 2′-fluoro modification, the sdRNA targeting a sequence selected from SEQ ID NOs: 281-300 and being capable of suppressing expression of PD1, and wherein the immunogenic composition further comprises immune cells modified by the sdRNA to suppress expression of PD1.
Overall, claim coverage in the partial content centers on chemically modified sdRNA with specified strand lengths and structural and chemical modification features that targets defined SEQ ID ranges and suppresses PD1 expression, and on immunogenic compositions that include immune cells modified by that PD1-suppressing sdRNA. Additional dependent claim content described in the partial content further constrains inhibition magnitude, adds specific chemical entities, extends checkpoint targeting including HAVCR2, and specifies immune cell selection or transformation-based production characteristics.
Stated Advantages
Reduced toxicity versus checkpoint inhibitor antibodies is described as a rationale.
Single-cell combination action is described as an advantage.
Documented Applications
Ex vivo melanoma combination strategies are described.
Delivery to PBMC subsets including CD3+ and CD19+ is described.
In vitro demonstrations of gene knockdown and checkpoint reduction in primary T-cells, NK and T-cell lines are described.
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