RNAi agents for inhibiting expression of HIF-2 alpha (EPAS1), compositions thereof, and methods of use
Inventors
Li, Zhen • Shu, Dongxu • Nicholas, Anthony • Zhu, Rui • Carlson, Jeffrey • Wong, So • Li, Xiaokai • Altenhofer, Erich • Fowler-Watters, Matthew • Chen, Bo
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12221610-B2
Publication Date
2025-02-11
Expiration Date
Abstract
The present disclosure relates to RNAi agents, for example, double stranded RNAi agents, able to inhibit HIF-2 alpha (EPAS1) gene expression. Also disclosed are pharmaceutical compositions that include HIF-2 alpha RNAi agents and methods of use thereof. The HIF-2 alpha RNAi agents disclosed herein may be linked or conjugated to targeting ligands (such as compounds that have affinity for integrins, including alpha-v-beta-3 and alpha-v-beta-5 integrins) and pharmacokinetic (PK) enhancers, to facilitate the delivery to cells and tissues, including to clear cell renal cell carcinoma (ccRCC) cells and tumors. Delivery of compositions comprising the HIF-2 alpha RNAi agents in vivo provides for inhibition of HIF-2 alpha gene expression. The HIF-2 alpha RNAi agents can be used in methods of treatment of various diseases and disorders, including ccRCC.
Core Innovation
The disclosure relates to an RNAi agent comprising an antisense strand comprising SEQ ID NO: 30 and a sense strand comprising SEQ ID NO: 761. The antisense and sense strands include defined 2′-O-methyl and 2′-fluoro nucleotides together with phosphorothioate linkage, and the pharmacological moiety is linked at the 2′ position of the nucleotide.
The pharmacological moiety is defined by X, Y, and Z, which independently represent a targeting group comprising one or more targeting ligands, a targeting ligand having a structure selected from Structure 2a, Structure 2.11a, Structure 29a, and Structure 32a, or a PK enhancer having a structure selected from C-18 diacid, C-18 triacid, Mal-C17-vinyl-PO3, and C20 acid. The linkage descriptors include Y-(NH-C6) s and (invAb) with linkage toward the 5′ end and 3′ end, and the examples include integrin-targeting ligands and PK enhancers.
The document further states that the RNAi agents can inhibit HIF-2α gene expression and includes examples in clear cell renal cell carcinoma (ccRCC) tumor-bearing mice. The reported in vivo assessment measures huHIF-2α mRNA knockdown in kidney tumors by probe-based qPCR normalized to PPIA.
Claims Coverage
The provided independent claim clm-00001 defines one RNAi agent with specified antisense and sense strands, defined nucleotide modifications, a phosphorothioate linkage, and a pharmacological moiety linked at the 2′ position with independently selected X, Y, and Z. Three inventive feature groups are repeatedly supported across the inputs.
RNAi agent with SEQ ID NO: 30 antisense and SEQ ID NO: 761 sense
An RNAi agent comprising an antisense strand comprising SEQ ID NO: 30 and a sense strand comprising SEQ ID NO: 761, with defined 2′-O-methyl and 2′-fluoro nucleotides and phosphorothioate linkage.
2′-position pharmacological moiety with independently selected X, Y, and Z
A pharmacological moiety comprising Z linked at the 2′ position of the nucleotide, wherein each X, Y and Z independently represents a targeting group comprising one or more targeting ligands, a targeting ligand having a structure selected from Structure 2a, Structure 2.11a, Structure 29a, and Structure 32a, or a PK enhancer having a structure selected from C-18 diacid, C-18 triacid, Mal-C17-vinyl-PO3, and C20 acid.
Linkage pattern with 5′-end and 3′-end linkage
The sense strand includes linkage descriptors such as Y-(NH-C6) s and (invAb), with linkage toward the 5′ end and toward the 3′ end as recited in the claim text.
The claim coverage centers on a defined RNAi agent with fixed antisense and sense strands, defined 2′-O-methyl and 2′-fluoro nucleoside modifications, phosphorothioate linkage, and a 2′-linked pharmacological moiety in which X, Y, and Z are independently selected from defined targeting ligands or PK enhancers.
Stated Advantages
Reduced human HIF-2α mRNA versus vehicle in harvested kidney tumors, with quantitative RT-qPCR normalized to PPIA.
Tumor growth inhibition observed in longer-regimen in vivo assessment.
Reduced HIF-2α protein signal shown by immunohistochemistry.
Substantial inhibition of huHIF-2α mRNA knockdown in kidney tumors is reported in multiple tables.
Documented Applications
In vivo evaluation of HIF-2α-targeting RNAi agents in tumor-bearing mice, including harvested kidney tumors and RT-qPCR quantitation of human HIF-2α mRNA normalized to PPIA.
Treatment or addressing clear cell renal cell carcinoma (ccRCC).
In vivo evaluation of HIF-2α RNAi agents in clear cell renal cell carcinoma (ccRCC) tumor-bearing mice, with assessment of kidney tumor huHIF-2α mRNA knockdown by probe-based qPCR normalized to PPIA.
In vivo inhibition of HIF2-alpha gene expression by at least about 30%.
Interested in licensing this patent?