The invention relates to antibody-drug conjugates (ADC) that are potentiated by co-administration of the ADC with a moiety comprising covalently linked saponin. The invention also relates to antibody-oligonucleotide conjugates (AOC) that are potentiated by co-administration of the AOC with a moiety comprising covalently linked saponin. The invention also relates to ADCs and AOCs which are conjugated with a saponin via a covalent linker. The invention further relates to an effector moiety such as a toxin or an antisense oligonucleotide such as for example a BNA, conjugated with a saponin via a covalent linkage. The invention also relates to a BNA covalently conjugated with a targeting moiety such as an antibody. The invention also relates to therapeutic combinations comprising a first pharmaceutical composition comprising a conjugate of a cell-targeting moiety such as an antibody and an antisense oligonucleotide such as a BNA covalently bound thereto, and comprising a second pharmaceutical composition comprising either a free saponin, or a conjugate of a cell-targeting moiety such as an antibody with a saponin covalently linked thereto. Furthermore, the invention relates to any of these conjugates or therapeutic compositions or therapeutic combinations, for use as a medicament. The invention also relates to any of these conjugates or therapeutic compositions or therapeutic combinations, for use in a method for the treatment or the prophylaxis of a cancer. Finally, the invention relates to methods for producing any of these conjugates of the invention.

One aspect of the present invention relates to an oral formulation for reducing or inhibiting the expression of a target gene in a subject, comprising a) double stranded iRNA agent comprising an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; 2′-OMe modifications to more than fifteen, more than twenty, more than twenty-five, or more than thirty nucleotides; and a carbohydrate-based ligand conjugated to at least one strand, optionally via a linker or carrier; and b) a penetration enhancer. Another aspect of the invention relates to a method of gene silencing, comprising orally administering to a subject in need thereof the oral formulation.

Covalently modified polypeptide antigens having improved immunogenicity and/or stability, as well as compositions, cells, and methods relating thereto, are described herein. Polypeptide antigens are covalently conjugated to a one or more of steroid acid moieties to improve their stability and/or to trigger improved cellular immunity, or improved cellular and humoral immunity, against the antigen upon administration to a subject. The steroid acids include bile acids and bile acid analogs that enhance endocytosis and/or endosomal escape of endosomally trapped cargoes by potentiating enzymatic cleavage of sphingomyelin to ceramide within endosomal membranes. The steroid acid moieties may be pre-conjugated to a peptide, and the steroid acid-peptide moiety subsequently conjugated to the polypeptide antigen. The peptide may comprise one or more domains that impart an additional functionality to the modified polypeptide antigen.

The present disclosure provides pharmaceutic compositions for oral delivery comprising an antisense oligonucleotide (e.g., CIVI 008) and an oral delivery agent such as 5-CNAC. In some aspects, the disclosure provides a capsule comprising a dry blend of CIVI 008 and 5-CNAC, and optionally a statin.

The present invention concerns methods and reagents useful in modulating gene expression in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Specifically, the invention relates to synthetic chemically modified small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin NA (shRNA) molecules capable of mediating RNA interference (RNAi) against target nucleic acid sequences. The small nucleic acid molecules are useful in the treatment of any disease or condition that responds to modulation of gene expression or activity in a cell, tissue, or organism.

Articles, compositions, kits, and methods relating to nanostructures, including synthetic nanostructures, are provided. Certain embodiments described herein include structures having a core-shell type arrangement; for instance, a nanostructure core may surrounded by a shell including a material, such as a lipid bilayer, and may include other components such as oligonucleotides. In some embodiments, the structures, when introduced into a subject, can be used to deliver nucleic acids and/or can regulate gene expression. Accordingly, the structures described herein may be used to diagnose, prevent, treat or manage certain diseases or bodily conditions. In some cases, the structures are both a therapeutic agent and a diagnostic agent.

The invention relates to a therapeutic combination, comprising a first proteinaceous molecule comprising a first binding site for binding to a first epitope of a first cell-surface molecule, the first proteinaceous molecule provided with at least one saponin covalently bound to an amino-acid residue of said first proteinaceous molecule, and comprising a second pharmaceutical composition comprising a second proteinaceous molecule different from the first proteinaceous molecule, the second proteinaceous molecule comprising a second binding site for binding to a second epitope of a second cell-surface molecule different from the first cell-surface molecule, and comprising an effector moiety, wherein the second epitope is different from the first epitope. An aspect of the invention is a composition comprising the first proteinaceous molecule and the second proteinaceous molecule of the invention. The invention also relates to a composition or therapeutic combination comprising an antibody-drug conjugate or antibody-oligonucleotide conjugate and the first proteinaceous molecule of the invention. An aspect of the invention relates to a pharmaceutical composition comprising the composition or the antibody-drug conjugate of the invention, and optionally further comprising a pharmaceutically acceptable excipient. The invention also relates to the therapeutic combination or the composition or the antibody-drug conjugate or the pharmaceutical composition of the invention, for use as a medicament. The invention also relates to the therapeutic combination of the invention for use in the treatment or prophylaxis of a cancer.

The disclosure features polymorphs of a prodrug dimer of dexamethasone linked at the 21-C and 21′-C carbons via a carbonate-triethylene glycol-carbonate linker. Also disclosed are pharmaceutical compositions and articles comprising said polymorphs, and the use thereof in the treatment of a disease or condition, e.g. via the extended or controlled release of dexamethasone from said articles.

Described herein are processable compositions comprising at least one moiety that is processable in its free form. Also described herein are compositions and methods for the treatment of ocular diseases or disorders including glaucoma, blepharitis, ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration (e.g., wet macular degeneration (AMD) or dry AMD), post-cataract surgery, and retinal vein occlusion. Said compositions and methods comprise steroids and prostaglandins which demonstrate anti-inflammatory activity, intraocular pressure (IOP) lowering, and/or other desirable activities. Injection of said compositions in the eye provides therapeutic benefit to patients suffering from ocular disorders.

An object is to provide a technique of forming CpG oligonucleotides and hydrophobized polysaccharides into complexes. This object is achieved by a complex comprising a modified CpG oligonucleotide containing a hydrophobic group A having a sterol skeleton, and a modified polysaccharide containing a hydrophobic group B.