The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

Cytotoxic lymphocytes expressing chimeric antigen receptors (CAR) that target and bind small conjugate molecules (SCM) are disclosed, as well as methods of using the cells and the SCMs in the treatment of cancer.

The present invention relates to an antibody drug conjugate using a bispecific antibody and its use. The antibody drug conjugate of the present invention can easily form a conjugate of an antibody and a drug without a multistep synthetic process though binding of a conjugate of a bivalent cotinine-peptide and a drug, and an anti-cotinine single chain variable fragment. In addition, the antibody drug conjugate can effectively deliver a drug to a target to which the antibody binds specifically, and can enhance a half-life of a drug in the body, thereby improving a therapeutic effect.

The present disclosure relates to methods of treating a patient with a cancer by administering to the patient a composition comprising CAR T cells wherein the CAR T cells comprise a CAR and the CAR comprises an E2 anti-fluorescein antibody fragment, and administering to the patient a small molecule linked to a targeting moiety by a linker. The disclosure also relates to compositions for use in such methods.

Aspects of the invention provide single stranded oligonucleotides for activating or enhancing expression of MECP2. Further aspects provide compositions and kits comprising single stranded oligonucleotides for activating or enhancing expression of MECP2. Methods for modulating expression of MECP2 using the single stranded oligonucleotides are also provided. Further aspects of the invention provide methods for selecting a candidate oligonucleotide for activating or enhancing expression of MECP2.

The invention provides a CLIPTAC comprising: (a) a first portion comprising a ligand for an intracellular target protein; (b) a second portion comprising a ligand for an E3 ubiquitin ligase; and (c) a linker portion covalently coupling the first and second portions; wherein the linker comprises a covalent bond produced by a bioorthogonal click reaction between a compatible pair of reactive moieties. CLIPTAC precursor compositions and CLIPTAC precursors are also provided, together with pharmaceutical compositions comprising the CLIPTAC, CLIPTAC precursor compositions and CLIPTAC precursors, and methods of treatment using the same.

The present invention relates to methods and compositions for the treatment of BAF-related disorders such as cancers and viral infections.

A bioorthogonal molecule can include a molecule having a structure according to:

##STR00001##

wherein R.sup.1—R.sup.8 are independently selected from H, a substituted or unsubstituted C.sub.1-C.sub.4 alkyl or alkylene group, COOH, COOR.sup.9, COR.sup.9, CONR.sup.9R.sup.10, CN, CF.sub.3, and SO.sub.2R.sup.9, and where R.sup.9 and R.sup.10 are independently selected from H and a substituted or unsubstituted C.sub.1-C.sub.4 alkyl or alkylene group, with the proviso that one of R.sup.3—R.sup.8 comprises a leaving group, and wherein X is O, S, N, SO, SO.sub.2, SR.sup.+, Se, PO.sub.2.sup.-, or NRR′.sup.+, and where Rand R′ are independently selected from H or a substituted or unsubstituted C.sub.1-C.sub.4 alkyl or alkylene group.

The present disclosure relates generally to compounds that simultaneously bind both mutant huntingtin protein (mHTT) and an ubiquitin E3 ligase and their use as therapeutic agents, for example, in treating diseases, such as neurodegenerative disorders caused by aggregation of mHTT.

Several embodiments of the present disclosure relate to therapeutic compositions configured to target the liver of a subject and that are useful in the treatment or prevention of one or more of transplant rejection, autoimmune disease, food allergy, and immune response against a therapeutic agent. In several embodiments, the compositions are configured to target the liver and deliver antigens to which tolerance is desired. In several embodiments, the compositions are configured for clearance of a circulating protein or peptide or antibody associated with one or more of the above-mentioned maladies. Methods and uses of the compositions for induction of immune tolerance are also disclosed herein.