The presently disclosed subject matter relates to immunoswitch particles that switch off immunosuppressive pathways on tumor cells or immunosuppressive molecules induced by tumor cells in the tumor microenvironment, or virus infected cells or immunosuppressive molecules induced by virus infected cells in the microenvironment surrounding the virus infected cells, while simultaneously switching on co-stimulatory or co-inhibitory pathways on T cells, as well as method for converting immunosuppressive signals in cells, tissues, and subjects into stimulatory signals, and immunotherapy-based methods for treating cancer and chronic viral infections.

This disclosure is based, at least in part, on an unexpected discovery that the novel nanobodies and variants thereof are able to specifically bind afucosylated or sialylated IgG Fc glycoforms. Glycosylation of the IgG Fc domain is a major determinant of the strength and specificity of antibody effector functions, modulating the binding interactions of the Fc with the diverse family of Fc? receptors. These Fc glycan modifications, such as removal of the core fucose residue, are newfound clinical markers for predicting severity of diseases, such as diseases caused by dengue virus (DENV) or SARS-CoV-2. However, it remains challenging to accurately distinguish specific IgG glycoforms without costly and time-intensive methods. The novel glycol-specific nanobodies and variants thereof, as disclosed herein, can be used as rapid clinical diagnostics or prognostics to risk stratify patients with viral and inflammatory diseases.

The purpose of the present invention is to provide a novel stereoselective method for preparing a cyclic dinucleotide derivative and a production intermediate therefor, which can be used for an antibody-immunostimulant conjugate. Also provided is a method for producing a cyclic dinucleotide-linker and an antibody-immunostimulant conjugate while using the above production method. Further provided is a method for preparing a cyclic dinucleotide derivative, the method including the step of subjecting a compound (I) and a compound (IV) to stereoselective condensation using an optically active phosphitylating agent (Rc-II) or (Sc-II).

There are provided a compound having two or more phosphor moieties of which light absorption characteristics are equivalent to each other, in which the phosphor moieties adjacent to each other are each linked through a group including a structure represented by General Formula (I), and a labeled biological substance using the compound.

##STR00001## In the formula, X.sup.1 to X.sup.3 represent O, S, >NR.sup.1, or >CR.sup.2R.sup.3. R.sup.1 to R.sup.3 represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an acyl group, NR.sup.8R.sup.9, OR.sup.10, or an anionic group. R.sup.1 to R.sup.10 represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an aryl group, a heteroaryl group, or an anionic group. n is an integer of 2 or more. * represents a bonding site.

The present invention relates to pharmaceutical compositions for use in the treatment of chemoresistant acute myeloid leukemia (AML). The inventors have established a powerful preclinical model to screen in vivo responses to conventional genotoxics and to mimic the chemoresistance and minimal residual disease as observed in AML patients after chemotherapy. The inventors showed that cytarabine-resistance mechanism involves the CD39-dependent crosstalk between energetic niche and AML mitochondrial functions through CD39-P2Y13-cAMP-PKA signaling axis. In particular, the present invention relates to an inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis for use in a method of treating chemoresistant acute myeloid leukemia (AML) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of said inhibitor.

The present disclosure provides methods for treating a cancer or resistant cancer with a combination of an anti-CD22 antibody-maytansine conjugate and one or more anti-cancer agents. The disclosure also encompasses methods for sensitizing a cancer with such combinations. Also provided are pharmaceutical compositions including such combinations.

The present disclosure relates generally to anti-C10orf54 antibodies, including antibody-drug conjugates comprising the antibodies, and methods of their use.

The presently disclosed subject matter relates to immunoswitch particles that switch off immunosuppressive pathways on tumor cells or immunosuppressive molecules induced by tumor cells in the tumor microenvironment, or virus infected cells or immunosuppressive molecules induced by virus infected cells in the microenvironment surrounding the virus infected cells, while simultaneously switching on co-stimulatory or co-inhibitory pathways on T cells, as well as method for converting immunosuppressive infections.

Compounds and compositions are disclosed in which a Drug Unit is linked to a targeting Ligand Unit through a self-stabilizing Linker Unit from which a drug compound or active drug moiety is released at the targeted site of action. Methods for treating diseases characterized by the targeted abnormal cells, such as cancer or an autoimmune disease using the compounds and compositions of the invention are also disclosed.

Provided are immunostimulatory bacteria and oncolytic viruses, and pharmaceutical compositions containing the bacteria and/or viruses, that act as three prime repair exonuclease 1 (TREX1) antagonists. The bacteria and viruses are for treating tumors that are human papillomavirus (HPV) positive or that have a high tumor mutational burden (TMB). The immunostimulatory bacteria and oncolytic viruses encode therapeutic products such RNAi, such as shRNA and microRNA, that mediate gene disruption and/or inhibit expression of TREX1, or that inhibit TREX1. The bacteria contain additional modifications to enhance their anti-tumor activity. The bacteria and viruses are used for treatment of tumors in which TREX1 expression correlates with the presence of the tumor or properties of the tumor, such that inhibition of TREX1 advantageously treats the tumor.