The present invention relates to compositions and methods for improving the safety of blood-brain barrier receptor-mediated blood-brain barrier transport.

The present invention provides novel pharmaceutical compositions comprising -(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine and methods of using the same for the treatment of Congenital adrenal hyperplasia (CAH).

The present invention provides novel pharmaceutical compositions comprising -(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine and methods of using the same for the treatment of Congenital adrenal hyperplasia (CAH).

A polypeptide containing an antibody Fc region variant which has an amino acid sequence in which an amino acid alteration at position 238 according to EU numbering is combined with other specific amino acid alteration(s), was found to have decreased binding activities to all activating FcγRs, in particular FcγRIIa (R type), while maintaining its FcγRIIb-binding activity, when compared to a polypeptide containing a native IgG Fc region.

The present invention is directed to selected anti-PD-1 antibodies capable of binding to both cynomolgus monkey PD-1 and to human PD-1 : PD-1 mAb 1, PD-1 mAb 2, PD-1 mAb 3, PD-1 mAb 4, PD-1 mA.b 5, PD-1 mA.b 6, PD-1 mAb 7, PD-1 mAb 8, PD-1 mAb 9, PD-1 mAb 10, PD-1 mAb 11, PD-1 mAb 12, PD-1 mAb 13, PD-1 mAb 14, or PD-1 mAb 15, and to humanized and chimeric versions of such antibodies. The invention additionally pertains to PD-1 -binding molecules that comprise PD-1 binding fragments of such anti-PD-1 antibodies, immunocongugates, and to bispecific molecules, including diabodies, BiTEs, bispecific antibodies, etc., that comprise (i) such PD-1 -binding fragments, and (ii) a domain capable of binding an epitope of a molecule involved in regulating an immune check point present on the surface of an immune cells. The present invention also pertains to methods of using molecules that bind PD-1 for stimulating immune responses, as well as methods of detecting PD-1.

Methods for treating and differential diagnosis between ACTH-Dependent and ACTH-Independent Cushing's syndrome are disclosed, in which a glucocorticoid receptor antagonist (GRA) is administered to a Cushing's syndrome patient with a basal ACTH level less than about 25 pg/mL. If i) the patients blood ACTH and ii) the patients blood cortisol, or adrenal hormone, or adrenal pre-hormone levels rise, or if the ACTH:cortisol ratio increases, then ACTH-Dependent Cushing's syndrome is diagnosed. If those levels do not rise, or if the ACTH:cortisol ratio decreases, then ACTH-Independent Cushing's syndrome is diagnosed. In some instances, the patient is recovering from surgery to remove an ACTH secreting tumor, and the method described herein is used to determine if the tumor resection was successful or complete. The GRA may be mifepristone, or a non-steroidal GRA having a heteroaryl-ketone fused azadecalin backbone, an octahydro fused azadecalin backbone, a cyclohexyl pyrimidine backbone, or a fused azadecalin backbone.

Methods and uses are disclosed for treating a subject suffering from a disorder selected from a liver disorder, Cushing's syndrome, or Cushing's Disease, cancer, an infection, an inflammatory condition, a cardiovascular, endocrine, or kidney disease, and combinations thereof, or other disorder for which they may be administered a drug which may cause liver toxicity, without adverse effects on the liver. Such liver disorders include fatty liver diseases are effective for reducing high levels of liver enzymes with a favorable safety profile. The methods and uses comprise administering to the subject an effective amount of a selective nonsteroidal glucocorticoid receptor modulator such as relacorilant, including methods and uses in combination with another drug, without adverse effects on liver enzyme levels, or on liver function. In embodiments, the other drug may be a drug that may cause liver toxicity, such as drugs that inhibit CYP3A enzymes, e.g., itraconazole or ketoconazole.

Methods and uses are disclosed for treating a subject suffering from a disorder selected from a liver disorder, Cushing's syndrome, or Cushing's Disease, cancer, an infection, an inflammatory condition, a cardiovascular, endocrine, or kidney disease, and combinations thereof, or other disorder for which they may be administered a drug which may cause liver toxicity, without adverse effects on the liver. Such liver disorders include fatty liver diseases are effective for reducing high levels of liver enzymes with a favorable safety profile. The methods and uses comprise administering to the subject an effective amount of a selective nonsteroidal glucocorticoid receptor modulator such as relacorilant, including methods and uses in combination with another drug, without adverse effects on liver enzyme levels, or on liver function. In embodiments, the other drug may be a drug that may cause liver toxicity, such as drugs that inhibit CYP3A enzymes, e.g., itraconazole or ketoconazole.

The present disclosure relates to methods for increasing telomere length in one or more human cells and/or increasing genome stability of one or more human cells, for example by contacting one or more human cells with an agent that increases expression of Zscan4 in the one or more human cells. Methods of treating a subject in need of telomere lengthening, treating a disease or condition associated with a genomic and/or chromosome abnormality, of rejuvenating one or more human cells, of rejuvenating tissues or organs, and of rejuvenating a subject in need thereof, for example by contacting one or more human cells in the subject with an agent that increases expression of Zscan4, or by administering to a subject in need thereof, an agent that increases expression of Zscan4 are also provided.

The invention provides a method of treating T-cell mediated diseases and a method of inhibiting the activation of T-cells using certain diketopiperazines. The invention also provides methods of synthesizing diketopiperazines and pharmaceutical compositions comprising certain diketopiperazines. The invention further provides methods of making improved pharmaceutical compositions of proteins and peptides by either increasing or decreasing the content of diketopiperazines in the compositions and the resultant improved pharmaceutical compositions.