Target site blockers and their use in enhancing Arginase 2 in macrophages to maintain macrophages in an anti-inflammatory and tissue repair phenotype are disclosed herein. Further disclosed are compositions and the use of the compositions for the treatment and/or prophylaxis of diseases mediated by macrophages such as inflammatory diseases, autoimmune diseases, neurological diseases or reparative diseases.

The invention disclosed herein provides methods and materials useful in gene therapy regimens designed to inhibit myelination abnormalities that occur in the urea cycle disorder arginase deficiency. The underlying cause of the progressive neurological dysfunction that occurs in this disorder has been previously unknown and conventional therapies, at best, only slow the onset of neurological dysfunction. This neurological dysfunction results at least in part from the dysmyelination that occurs in the central nervous system due to the lack of adequate hepatic expression of arginase 1. We have discovered an origin of this neurological dysfunction and, using this information, designed materials and associated methods of gene therapy. The methods and materials disclosed herein can inhibit and essentially prevent neurological dysfunction in a murine model of arginase deficiency.

The present disclosure provides a carrier protein for improving properties of a bioactive protein. The carrier protein has a G-X-Y ternary repetitive structure, G is glycine, and X and Y are independently selected from proline, alanine and glutamic acid. The present disclosure further provides a fusion protein containing the carrier protein and the bioactive protein. The fusion protein of the present disclosure has improved biological properties, such as improved pharmacokinetic and physicochemical properties.

The present invention concerns a method for treating cancer, including haematological and solid tumors. In an embodiment, the method comprises impairing arginase activity and/or expression in immune cells, in particular T cells of a patient suffering from cancer. Arginase expression may be impaired by mutation (including deletion or truncation) of the arginase encoding gene, by RNA interference or by administration of an arginase inhibitor. In a preferred embodiment, the T cells are modified in the frame of CAR (Chimeric Antigen Receptor) therapy. The invention also provides a method of treatment combining impaired arginase activity with antibody-mediated blockage of negative immune checkpoint regulators (PDLL-PD1 and B7-CTLA4 inhibitory pathways).

Compositions and methods for the preparation of high purity arginase and high efficiency preparation of monosubstituted polyethylene glycol conjugation of arginase are provided, as are methods for using arginase in combination with asparaginase to inhibit cancer cells. High purity arginase is provided by applying an initial high temperature precipitation step, followed by ion exchange to provide arginase at a purity of 90% or greater. Conjugation with either linear or branched polyethylene glycol is performed using a maleimide-derivatized polyethylene glycol at low molar excess relative to arginase and at reduced temperature. Such polyethylene glycol-derivatized arginase is useful in combination with asparaginase in inhibiting the growth of cancer cells, particularly cells that have low endogenous asparaginase expression.

Described are methods for producing recombinant Arginase, such as PEGylated, cobalt-substituted recombinant human Arginase 1. Also described are pharmaceutical compositions comprising such recombinant Arginase, as well as methods of treatment and uses of such recombinant Arginase.

Compositions and methods for the treatment of cancer are described, and, more preferably, to the treatment of cancers that do not express, or are otherwise deficient in, argininosuccinate synthetase, with enzymes that deplete L-Arginine in serum. In one embodiment, the present invention contemplates an arginase protein, such as a human Arginase I protein, comprising at least one amino acid substitution and a metal cofactor, said protein comprising an increased catalytic activity when compared with a native human Arginase I.

The present invention relates to immunogenic polypeptide fragments of a human Arginase protein. The fragments are in particular useful for the treatment or prevention of cancer.

The present disclosure provides methods for inducing intermittent fasting and modulating autophagy in cells or organs in a subject via periodic administration of arginine-depleting agents. Induction of intermittent fasting and modulation of autophagy are useful in preventing and/or treating diseases, including those associated with deficits in autophagy, promoting the clearance of intracellular pathogens and protein aggregates, and promoting regeneration and longevity. The methods can be used alone or in combination with other agents to enhance intermittent fasting and autophagy activity to potentiate the health benefit(s).

Described herein are methods and compositions relating to methods of inhibiting neutrophils, e.g., inhibiting NET release or NETosis, by means of a DEspR inhibitor, e.g., an anti-DEspR antibody reagent. In some embodiments, the methods can relate to the treatment of a disease, e.g., cancer or a disease wherein neutrophils; NETs; or NETosing or NETting neutrophils contribute to pathogenesis, chronicity, or worsening of disease. In some embodiments, the DEspR inhibitor can be a bi-specific reagent or an antibody-drug conjugate.