Abstract: The present invention relates to a composition comprising a population of polysaccharide derivatives of a protein, wherein the protein is insulin or an insulin-like protein and the polysaccharide is anionic and comprises between 2 and 125 saccharide units, and wherein the population consists of substantially only N-terminal derivatives of the protein. Typically, the polysaccharide is PSA. The present invention also relates to pharmaceutical compositions comprising the novel compounds, and methods for making the novel compounds.

Abstract: Novel proteins and compounds conjugated with polysialic acid (PSA) are provided herein. Also provided are methods of using these compounds and methods of treatment of various diseases and disorders. The novel compounds provided herein have improved pharmacodynamic and/or pharmacokinetic properties, improved effectiveness, and other desirable properties.

Abstract: A composition comprising a population of polysaccharide-blinatumomab conjugates, wherein the polysaccharide is covalently linked to the blinatumomab. A method of increasing the efficacy of a therapeutic agent in the treatment of B-cell precursor acute lymphoblastic leukemia (ALL), wherein the therapeutic agent is a PSA-drug conjugate, wherein the conjugate comprises PSA covalently linked to blinatumomab, and wherein the PSA of the conjugate binds to DNA and histones of NET extracellular fibrils.

Abstract: The present invention demonstrates that erythropoietin (EPO)-receptor (EPOR) is a malignant myeloma biomarker of sensitivity to EPO treatment and, itself a target for myeloma treatment. A low EPOR level in a myeloma cells of the subject indicates non-response to EPO treatment. Patients having high EPOR level in myeloma cells can be effectively treated with EPO, in particular an EPO derivatized with polysialic acid.

Abstract: The present invention provides conjugates of deoxyribonuclease enzymes with water soluble polymers such as PSA having improved pharmacokinetic attributes. These modifications provide unexpectedly high levels of DNA hydrolytic activity in blood and other bodily tissues over the time due to markedly increased distribution phase and reduced clearance of DNase conjugates after delivery to blood circulation relative to the unconjugated compounds, while half-life and residence time of conjugates remains almost unchanged compared to the unconjugated DNase compounds. The compositions of the invention are used for parenteral treatment of diseases related to NET formation and the presence of extracellular DNA.

Abstract: A water soluble polymer, in particular polysialic acid (PSA) or a modified PSA (mPSA), is conjugated to an oxidized carbohydrate moiety of a glycoprotein other than a blood coagulation protein or to a ganglioside or drug delivery system by contacting the oxidized carbohydrate moiety with the water soluble polymer, wherein said water soluble polymer contains an aminooxy group and an oxime linkage is formed between the oxidized carbohydrate moiety and the aminooxy group on the water soluble polymer or wherein said water soluble polymer contains a hydrazide group and a hydrazone linkage is formed between the oxidized carbohydrate moiety and the hydrazide group on the water soluble polymer. Conjugates of aminooxy- or hydrazide-water soluble polymer, such as PSA and mPSA, are thus obtained in which the PSA or mPSA is attached via a carbohydrate moiety.

Abstract: The present invention demonstrates that erythropoietin (EPO)-receptor (EPOR) is a malignant myeloma biomarker of sensitivity to EPO treatment and, itself a target for myeloma treatment. A low EPOR level in a myeloma cells of the subject indicates non-response to EPO treatment. Patients having high EPOR level in myeloma cells can be effectively treated with EPO, in particular an EPO derivatized with polysialic acid.

Abstract: Polydisperse and charged polysaccharides are fractionated into low polydispersity fractions (preferably having pd<1.1), each containing species within a narrow range of molecular weights. An aqueous solution of the polydisperse polysaccharides is contacted with an ion exchange resin in a column and the polysaccharides are subjected to selective elution by aqueous elution buffer. The selective elution consists of at least 3 sequential elution buffers having different and constant ionic strength and/or pH and in which the subsequent buffers have ionic strength and/or pH than those of the preceding step. The new preparations are particularly suitable for the production of PSA-derivatised therapeutic agents intended for use in humans and animals.

Abstract: Derivatives are synthesized of starting materials, usually polysaccharides, having sialic acid at the reducing terminal end, in which the reducing terminal unit is transformed into an aldehyde group. Where the polysaccharide has a sialic acid unit at the non-reducing end it may be passivated, for instance by converting into hydroxyl-substituted moiety. The derivatives may be reacted with substrates, for instance containing amine or hydrazine groups, to form non-cross-linked polysialylated compounds. The substrates may, for instance, be therapeutically useful drugs peptides or proteins or drug delivery systems.

Abstract: The invention provides a method for treatment of primary progesterone receptor-negative (PR?) endometrial cancer comprising administering (i) cridanimod or a salt or an ester thereof and (ii) a progesterone receptor (PR) agonist. The invention further provides a method for treatment of a primary estrogen receptor-negative (ER?) breast cancer, comprising administering (i) cridanimod or a salt or an ester thereof and (ii) a selective estrogen receptor modulator (SERM) or a selective estrogen receptor down-regulator (SERD). Also provided are compositions related to the above methods.

Abstract: The present invention relates to a composition comprising a population of polysaccharide derivatives of a protein, wherein the protein is insulin or an insulin-like protein and the polysaccharide is anionic and comprises between 2 and 125 saccharide units, and wherein the population consists of substantially only N-terminal derivatives of the protein. Typically, the polysaccharide is PSA. The present invention also relates to pharmaceutical compositions comprising the novel compounds, and methods for making the novel compounds.

Abstract: The present invention relates to process for reducing the endotoxin content of a sample of fermentation broth containing polysialic acid and endotoxin comprising the sequential steps: (i) adding to the sample a base having a pKa of at least 12 to form a basic solution having a pH of at least 12, incubating the solution for a pre-determined time at a pre-determined temperature; and (ii) recovery of PSA, suitably by (iii) passing the sample through an anion-exchange column whereby polysialic acid is absorbed on the ion exchange resin; (iv) washing the column with one washing buffer, whereby polysialic acid remains absorbed on the ion exchange resin; and (v) eluting the polysialic acid from the column using an elution buffer to provide a product solution of polysialic acid having reduced endotoxin content.

Abstract: The present invention relates to a composition comprising a population of polysaccharide derivatives of a protein, wherein the protein is insulin or an insulin-like protein and the polysaccharide is anionic and comprises between 2 and 125 saccharide units, and wherein the population consists of substantially only N-terminal derivatives of the protein. Typically, the polysaccharide is PSA. The present invention also relates to pharmaceutical compositions comprising the novel compounds, and methods for making the novel compounds.

Abstract: The present invention provides conjugates of deoxyribonuclease enzymes with water soluble polymers such as PSA having improved pharmacokinetic attributes. These modifications provide unexpectedly high levels of DNA hydrolytic activity in blood and other bodily tissues over the time due to markedly increased distribution phase and reduced clearance of DNase conjugates after delivery to blood circulation relative to the unconjugated compounds, while half-life and residence time of conjugates remains almost unchanged compared to the unconjugated DNase compounds. The compositions of the invention are used for parenteral treatment of diseases related to NET formation and the presence of extracellular DNA.

Abstract: Derivatives of PSAs are synthesised, in which a reducing and/or non-reducing end terminal sialic acid unit is transformed into a N-hydroxysuccinimide (NHS) group. The derivatives may be reacted with substrates, for instance substrates containing amine or hydrazine groups, to form non-cross-linked/crosslinked polysialylated compounds. The substrates may, for instance, be therapeutically useful drugs, peptides or proteins or drug delivery systems.

Abstract: Derivatives of PSAs are synthesized, in which a reducing and/or non-reducing end terminal sialic acid unit is transformed into a N-hydroxysuccinimide (NHS) group. The derivatives may be reacted with substrates, for instance substrates containing amine or hydrazine groups, to form non-cross-linked/crosslinked polysialylated compounds. The substrates may, for instance, be therapeutically useful drugs, peptides or proteins or drug delivery systems.

Abstract: Polydisperse and charged polysaccharides are fractionated into low polydispersity fractions (preferably having pd 21 1.1), each containing species within a narrow range of molecular weights. An aqueous solution of the polydisperse polysaccharides is contacted with an ion exchange resin in a column and the polysaccharides are subjected to selective elution by aqueous elution buffer. The selective elution consists of at least 3 sequential elution buffers having different and constant ionic strength and/or pH and in which the subsequent buffers have ionic strength and/or pH than those of the preceding step. The new preparations are particularly suitable for the production of PSA-derivatised therapeutic agents intended for use in humans and animals.

Abstract: The present invention relates to a composition comprising a population of polysaccharide derivatives of a protein, wherein the protein is insulin or an insulin-like protein and the polysaccharide is anionic and comprises between 2 and 125 saccharide units, and wherein the population consists of substantially only N-terminal derivatives of the protein. Typically, the polysaccharide is PSA. The present invention also relates to pharmaceutical compositions comprising the novel compounds, and methods for making the novel compounds.

Abstract: A polysialic acid compound is reacted with a hetero-bifunctional reagent to introduce a pendant functional group for site-specific conjugation to sulfhydryl groups, for instance side chains of cysteine units in drugs, drug delivery systems, proteins or peptides. The functional group is, for instance, an N-maleimide group.

Abstract: Polydisperse and charged polysaccharides are fractionated into low polydispersity fractions (preferably having pd<1.1), each containing species within a narrow range of molecular weights. An aqueous solution of the polydisperse polysaccharides is contacted with an ion exchange resin in a column and the polysaccharides are subjected to selective elution by aqueous elution buffer. The selective elution consists of at least 3 sequential elution buffers having different and constant ionic strength and/or pH and in which the subsequent buffers have ionic strength and/or pH than those of the preceding step. The new preparations are particularly suitable for the production of PSA-derivatized therapeutic agents intended for use in humans and animals.