Abstract: The present invention relates to a pharmaceutical formulation comprising insulin, an insulin analogue or an insulin derivate and ethylenediamine or salts thereof and an antimicrobial preservative agent.

Abstract: IGF-I variants having an alanine, glycine, or serine amino acid residue at position 16, 25, 49 or at positions 3 and 49 of native-sequence IGF-I are provided that are useful to treat a disorder characterized by dysregulation of the GH/IGF axis in a mammal, such as a renal disorder.

Abstract: The present invention provides a method for preparing a site-specific physiologically active polypeptide conjugate in a high yield by treating a physiologically active polypeptide with a non-peptidyl polymer in the presence of an alcohol at a specific pH, which can be desirably employed in the development of long acting formulations of various peptide drugs having high in-vivo activity and markedly prolonged in-blood half-life.

Abstract: A method for treating an rheumatoid arthritis in a mammalian subject in need of same wherein the method comprises: administering to the mammalian subject an agent capable of modulating a ganglioside GM-1 associated activity in an amount effective to treat the disease.

Abstract: PEGylated, extended insulins are insulins which, compared with human insulin, has one or more extensions extended from the A1, B1, A21 and/or B30 position(s), said extension(s) consist(s) of amino acid residue(s) and wherein a PEG moiety, via a linker, is attached to one or more of the amino acid residues in the extension(s). PEG is polyethyleneglycol. Such PEGylated, extended insulins have higher bioavailability and a longer time-action profile than regular insulin and are in particular suited for pulmonary administration and can, conveniently, be used to treat diabetes.

Abstract: The present invention relates to a cell line selected from the group consisting of (a) a cell line denominated NM-F9 having the DSMZ accession number DSM ACC2606; (b) a cell line denominated NM-D4 having the DSMZ accession number DSM ACC2605; and subclones of (a) or (b). Additionally, the present invention provides a lysate of the cell lines or a molecule or mixture of molecules obtained from these cell lines as well as dendritic cells loaded with said lysate, co-cultivated or fused with cells from the cell lines, or a molecule or mixture of molecules obtained from these cell lines of the present invention. Moreover compositions, preferably pharmaceutical or vaccine compositions are provided which comprise the cell lines, lysate, molecules, mixture of molecules or dendritic cells of the present invention. In another aspect the present invention relates to methods for producing the aforementioned compositions.

Abstract: An injectable formulation containing a rapid acting insulin and a long acting insulin has been developed. The pH of the rapid acting insulin is adjusted so that the long acting insulin, remains soluble when they are mixed together. Preferably, the formulation is administered before breakfast, provides adequate bolus insulin levels to cover the meal and basal insulin for up to 24 hours, and does not produce hypoglycemia after the meal. Lunch and dinner can be covered by two bolus injections of a fast, rapid, or very rapid acting insulin. Alternatively, by adjusting the ratio of rapid to long acting insulin, the long acting insulin may be shortened to a 12 hour formulation, and re-administered to the patient at dinner time, providing a safe and effective basal insulin level until morning. As a result, a patient using intensive insulin therapy should only inject three times a day.

Abstract: A method for increasing intestinal function is provided. The method comprising orally and/or enterally administering to a subject in need thereof a therapeutically effective amount of insulin, thereby increasing intestinal function.

Abstract: Conjugates which comprise a drug and a ligand which includes a first saccharide; wherein the conjugate is characterized in that, when the conjugate is administered to a mammal, at least one pharmacokinetic or pharmacodynamic property of the conjugate is sensitive to serum concentration of a second saccharide. Exemplary conjugates and sustained release formulations are provided in addition to methods of use and preparation.

Abstract: Insulin analogues wherein the B25 amino acid residue is His or Asn with the proviso that if the B25 amino acid residue is His, then the B27 amino acid residue is Asp or Glu and the A14 amino acid residue is different from Glu, have liver preferential actions.

Abstract: The present invention relates to insulin derivatives having a side chain attached either to the -amino group of the N-terminal amino acid residue of the B chain or to the amino group of a Lys residue present in the B chain of the parent insulin via an amide bond which side chain comprises at least one aromatic group; at least one free carboxylic acid group or a group which is negatively charged at neutral pH, a fatty acid moiety with 4 to 22 carbon atoms in the carbon chain; and possible linkers which link the individual components in the side chain together via amide bonds.

Abstract: The present invention discloses a method for targeting maytansinoids to a selected cell population, the method comprising contacting a cell population or tissue suspected of containing the selected cell population with a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is covalently linked to the cell-binding agent via a non-cleavable linker and the cell-binding agent binds to cells of the selected cell population.

Abstract: In one aspect, the disclosure provides cross-linked materials that include multivalent polynucleotide aptamers that bind a target molecule; and conjugates that include two or more separate affinity ligands bound to a conjugate framework, wherein the two or more affinity ligands compete with the target molecule for binding with the aptamers and wherein conjugates are cross-linked within the material as a result of non-covalent interactions between aptamers and affinity ligands on different conjugates. These materials are designed to release amounts of conjugate in response to desired concentrations of the target molecule. Depending on the end application, in various embodiments, the conjugates may also include a drug and/or a detectable label. The drug, detectable label and affinity ligands may be covalently or non-covalently bound to the conjugate framework.

Abstract: The present disclosure provides crystalline insulin-conjugates. The present disclosure also provides formulations, methods of treatment, methods of administering, and methods of making that encompass these crystalline insulin-conjugates.

Abstract: A new and improved method for extending the half life of pharmaceutical compounds for use in diagnostic imaging or therapy uses a novel linker to attach a diagnostic or therapeutic moiety to a targeting peptide or another diagnostic or therapeutic moiety. The resulting compound may have the general formula M-N—O—P-Q, wherein M is the diagnostic or therapeutic moiety, N—O—P is the linker of the present invention, and Q is the targeting peptide. In another embodiment the compounds may have the formula M-N—O—P-M, wherein M is independently a diagnostic or therapeutic moiety and N—O—P is the linker of the invention. Methods for imaging or treating a patient using the compounds of the invention are also provided. Methods and kits for preparing a diagnostic imaging agent from the compound are further provided. Methods for radiotherapy of a patient using the compounds are further provided, as are methods for preparing a radiotherapeutic agent from the compounds.

Abstract: The invention claims a process for making an insulin-oligomer conjugate IN-105. IN-105 precursor having formula G-A-V-R-[B-Chain]-R-D-A-D-D-R-[A-Chain] is cloned and expressed in Pichia. The biosynthetic precursor is then conjugated with an activated oligomer. The IN-105 precursor-oligomer conjugate is then treated with protease and purified to afford active insulin-oligomer conjugate of formula insulin-OC—CH2—CH2—(OCH2CH2)3—OCH3.

Abstract: The present disclosure provides a cross-linked material comprising conjugates which include two or more separate affinity ligands bound to a non-polymeric framework, wherein the molecular weight of the non-polymeric framework is less than 10,000 Da; and multivalent cross-linking agents that non-covalently bind the affinity ligands of the conjugates and thereby cross-link the conjugates to form a cross-linked material, wherein the non-covalent bonds between the multivalent cross-linking agents and the affinity ligands are competitively dissociated in the presence of excess amounts of a target molecule. The present disclosure also provides methods of making and methods of using these materials. In other aspects, the present disclosure provides exemplary conjugates including conjugates for use in glucose responsive cross-linked materials.

Abstract: The invention relates to insulin glargine which is modified by amidation, especially Gly(A21), Arg(B31), Arg amide (B32) human insulin (insulin glargine amide).

Abstract: Prodrug formulations of insulin and insulin analogs are provided wherein the insulin peptide has been modified by an amide bond linkage of a dipeptide prodrug element. The prodrugs disclosed herein have extended half lives of at least 10 hours, and more typically greater than 2 hours, 20 hours and less than 70 hours, and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Abstract: Full potency analogs of insulin are provided wherein the analog comprises a modification of the tyrosine residue at position 19 of the A chain.

Abstract: Methods are provided for drying a particle. Specifically, there is provided a spray-dried diketopiperazine-insulin particle formulation having improved aerodynamic performance and in which the active agent is more stabile and efficiently delivered as compared to that of the lyophilized diketopiperazine-insulin formulation. The dry powders have utility as pharmaceutical formulations for pulmonary delivery.

Abstract: A method is provided for producing hIGF-I with high purity and yield. This is a method for producing human insulin-like growth factor I, having a step of removing modified human insulin-like growth factor I from the human insulin-like growth factor I, the step including: (A) a step of adjusting the pH of a culture liquid of a human insulin-like growth factor I producing bacteria to 8 or more after completion of culture; (B) a step of letting the culture liquid obtained in step (A) stand; and (C) a step of removing the producing bacteria from the culture liquid obtained in step (B).

Abstract: The present invention relates to human insulin analogues having a fast onset of action. These analogues may have amino acid in position B26 substituted with Phe, or be Des(B30) analogues of human insulin. The invention also relates to compositions comprising such insulin analogues, and to compositions comprising a mixture of an insulin analogue having a fast onset of action and insulin having a protracted action.

Abstract: Insulin-like growth factor analogs are disclosed wherein substitution of the IGF native amino acids, at positions corresponding to positions B16 and B17 of native insulin, with tyrosine and leucine, respectively, increases potency of the resulting analog at the insulin receptor by tenfold. Also disclosed are prodrug and depot formulations of the IGF analogs, wherein the IGF analog has been modified by the linkage of a dipeptide to the analog through an amide bond linkage. The prodrug and depot formulations disclosed herein have extended half lives of at least 2 hours, 10 hours, and more typically greater than 2 are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Abstract: The invention relates to methods of separation and/or purification of impurities yielding a purified heterologous protein product devoid of related impurities or with substantially minimal quantities of such glycosylated impurities. More specifically, the invention relates to the identification of glycosylated forms of insulin analogues such as glargine impurities characterized post expression in yeast based systems such as Pichia pastoris. The invention also relates to methods used to clone gene encoding the protein insulin glargine; inserting the related gene in a suitable yeast host; producing culture of the recombinant strain, stimulating expression of the heterologous polypeptide, its secretion and purification post fermentation and related enzymatic conversions.

Abstract: We disclose insulin fusion polypeptides and dimers; nucleic acid molecules encoding said polypeptides and methods of treatment that use said polypeptides/dimers.

Abstract: The present invention relates to an insulin derivative for the treatment of a condition or disease where administration of insulin will be of benefit, comprising administering, to a patient in need thereof, effective dosages of the insulin derivative, wherein said insulin derivative exhibits a prolonged profile of action and wherein said dosages are administered at intervals longer than 24 hours.

Abstract: High-specificity antibodies can distinguish between modified (e.g, hIGF-1/Ea 3mut) and endogenous wild-type human IGF-1 proteins. These antibodies have little or no cross-reactivity with hIGF-1 or hIGF-2. They also have little or no cross-reactivity with rodent IGF-1 or IGF-2. The antibodies can be used in pharmacokinetic (PK)/pharamcodynamic (PD) assessments of IGF-1/E peptides that have been administered to humans or animals. A sandwich ELISA assay, using the antibody of the invention as a capture antibody, can quantify the mutant IGF-1/E proteins in samples.

Abstract: The invention describes compositions of peptide analogs that are active in blood or cleavable in blood to release an active peptide. The peptide analogs have a general formula: A-(Cm)x-Peptide (SEQ ID NO: 76), wherein A is hydrophobic moiety or a metal binding moiety, e.g., a chemical group or moiety containing 1) an alkyl group having 6 to 36 carbon units, 2) a nitrilotriacetic acid group, 3) an imidodiacetic acid group, or 4) a moiety of formula (ZyHisw)p (SEQ ID NO: 50), wherein Z is any amino acid residue other than histidine, His is histidine, y is an integer from 0-6; w is an integer from 1-6; and p is an integer from 1-6; wherein if A has alkyl group with 6 to 36 carbon units x is greater than 0; and Cm is a cleavable moiety consisting of glycine or alanine or lysine or arginine or N-Arginine or N-lysine, wherein x is an integer between 0-6 and N may be any amino acid or none. The peptide analogs are complexed with polymeric carrier to provide enhanced half-life.

Abstract: A method treating a mammal by administering a physiologically effective amount of an insulin analogue or a physiologically acceptable salt thereof where the insulin analogue displays more than twofold greater binding affinity to insulin receptor isoform A (IR-A) than insulin receptor isoform B (IR-B). The insulin analogue may be a single-chain insulin analogue or a physiologically acceptable salt thereof, containing an insulin A-chain sequence or an analogue thereof and an insulin B-chain sequence or an analogue thereof connected by a polypeptide of 4-13 amino acids. A single-chain insulin analogue may display greater in vitro insulin receptor binding to IR-A but lower binding to IR-B than normal insulin while displaying less than or equal binding to IGFR than normal insulin.

Abstract: Using the Sup35 prion proteins of two distantly related yeast species, it is established that prion replication is initiated by small elements of primary sequence, which can be identified using arrays of short peptides. Subtle differences in replication elements govern the formation of distinct aggregate conformations (prion strains) and also determine their species-specific seeding activities. A Sup35 chimera that promiscuously forms prions in more than one species does so by virtue of carrying the replication element of each species. Mutations or conditions that cause the chimera to assemble into distinct prion strains favor recognition of distinct replication elements. Therefore, subtle differences in small sequences that constitute prion replication elements encode important determinants of prion propagation and transmission.

Abstract: The application relates to a composition comprising a hyperbranched polymer attached to a core and a biologically active moiety. The biologically active moiety is attached to the core by means of a substantially non-enzymatically cleavable linker L. The composition can be used to deliver the biologically active moiety to its target.

Abstract: Provided herein are water-soluble carbohydrate polymers which are monoderivatized at their reducing terminus, such that the carbohydrate polymers can be selectively conjugated at a single location. Also provided are methods of preparation and conjugation of the monoderivatized carbohydrate polymers.

Abstract: The invention relates to novel insulin analogs having a basal time-action profile, which are characterized by the addition and/or substitution of negatively and positively charged amino acid residues and by an amidation of the C-terminal carboxy group of the B chain and histidine in position 8 of the insulin A chain. The invention also relates to the production and use thereof.

Abstract: The present invention discloses a process for making an insulin-oligomer conjugate as a one-pot reaction by conjugation of insulin-ester with an activated oligomer wherein simultaneous deblocking and conjugation is carried out.

Abstract: An insulin analogue comprises a B-chain polypeptide incorporating a halogenated phenylalanine at position B24, B25 or B26. The halogenated phenylalanine may be ortho-monofluoro-phenylalanine, ortho-monobromo-phenylalanine, ortho-monochloro-phenylalanine, or para-monochloro-phenylalanine. The analogue may be of a mammalian insulin, such as human insulin. A nucleic acid encodes such an insulin analogue. The halogenated insulin analogues retain significant activity. A method of treating a patient comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient. Halogen substitution-based stabilization of insulin may enhance the treatment of diabetes mellitus in regions of the developing world lacking refrigeration.

Abstract: The invention provides peptides that are chemically modified by covalent attachment of a water-soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the characteristics of the peptide not attached to the water-soluble oligomer.

Abstract: The invention provides processes for preparing a cell-binding agent chemically coupled to a drug. A first process comprises covalently attaching a linker to a cell-binding agent, an optional purification step, conjugating a drug to the cell-binding agent, a subsequent purification step, and optional holding steps. A second process comprises covalently attaching a linker to a cell-binding agent, a purification step, conjugating a drug to the cell-binding agent, a subsequent purification step, holding steps, and optionally a tangential flow filtration (TFF) step.

Abstract: This disclosure provides peptides, polypeptides, fusion polypeptides, compositions, and methods for enhancing or increasing the stability of a polypeptide (e.g., Taq polymerase). Such peptides, polypeptides, fusion polypeptides, or compositions include polypeptides linked to a peptide tag that enhances the stability of the polypeptide. The peptides, polypeptides, fusion polypeptides, compositions may also enhance the activity, specificity, and/or fidelity of other polypeptides in a reaction mixture. The disclosure also provides methods of using such peptides, polypeptides, fusion polypeptides, compositions.

Abstract: Brown adipose tissue (“BAT”) progenitor cells and methods for identifying BAT progenitor cells in a population of cells are provided. Methods are also provided for inducing differentiation of BAT progenitor cells into differentiated brown adipocytes, inducing expression or increased activity levels of BAT uncoupling protein-1 (“UCP1”), and for identifying agents capable of inducing differentiation of BAT progenitor cells into brown adipocytes and/or inducing expression or increased activity levels of UCP1. Differentiated brown adipocytes and agents and methods for inducing differentiation of BAT progenitor cells can be used for treatment of or the making of medicaments for the treatment of metabolic diseases or conditions in a patient such as obesity, overweight, impaired glucose tolerance, insulin-resistance, type 2 diabetes, dyslipidemia, hypertension, cardiovascular diseases, metabolic syndrome, and the like.

Abstract: The present invention relates to a polymer comprising a cholane core having at least one derivatizable group covalently bonded thereto and a hydrophilic polymer chain covalently bonded to derivatizable group(s) and a process for producing it The present invention also relates to micellar aggregate formed from the polymer of the present.

Abstract: New biosynthetic analogues of recombined human insulin of prolonged therapeutical activity, which can find place in prophylactic and treatment of diabetes.

Abstract: An insulin compound coupled to a modifying moiety having a formula: —X—R1—Y—PAG-Z—R2??(Formula VI) where, X, Y and Z are independently selected linking groups and each is optionally present, and X, when present, is coupled to the insulin compound by a covalent bond, either R1 or R2 is a lower alkyl, optionally including a carbonyl group, and when R1 is a lower alkyl, R2 is a capping group, and PAG is a linear or branched carbon chain incorporating one or more alkalene glycol moieties, and optionally incorporating one or more additional moieties selected from the group consisting of —S—, —O—, —N—, and —C(O)—.

Abstract: The present invention relates to processes for the production of peptides, and the peptides produced accordingly. Peptides produced according to the invention may be produced more efficiently than peptides produced according to prior art processes. The production process of the invention may lead to advantages in yield, purity, and/or price. Methods of marketing peptides are also disclosed.

Abstract: Reactors, reactor systems and methods for producing particles in a precipitation process are provided. The reactor includes a housing defining a reaction chamber, a stator assembly including two or more stators, a rotor assembly including two or more rotors, the rotor assembly configured for rotation about an axis of rotation relative to the stator assembly, a first inlet to supply a first reactant material to the reaction chamber at a first radial location, a second inlet to supply a second reactant material to the reaction chamber at a second radial location different from the first radial location, wherein the first and second reactant materials react to produce precipitation of particles in the reaction chamber, and an outlet to supply the particles formed in the reaction chamber.

Abstract: Novel acylated insulin analogues exhibiting resistance towards proteases can, effectively, be administered pulmonary or orally. The insulin analogues contain B25H and A14E or A14H.

Abstract: A method of preparing an oxidised polysaccharide-protein conjugate by oxidising a polysaccharide with an oxidising agent to form an oxidised polysaccharide and combining such oxidized polysaccharide with a protein. The oxidised polysaccharide is reacted with a protein to form a composition comprising a conjugate wherein the oxidised polysaccharide and the protein are conjugated via one or more imine bonds and wherein the oxidised polysaccharide comprises essentially no alpha-hydroxy aldehyde units. The conjugate may be used to provide sustained or latent activity of the protein.

Abstract: The present invention relates to the field of diabetes. More particularly, the invention relates to PEGylated insulin lispro compounds that are PEGylated with high molecular weight poly(ethylene glycol), are highly soluble at physiological pH, have an extended duration of action, and characterized by pharmacokinetic, pharmacodynamic, and/or activity peak-trough ratios of less than 2. The invention also relates to methods of providing such molecules, to pharmaceutical compositions containing them, and to their therapeutic uses.

Abstract: An acylated insulin analogue wherein the insulin analogue comprises a lysine residue connected C-terminally to the A21 amino acid residue or a peptide residue of up to 4 amino acid residues comprising a lysine residue which peptide residue is connected C-terminally to the A21 amino acid residue, characterized in that an acyl moiety comprising an alkylene glycol moiety is attached to the lysine residue in the A22 position or attached to a lysine residue present in the peptide residue that is attached to the C terminal end of the A21 amino acid residue and wherein there is only one lysine (K, Lys) in the insulin analogue, can conveniently be administered pulmonary.

Abstract: Acylated insulins wherein an acyl moiety is attached to the parent insulin and wherein said acyl moiety comprises repeating units of alkylene glycol containing amino acids and wherein there is only one lysine residue (K & Lys) in the parent insulin have satisfactory properties when administered pulmonary.