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BOULDER, CO, United States

Bolder Biotechnology, Inc. | Date: 2010-09-29

The present invention relates to novel methods for making and refolding insoluble or aggregated proteins having free cysteines in which a host cell expressing the protein is exposed to a cysteine blocking agent. The soluble, refolded proteins produced by the novel methods can then be modified to increase their effectiveness. Such modifications include attaching a PEG moiety to form PEGylated proteins.

Bolder Biotechnology, Inc. | Date: 2013-11-25

Disclosed is a method for refolding a protein or peptide that does not contain essential disulfides and that contains at least one free cysteine residue. Also disclosed are polymer IFN- conjugates that have been created by the chemical coupling of polymers such as polyethylene glycol moieties to IFN-, particularly via a free cysteine in the protein. Also disclosed are analogs of bioactive peptides that may be used to create longer acting versions of the peptides, including analogs of glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, Gastric inhibitory peptide (GIP), PYY, exendin, ghrelin, gastrin, amylin, and oxyntomodulin.

Bolder Biotechnology, Inc. | Date: 2010-05-10

The present invention relates to novel methods for making fusion proteins comprising a cytokine or growth factor fused to an immunoglobulin domain. The growth factor/cytokine can be fused directly to an immunoglobulin domain or through a peptide linker. The purified growth factor/cytokine-IgG fusion proteins produced by the novel methods are biologically active and can be used to treat diseases for which the non-fused growth factor/cytokine are useful.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.24M | Year: 2009

DESCRIPTION (provided by applicant): Anemia is a frequent finding in patients with chronic kidney disease (CKD) and is present in over 90% of CKD patients with end-stage renal disease. Anemia typically results from inability of the diseased kidney to produce erythropoietin (EPO), which stimulates production of red blood cells. Anemia leads to fatigue, a decreased quality of life and correlates with increased mortality in CKD patients. Recombinant EPO is effective at reversing anemia in about 90% of CKD patients. Recombinant EPO products had worldwide sales of 11.6 billion in 2006 and are the single most expensive renal disease medicine in terms of total product sales. EPO has a short circulating half- life and generally is administered to patients two to three times per week. Bolder BioTechnology has created a highly potent, long-acting EPO analog that has a significantly increased circulating half-life and superior efficacy in animal erythropoiesis models compared to EPO. Based upon animal studies we anticipate that our long-acting EPO analog will be effective when administered once every 4-8 weeks in humans. The improved in vivo characteristics of this novel EPO analog will reduce the need for frequent injections, improve patient quality of life and potentially lead to improved therapeutic efficacy. Our long-acting EPO analog has the potential to significantly reduce healthcare costs by reducing the amount of drug required by patients, by reducing costs associated with patient visits to treatment centers and by reducing healthcare worker time associated with providing treatments. Because of its unique structure, manufacturing costs for our long-acting EPO analog are anticipated to be significantly less than for other EPO products. The goal of this proposal is to develop this long-acting EPO analog for the treatment of anemia associated with CKD. During Phase I of this proposal, we optimized the manufacturing process and developed and validated supporting assay methods to produce material for GLP (Good Laboratory Practices) pharmacology and toxicology studies. During Phase I we also designed clinical protocols for Phase 1 safety and Phase 2 dose ranging efficacy studies in humans. The main goal of the Phase II SBIR proposal is to complete the animal toxicology and pharmacology studies required by the FDA prior to testing this product in humans. Successful development of our long-acting EPO analog will provide CKD patients with a longer-acting, significantly less expensive alternative for the effective management of anemia. PUBLIC HEALTH RELEVANCE: Recombinant erythropoietin (EPO) is widely used to ameliorate anemia in patients with chronic kidney disease, which affects 20- 40 million people in the United States. EPO typically is administered to patients by twice weekly or thrice weekly injections due to its short half-life in people. We created longer acting and more potent EPO analogs that may potentially reduce the amount of EPO required per patient, improve patient safety, compliance and quality of life, and result in considerable cost savings to patients and healthcare providers. The goals of this Phase II grant proposal are to manufacture the protein under GLP (Good Laboratory Practices) conditions and measure the safety profile and pharmacokinetic properties of the protein in animal pharmacology and toxicology studies, which are required by the FDA prior to testing the compound in humans.

Bolder Biotechnology, Inc. | Date: 2010-09-21

The growth hormone supergene family comprises greater than 20 structurally related cytokines and growth factors. A general method is provided for creating site-specific, biologically active conjugates of these proteins. The method involves adding cysteine residues to non-essential regions of the proteins or substituting cysteine residues for non-essential amino acids in the proteins using site-directed mutagenesis and then covalently coupling a cysteine-reactive polymer or other type of cysteine-reactive moiety to the proteins via the added cysteine residue. Disclosed herein are preferred sites for adding cysteine residues or introducing cysteine substitutions into the proteins, and the proteins and protein derivatives produced thereby. Also disclosed are therapeutic methods for using the cysteine variants of the invention.

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