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Polymer conjugates of cytokines, chemokines, growth factors, polypeptide hormones and antagonists thereof with preserved receptor-binding activity

A technology of cytokines and growth factors, applied in the fields of protein biochemistry, pharmacy and medicine, which can solve problems such as large size and space obstacles

Inactive Publication Date: 2006-11-08
MOUNTAIN VIEW PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Without wishing to be bound by theory, the mechanism for such adverse PEGylation effects may involve steric hindrance of receptor interaction by bulky PEG groups, charge neutralization, or both

Method used

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  • Polymer conjugates of cytokines, chemokines, growth factors, polypeptide hormones and antagonists thereof with preserved receptor-binding activity
  • Polymer conjugates of cytokines, chemokines, growth factors, polypeptide hormones and antagonists thereof with preserved receptor-binding activity
  • Polymer conjugates of cytokines, chemokines, growth factors, polypeptide hormones and antagonists thereof with preserved receptor-binding activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] Example 1: PEG-interferon-alpha conjugates

[0171] Interferon-alpha is a commercially important medical protein with a global market of more than $2 billion in 2001, mainly used to treat patients infected with hepatitis C virus ("HCV"). In the United States, 3 to 4 million people are chronically infected with hepatitis C virus, and approximately 10,000 people die each year from HCV-related causes (Chander, G., et al., (2002) Hepatology 36:5135-5144). In an effort to improve the usefulness of interferon-alpha, the two main companies responsible for the development and marketing of interferon-alpha (Schering-Plough and F. Hoffmann-La Roche AG) ) has developed a conjugate of interferon-alpha with monomethoxypoly(ethylene glycol) or "mPEG" and has released this product commercially. In each case, mPEG was attached to each molecule of interferon-α at only one point of attachment. In each case, the product contained a mixture of positional isomers with significantly reduce...

Embodiment 2

[0176] Example 2: PEG-Interleukin-2 Conjugates

[0177] Interleukin-2 ("IL-2") is a cytokine that exhibits immunomodulatory activity against certain cancers, including renal cell carcinoma and malignant melanoma. However, clinical efficacy is poor, with the result that only a small fraction of patients experience partial or complete responses (Weinreich, D.M., et al., (2002) J Immunother 25:185-187). The short half-life of IL-2 in the bloodstream makes it slow to induce remission in cancer patients. Attempts to make IL-2 more useful by random pegylation of lysine residues have not been ideal (Chen, S.A., et al. (2000) J Pharmacol Exp Ther 293:248-259). Attempts to attach PEG selectively to glycosylation sites of IL-2 (Goodson, R.J., et al., supra), or to IL-2 containing cysteine ​​(between residues 1 and 20) Attempts at non-essential cysteine ​​(Cys125) or mutants thereof (Katre, N., et al., U.S. Patent No. 5,206,344) have not resulted in a clinically useful product.

[017...

Embodiment 3

[0180] Example 3: Synthesis and analysis of N-terminal PEGylated EGF and IGF-1

[0181] respectively according to Figure 5 and 7 In the molecular model (which shows EGF and IGF-1 as RN growth factors), epidermal growth factor ("EGF"; SEQ ID NO: 7) and insulin-like growth factor-1 ("IGF-1"; SEQ ID NO :9) to carry out N-terminal PEGylation. 5-kDa PEG-propionaldehyde (NOF Corporation, Tokyo) was dissolved in 1 mM HCl so that the final concentration became 15 mg / ml to prepare a 3 mM solution of 5-kDa PEG-aldehyde. Borane-pyridine was prepared by diluting 35 microliters (mcL) of 8M borane-pyridine (Aldrich) in 0.3 mL of acetonitrile plus 0.15 mL of water to a final concentration of 0.58M. A buffer (pH 6.3) containing 0.2M each of sodium phosphate and sodium acetate was prepared and filtered through a 0.1 micron pore sterile filter. Recombinant human EFG from Invitagen (Casbain, CA) was dissolved in water at a concentration of 1 mg / ml. To 0.6 ml of this solution were added 70 ...

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Abstract

Methods are provided for the synthesis of polymer conjugates of cytokines and receptor-binding antagonists thereof, especially a non glycosylated interferon-beta, which conjugates retain unusually high biological potency. Preparation of polymer conjugates according to the methods of the present invention diminishes or avoids steric inhibition of receptor-ligand interactions that commonly results from the attachment of polymers to receptor-binding regions of cytokines, as well as to agonistic and antagonistic analogs thereof. The invention also provides conjugates and compositions produced by such methods. The conjugates of the present invention retain a high level of biological potency compared to those produced by traditional polymer coupling methods that are not targeted to avoid receptor-binding domains of cytokines. In assays in vitro, the biological potency of the conjugates of non-glycosylated interferon-beta of the present invention is substantially higher than that of unconjugated interferon-beta and is similar to that of interferon-beta-1a that is glycosylated. The conjugates of the present invention also exhibit an extended half-life in vivo compared to the corresponding unconjugated cytokine. The present invention also provides kits comprising such conjugates and / or compositions, and methods of use of such conjugates and compositions in a variety of diagnostic, prophylactic, therapeutic and bioprocessing applications, including treatment of multiple sclerosis.

Description

Background of the invention [0001] The present invention is in the fields of protein biochemistry and pharmacy and medicine. In particular, the present invention provides methods for producing conjugates of water-soluble polymers (e.g., poly(ethylene glycol) and derivatives thereof) and certain biologically active components that are compatible with standard Compared with the polymer-bioactive component conjugates, it has increased receptor-binding activity. More specifically, the present invention provides methods for producing polymer conjugates of certain receptor-binding proteins with very high receptor-binding activity. The invention also provides conjugates produced by such methods, compositions containing such conjugates, kits containing such conjugates and compositions, and the use of such conjugates and compositions to prevent, Methods of diagnosing and treating a wide variety of medical and veterinary conditions. [0002] related technology [0003] The following...

Claims

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Application Information

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IPC IPC(8): A61K47/00A61B10/00C12P21/00
Inventor 谢姆·S·巴斯卡伦梅瑞·R·歇尔曼马克·G·P·塞佛艾尔·D·威廉斯
Owner MOUNTAIN VIEW PHARMA
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