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Prevention and reduction of blood loss

a technology of blood loss and prevention, applied in the direction of antinoxious agents, peptide sources, peptide/protein ingredients, etc., can solve the problems of contact activation, perioperative blood loss, etc., to prevent or reduce the onset of systemic inflammatory response, prevent or reduce the effect of ischemia

Inactive Publication Date: 2007-10-25
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These peptides provide high specificity and affinity for kallikrein, reducing the risk of complications associated with current inhibitors, effectively preventing perioperative blood loss and systemic inflammatory response during invasive surgeries, while minimizing the risk of thrombotic events and hypersensitivity reactions.

Problems solved by technology

Perioperative blood loss results from invasive surgical procedures that lead to contact activation of complement components and the coagulation / fibrinolysis systems.

Method used

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  • Prevention and reduction of blood loss
  • Prevention and reduction of blood loss
  • Prevention and reduction of blood loss

Examples

Experimental program
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Effect test

example 1

A Representative KI Polypeptide

[0064] A non-naturally occurring, KI polypeptide useful in the compositions and methods of the invention was identified as a kallikrein binding polypeptide displayed on a recombinant phage from a phage display library. PEP-1 has the following amino acid sequence: Glu Ala Met His Ser Phe Cys Ala Phe Lys Ala Asp Asp Gly Pro Cys Arg Ala Ala His Pro Arg Trp Phe Phe Asn Ile Phe Thr Arg Gln Cys Glu Glu Phe Ile Tyr Gly Gly Cys Glu Gly Asn Gln Asn Arg Phe Glu Ser Leu Glu Glu Cys Lys Lys Met Cys Thr Arg Asp (SEQ ID NO:2). The molecular weight of PEP-1 is 7,054 Daltons.

[0065] The nucleotide sequence (SEQ ID NO:3) encoding the PEP-1 amino acid sequence (SEQ ID NO:2), was derived from a peptide that was isolated and sequenced by standard methods determined from the recombinant phage DNA. PEP-1 was produced in amounts useful for further characterization as a recombinant protein in His4.sup.-phenotype host cells of yeast strain Pichia pastoris.

example 2

Construction of a Recombinant Plasmid to Express KI Polypeptides

[0066] The initial plasmid, pHIL-D2, is ampicillin resistant and contains a wild-type allele of His4 from P. pastoris. The final DNA sequence comprising the coding sequence for the mat.alpha. Prepro-PEP-1 fusion protein in the recombinant expression plasmid pPIC-K503 is shown in FIG. 2. The DNA sequence of pHIL-D2 was modified to produce pPIC-K503, as follows:

[0067] 1. The BstBI site in the 3′ AOX1 region of pHIL-D2, located downstream of the His4 gene, was removed by partial restriction digestion, fill-in, and ligation, altering the sequence from TTCGAA (SEQ ID NO:23) to TTCGCGAA (SEQ ID NO:24). This modification was made to facilitate and direct the cloning of the expression cassette into the plasmid.

[0068] 2. The AatII site bearing the bla gene located downstream of His4 was removed by restriction digestion, fill-in, and ligation modifying the sequence from GACGTC (SEQ ID NO:25) to GACGTACGTC (SEQ ID NO:26). This ...

example 3

Manufacture of PEP-1 from Recombinant Yeast Cell Line

[0070] Spheroplasts of P. pastoris GS115 having the His4.sup.-phenotype were transformed with the expression plasmid pPIC-K503 (above) following linearization of the plasmid at the SacI site and homologous recombination of the plasmid DNA into the host 5′ AOX1 locus. The phenotype of the production strain is His4.sup.+. The entire plasmid was inserted into the 5′ AOX1 genomic sequence of the yeast.

[0071] Isolates from the transformation were screened for growth in the absence of exogenous histidine with methanol as the sole carbon source. Greater than 95% of the transformants retained the wild-type ability to grow with methanol as the sole carbon source, thereby demonstrating that the plasmid had been inserted into the host genome by homologous recombination rather than transplacement. These transformants did not require exogenous histidine for growth, thereby demonstrating that the plasmid had integrated into the host genome. S...

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Abstract

Methods are described for preventing or reducing ischemia and / or systemic inflammatory response in a patient such as perioperative blood loss and / or systemic inflammatory response in a patient subjected to cardiothoracic surgery, e.g. coronary artery bypass grafting and other surgical procedures, especially when such procedures involve extra-corporeal circulation, such as cardiopulmonary bypass.

Description

RELATED APPLICATION [0001] This application claims the benefit of U.S. application Ser. No. 10 / 456,986, filed Jun. 6, 2003, which claims the benefit from U.S. Provisional Application No. 60 / 387,239, filed Jun. 7, 2002, and U.S. Provisional Application No. 60 / 407,003, filed Aug. 28, 2002. [0002] The entire teachings of the above applications are incorporated herein by reference.BACKGROUND OF THE INVENTION [0003] Proteases are involved in a broad range of biological pathways. In particular, serine proteases such as kallikrein, plasmin, elastase, urokinase plasminogen activator, thrombin, human lipoprotein-associated coagulation inhibitor, and coagulation factors such as factors VIIa, IXa, Xa, XIa, and XIIa have been implicated in pathways affecting blood flow, e.g., general and focal ischemia, tumor invasion, fibrinolysis, perioperative blood loss, and inflammation. Inhibitors of specific serine proteases, therefore, have received attention as potential drug targets for various ischem...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/47A61K38/17
CPCC07K14/8121C07K14/8114
Inventor LADNER, ROBERT C.LEY, ARTHUR C.HIRANI, SHIRISHWILLIAMS, ANTHONY
Owner TAKEDA PHARMA CO LTD
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