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Serum half-life extension using igbd

a technology of serum and half-life extension, which is applied in the direction of fused cells, drug compositions, immunological disorders, etc., can solve the problems of drug concentrations in blood that are not instantaneous, albumin and abd fusion proteins cannot reach the long half-life of igg molecules, and the drug concentration does not reach instantaneous distribution,

Inactive Publication Date: 2014-08-07
UNIV STUTTGART
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a complex of an immunoglobulin binding moiety and a pharmaceutically active moiety, which specifically binds to the constant domain 1 of the heavy chain of an immunoglobulin molecule. The invention also provides a nucleic acid molecule, vector, isolated cell, pharmaceutical composition and uses of the complex in extending the serum half-life and as a medicament. The technical effect of the invention is the development of a novel complex that targets a specific molecule in the body, potentially improving the efficacy and safety of drugs.

Problems solved by technology

However, the drug does not achieve instantaneous distribution, i.e. equilibration, between the two compartments.
Immediately after the dose is given, there is a phase of rapid drug disappearance from the blood, usually lasting from a few minutes to an hour or two, which may lead to a very substantial decrement in drug concentrations in blood.
These studies, however, also revealed that albumin and ABD fusion proteins do not reach the long half-life of IgG molecules.
However, many disadvantages are associated with above strategies of extending the plasma half-life of pharmaceuticals.
The usage of PEG, polysialic acid and HES requires their chemical conjugation to the pharmaceutical, which consequently complicates the production and analysis of the final product.
PEG is not biologically degradable and may accumulate in the body of a patient which may lead to further complications.
Moreover, it has been shown that these modification were only able to prolong the serum half-life of pharmaceuticals to a limited extend.
They are thus, competing with the FcRn binding and may negatively influence the recycling of the immunoglobulin molecule via the FcRn.

Method used

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  • Serum half-life extension using igbd
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  • Serum half-life extension using igbd

Examples

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embodiments

[0086]In a first aspect the present invention relates to a complex comprising (i) an immunoglobulin (Ig) binding moiety and (ii) a pharmaceutically active moiety, wherein the Ig binding moiety specifically binds to the constant domain 1 of the heavy chain (CH1) of an Ig molecule.

[0087]In preferred embodiments, the Ig binding moiety prolongs the serum half-life of the pharmaceutically active moiety, i.e. the pharmaceutically active moiety exhibits a prolonged serum half-life when being part of the complex of the first aspect of the invention. In preferred embodiments the complex of the first aspect is thus, used for extending the serum half-life, preferably the serum half-life of the pharmaceutically active moiety. It is particularly preferred that the initial and / or the terminal serum half-life are extended. It is further preferred that the bioavailabilty, more preferably the bioavailabilty of the pharmaceutically active moiety, is increased.

[0088]In the context of the present inven...

example 1

Construction and Production of scDb-IgBD Fusion Proteins

[0133]DNA encoding the IgBDs (IgBD SpAB, SpAD, SPAEZ4, SPGC3, and PpLC4*) including a hexahistidyl-tag at the C-terminus were synthesized by GeneArt (Regensburg, Germany) adding a NotI at the 5′ end and an EcoRI and XbaI site at the 3′ end. IgBD SpAB was cloned into mammalian expression vector pSecTagAHis scDb-CEACD3-ABD-L (Hopp et al. (2010) Protein Eng. Des. Sel. 23:827-834) cut with NotI and XbaI. The IgBD SpAD, SpAEZ4, SpGC3, and PpLC4* were then cloned into scDb-CEACD3-SpAB as NotI-EcoRI fragments substituting the SpAB IgBD. Composition of the scDb-IgBD fusion proteins are given in FIG. 2a. HEK293 cells were stably transfected and the fusion proteins scDb-SpAB, scDb-SpAD, scDb-SpAEZ4, scDb-SpGC3, and scDb-PpLC4* were purified from cell culture supernatant by IMAC essentially as described previously (Müller et al. (2007) J. Biol. Chem. 282:12650-12660). Yields of 2 to 22 mg / L supernatant were obtained. SDS-PAGE of purified ...

example 2

Construction and Production of scFv-IgBD Fusion Proteins

[0134]DNA encoding the IgBDs (IgBD SpAB, SpAD, SPAEZ4, SPGC3, and PpLC4*) including a hexahistidyl-tag at the C-terminus were synthesized by GeneArt (Regensburg, Germany) adding a NotI at the 5′ end and an EcoRI and XbaI site at the 3′ end. The DNA was digested with NotI and EcoRI and cloned into vector pSecTagA-scFvCEA-4-1BBL (Müller et al. (2008) J. Immunol. 31:714-722). Composition of the scFv-IgBD fusion proteins are given in FIG. 2a. HEK293 cells were stably transfected and the fusion proteins scFv-SpAB, scFv-SpAD, scFv-SpAEZ4, scFv-SpGC3, and scFv-PpLC4* were purified from cell culture supernatant by IMAC essentially as described previously (Müller et al., (2007) J. Biol. Chem. 282:12650-12660). SDS-PAGE of purified fusion proteins was performed. Two micrograms proteins were analyzed per lane and the gel was stained with Coomassie brilliant blue G-250 (M, molecular weight standards). SDS-PAGE analysis revealed a single ba...

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Abstract

The present invention relates to complexes comprising (i) an immunoglobulin (Ig) binding moiety and (ii) a pharmaceutically active moiety, wherein the Ig binding moiety specifically binds to the constant domain 1 of the heavy chain (CH1) of an Ig molecule and their use for therapy and prophylaxis.

Description

[0001]The present invention relates to complexes comprising (i) an immunoglobulin (Ig) binding moiety and (ii) a pharmaceutically active moiety, wherein the Ig binding moiety specifically binds to the constant domain 1 of the heavy chain (CH1) of an Ig molecule and their use for therapy and prophylaxis.BACKGROUND[0002]Most of the therapeutic applications of pharmaceuticals benefit from maintaining a therapeutic effective concentration over a prolonged period of time, often requiring a frequent administration or infusions, or a loco-regional application or subcutaneously of the drug utilizing a slow adsorption into the blood stream in order to maintain an effective concentration over a prolonged period of time. When a drug is administered by rapid intravenous injection into the vascular system, its removal from the blood almost always occurs in a biphasic fashion (see Greenblatt (1985) Ann. Rev. Med. 36:421-427). This can be mathematically described by a two-compartment model, which ...

Claims

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Application Information

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IPC IPC(8): A61K47/48
CPCA61K47/48676A61K47/48715A61P5/06A61P37/04A61P37/06A61P43/00C07K14/31C07K14/315C07K16/2809C07K16/2863C07K16/3007C07K2317/31C07K2317/34C07K2317/622C07K2317/626C07K2317/94C07K2319/00C07K2319/21C07K2319/30C07K2319/31A61K39/39591C07K16/2875
Inventor KONTERMANN, ROLANDUNVERDORBEN, FELIXHUTT, MEIKE
Owner UNIV STUTTGART
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