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Hybrid immunoglobulins with moving parts

a technology of immunoglobulins and moving parts, which is applied in the field of hybrid immunoglobulins with moving parts, can solve the problems of inflexible connections between the two binding domains that do not provide machine-like motion, and the number of parts or connections in any machine is counterproductive, and numerous attempts to engineer antibodies and immunoadhesins that bind symmetrically have failed

Inactive Publication Date: 2008-10-16
BIOMOLECULAR HLDG LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]Genetic devices disclosed herein comprise two or more stretches of consecutive amino acids that are connected at a predefined terminus by a non-peptide bond. Such genetic devices are both symmetric and symmetrically binding with respect to one or more important targets (i.e., cooperative). The genetic devices herein are protein-like molecules may be described by a number of related terms that include symmetroadhesins, immuno-

Problems solved by technology

One challenging aspect of creating useful nano-machines is striking a balance in the number of moving parts and the number of interconnections.
Above a certain threshold, increasing the number of parts or connections in any machine is counterproductive.
The inflexible connections between the two binding domains do not provide the machine-like motion that would permit cooperative binding.
Numerous attempts to engineer antibodies and immunoadhesins that bind symmetrically have failed because of the difficulty in achieving the precise geometry needed for complementary symmetries between the binding sites and target sites.
Unlike materials used to make conventional machines, such as wood, metals, plastics, ceramics, and the like, molecules cannot simply be cut, wrought, cast, machined or joined to an exact size and shape.

Method used

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  • Hybrid immunoglobulins with moving parts
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  • Hybrid immunoglobulins with moving parts

Examples

Experimental program
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Effect test

example 1

Preparation of Immunoglobulin Fc with N-Terminal-S-Termini (S-Fc)

[0380]Digestion of immunoglobulin (IgG) with papain yields two Fab fragments and one Fc fragment (Porter (1959) Biochem. 73, 119-126). The site of proteolysis in human IgG is the heavy chain hinge region between the cys-5 and cys-11 residues, EPKSCDKTHTCPPCP, (Fleischman et al., Biochem J. (1963) 88, 220-227; Edelman et al. (1969) Proc. Natl. Acad. Sci. 63, 78-85). The cys-5 residue normally forms a disulfide bond with the human IgG light chain, which is easily cleaved under mild reducing conditions, making it an ideal candidate for Fc-like molecules with N-terminal-S-termini (S-Fc).

[0381]Accordingly, host cells were transfected with expression vectors encoding IgG1 pre-Fc chimeric polypeptides consisting of a signal peptide joined at its C-terminus by a peptide bond to the N-terminus of an Fc domain beginning at the cys-5 residue, CDKTHTCPPCP (FIG. 35A). The heterologous signal peptides used are selected from proteins...

example 2

Preparation of Immunoglobulin Fc with N-Terminal-X-Termini (X-Fc)

[0410]Selenocysteine (sec) is the 21st amino acid incorporated during ribosome-mediated protein synthesis (Zinoni et al. (1986) Proc. Natl. Acad. Sci. 83, 4650-4654; Chambers et al. (1986) EMBO J. 5, 1221-1227). The process is complex and distinct from cysteine incorporation, requiring an mRNA selenocysteine insertion element in order to decode a UGA stop codon. Protein semi-synthesis offers an alternative means for preparing Fc-like molecules having N-terminal-X-termini (X-Fc) that begin at cysteine (cys) and / or selenocysteine (sec).

[0411]Accordingly, host cells are transfected with constructs that encode pre-Fc chimeric polypeptides consisting of a signal peptide joined at its C-terminus by a peptide bond to the N-terminus of an Fc domain beginning at cys-11, CDKTHTCPPCP (FIG. 36A) and cys-14 CDKTHTCPPCP (FIG. 36B). The heterologous signal peptides used are selected from proteins with N-terminal cysteines (part i). T...

example 3

Preparation of Immuoglobulin Fc with C-Terminal-X-Termini (Fc-X)

[0421]IgG is expressed in two abundant forms, the soluble antibody molecule and the cell-bound B-cell receptor. Both forms arise from a single messenger RNA by alternative splicing with the result that two additional exons are added to the IgG heavy chain coding region (Tyler et al. (1982) Proc. Natl. Acad. Sci. 79, 2008-2012; Yamawaki-Kataoka et al. (1982) Proc. Natl. Acad. Sci. 79, 2623-2627). The first exon added (M1 exon) encodes a stretch of 18 amino acids, ELQLEESCAEAQDGELDG, which flexibly tethers IgG to the cell surface, making it a good choice for novel Fc-like molecules with a C-terminal-X-terminus (Fc-X). The C-terminal gly-18 residue of the M1 domain is also well-suited for preparing Fc-intein fusion proteins used in generating a C-terminal activated thioester. Following an intein autocleavage reaction, a thioester intermediate is generated that permits the facile addition of cysteine or selenocysteine to th...

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Abstract

Hybrid immunoglobulins containing moving parts are provided as well as related compositions and methods of use and methods of production. In addition, analogous genetic devices are provided as well as related compositions and methods of use and methods of production.

Description

[0001]This application claims benefit of U.S. Provisional Application No. 60 / 856,864, filed Nov. 2, 2006, the contents of which are hereby incorporated by reference into this application.[0002]Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.BACKGROUND OF THE INVENTION[0003]All machines and devices have moving parts. The function of the moving parts is to perform work, by transforming a source of energy, in order to carry out a useful task. Moving parts cover a spectrum of sizes and shapes. At one end of the spectrum is a visible world evident in machines that perform mechanical tasks. At the other end of the spectrum is an invisible world of charge carriers utilized by devices that carry out electrical wo...

Claims

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Application Information

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IPC IPC(8): C12P21/04C07K16/18C07K1/00
CPCA61K47/48507A61K47/48661A61K51/1084C07K2319/30C12N15/62C12N15/625C07K2317/52A61K47/6835A61K47/6875A61P11/06A61P17/06A61P19/02A61P29/00A61P35/00A61P35/02A61P35/04C07K19/00C07K16/18C12P21/02
Inventor CAPON, DANIEL J.
Owner BIOMOLECULAR HLDG LLC
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