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Neonatal Fc receptor (FcRn)-binding polypeptide variants, dimeric Fc binding proteins and methods related thereto

An amino acid, charged technology, used in the preparation of polypeptides containing this mutation, identification of desired amino acid mutations, and preparation of the altered polypeptides, PCT application field, can solve the problems of circulating half-life antibodies that cannot be used as therapeutic agents, low bioavailability, etc.

Inactive Publication Date: 2008-02-13
BIOGEN IDEC MA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is not to say, however, that current antibody-based therapies have been completely successful; in some cases, limited circulation times and / or low bioavailability of therapeutic agents have resulted in a relatively low percentage of patients exhibiting a complete response to antibody-based therapy, or in other In some cases, toxicity due to prolonged circulating half-life or exposure to non-target tissues may render the antibody unsuitable for use as a therapeutic agent

Method used

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  • Neonatal Fc receptor (FcRn)-binding polypeptide variants, dimeric Fc binding proteins and methods related thereto
  • Neonatal Fc receptor (FcRn)-binding polypeptide variants, dimeric Fc binding proteins and methods related thereto
  • Neonatal Fc receptor (FcRn)-binding polypeptide variants, dimeric Fc binding proteins and methods related thereto

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[0715]Example I-Preparation of modified antibodies with chimeric Fc region

[0716] In order to evaluate the binding of the human rabbit IgG chimeric construct, the amino acids that may affect the binding are first determined to be within 10 Ȧ of the interaction interface between the two interacting proteins. Based on the crystal structures of rat IgG2a and rat FcRn, the amino acids on rat IgG2a Fc located within 10 Ȧ of the interface between these two molecules were determined. Then the homology comparison of the rabbit IgG1 Fc and rat IgG1 Fc regions allows to determine which amino acids on the rabbit Fc region may be within 10 A of the interaction interface. The rat and human Fc region counterparts were then determined. The chimeric molecule is then constructed, including all mutants within the 10 Ȧ interface. Then each single amino acid was substituted into hFc separately, and analyzed to determine the contribution of each single component amino acid to the binding. A combinat...

Embodiment 2

[0724] Example 2-Identification of candidate residues by electrostatic optimization

[0725] In this example, a method for modifying the affinity of the constant region of an antibody to human FcRn is described. In order to obtain mutants whose Fc region has altered binding affinity to FcRn at acidic pH and neutral pH, we applied electrostatic charge optimization technology to a homologous model of human Fc that binds to human FcRn. The model of the human Fc / FcRn complex at acidic (6.0) pH and neutral (7.4) pH uses the MODELLER program (Accelrys, Inc., San Diego, CA) from the crystal structure of the rat Fc / FcRn complex (PDB) Code: 1I1A) was derived and energy minimization was performed in CHARMM (Accelrys, Inc., San Diego, CA). In the process of computational optimization, we use electrostatic charge optimization to determine the positions of Fc residues that can adjust the binding of Fc and FcRn at acidic pH and neutral pH (Lee and Tidor, J. Chem. Phys. 106: 8681-8690 , 1997; Ka...

Embodiment 4

[0752] Example 4: Construction of modified Fc polypeptide

[0753] The changes predicted by the method of the present invention are introduced into the starting polypeptide encoding the heavy chain of the humanized IgG1 monoclonal antibody huCBE11. Figures 1A and 1B show the nucleotide sequence (SEQ ID NO: 3) and predicted amino acid sequence (SEQ ID NO: 4) of the heavy chain, respectively. Using standard recombinant DNA technology, site-directed mutagenesis was used to introduce mutations into the huCBE11 heavy chain carried on an expression vector called pEAG1787. The antibody variable region is the residues 1-120, and the human IgG1 constant region is the 121-449 residues. The C-terminal lysine residue of huIgG1 was genetically removed. For reference: the N-linked glycosylation site (EU residue number N297) in the above sequence is the 300th residue. Figure 2 shows the amino acid sequence of the Fc region of huCBE11 according to the EU numbering index.

[0754] HuCBE11 monoclon...

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Abstract

The compositions and methods of the invention are based in part on our discovery that effector functions mediated by Fc-containing polypeptides can be altered by modifying one or more amino acid residues in the polypeptide (by, eg, electrostatic optimization). Polypeptides that can be produced according to the methods of the invention are highly variable and they can include antibodies and fusion proteins comprising Fc regions or biologically active portions thereof.

Description

[0001] Related application [0002] This application claims the benefit of U.S. Provisional Application Serial No. 60 / 519,744, entitled "Antibodies and Variants Containing Altered Constant Regions", filed on November 12, 2003. This application also claims the benefit of US Application Serial No. 60 / 519,743 filed on November 12, 2003, entitled "Fc Receptor Binding Polypeptides, pH Specific Variants Derived by Electrostatic Optimization and Their Uses". This application also claims the benefit of US Application Serial No. 60 / 519,733, filed on November 12, 2003, entitled "Mutant Defined by Electrostatic Modeling in Human Fc Domain That Can Adjust the Half-life of Human Antibody". This application also relates to PCT application XXXXXXXX entitled "Fcγ receptor binding polypeptide variants and related methods" filed on the same date as this application. The complete content of all these applications is incorporated here as a reference. Background technique [0003] Many biological pro...

Claims

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Application Information

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IPC IPC(8): C07K16/00A61K39/395C12N15/13C12N15/10C07K16/06
Inventor 格雷厄姆·K·法林顿亚历克西·A·卢戈夫斯科伊约翰·K·埃尔德雷奇埃伦·加伯
Owner BIOGEN IDEC MA INC
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