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

a technology of fc receptor and binding protein, which is applied in the field of fcrn-binding polypeptide variants and dimeric fc binding proteins, can solve the problem of a relative low percentage of patients that exhibit a complete response, and achieve the effect of increasing decreasing the binding affinity of altered fc-containing polypeptides, and decreasing the free energy of binding

Inactive Publication Date: 2007-06-28
BIOGEN MA INC
View PDF19 Cites 329 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0277] In one embodiment, the mutation increases the free energy of binding between altered Fc-containing polypeptide and FcRn when bound in a solvent, thereby decreasing binding affinity of the altered Fc-containing polypeptide for FcRn.
[0278] In one embodiment, the mutation decreases the free energy of binding between altered Fc-containing polypeptide and FcRn when bound in a solvent, thereby increasing binding affinity of the altered Fc-containing polypeptide for FcRn.

Problems solved by technology

This is not to say that present antibody-based therapies have been entirely successful; in some instances, the limited circulation time and / or low bioavailability of a therapeutic results in a relatively low percentage of patients that exhibit a complete response to an antibody-based therapeutics, or in other cases toxicity due to prolonged circulatory half-life or exposure of non-target tissue may preclude use of the antibody as a therapy.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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

example 1

Production of Altered Antibodies with Chimeric Fc Regions

[0683] To evaluate the binding of human rabbit IgG chimera constructs, the amino acids likely to impact binding were first defined as being within 10 Å of the interface of interaction between the two interacting proteins. Based on the crystal structure of the ratIgG2a and rat FcRn, the amino acids on the ratIgG2a Fc within 10 Å of the interface for these two molecules was defined. A homology alignment of rabbit IgG1 Fc and the rat IgG1 Fc regions then allows determination of which amino acids on the rabbit Fc region are likely to be within 10 Å of the interaction face. Correspondence of the rat and human Fc regions is then determined. A chimeric molecule is then constructed including all of the mutants within the 10 Å interface. The individual amino acids are then substituted into the hFc and assayed to determine the contribution of the individual component amino acids to binding. Combinations of the amino acid mutants are th...

example 2

Identification of Candidate Residues by Electrostatic Optimization

[0691] In this example, method for modifying the antibody constant domain affinity towards human FcRn is described. To obtain mutants with altered binding affinity of an Fc region to FcRn at acidic pH and neutral pH, we applied electrostatic charge optimization techniques to a homology model of human Fc bound to human FcRn. The models of human Fc / FcRn complex at acidic (6.0) pH and neutral (7.4) pH were derived from a crystal structure of rat Fc / FcRn complex (PDB code: 1I1A) using MODELLER program, (Accelrys, Inc., San Diego, Calif.) and were energy-minimized in CHARMM (Accelrys, Inc., San Diego, Calif.). In a computational optimization procedure, we used electrostatic charge optimization to determine the position(s) of the Fc residue(s) that can modulate Fc binding (Lee and Tidor, J. Chem. Phys. 106:8681-8690, 1997; Kangas and Tidor, J. Chem. Phys. 109:7522-7545, 1998) to FcRn at acidic pH and neutral pH. These calc...

example 4

Construction of Altered Fc Polypeptides

[0699] Alterations predicted by the methods of the invention were introduced into a starting polypeptide encoding the heavy chain of humanized IgG1 monoclonal antibody huCBE11. FIGS. 1A and 1B display the nucleotide (SEQ ID NO. 3) and predicted amino acid sequence (SEQ ID NO. 4) of this heavy chain respectively. Mutations were introduced in the huCBE11 heavy chain carried on an expression vector called pEAG1787 using site-directed mutagenesis by standard recombinant DNA techniques. The variable domain of the antibody is residues 1-120, the human IgG1 constant domain is residues 121-449. The huIgG1's C-terminal lysine residue was genetically removed. For reference: the N-linked glycosylation site (EU residue number N297) is residue 300 in the sequence above. FIG. 2 displays the amino acids sequence of the Fc region of huCBE11 in EU numbering index.

[0700] The huCBE11 monoclonal antibody is a humanized IgG1, kappa recombinant antibody that recog...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The compositions and methods of the present invention are based, in part, on our discovery that an effector function mediated by an Fc-containing polypeptide can be altered by modifying one or more amino acid residues within the polypeptide (by, for example, electrostatic optimization). The polypeptides that can be generated according to the methods of the invention are highly variable, and they can include antibodies and fusion proteins that contain an Fc region or a biologically active portion thereof.

Description

RELATED APPLICATIONS [0001] This application is a continuation application of International Patent Application No. PCT / US2004 / 037929, filed Nov. 12, 2004, titled “NEONATAL Fc RECEPTOR (FcRn)-BINDING POLYPEPTIDE VARIANTS, DIMERIC Fc BINDING PROTEINS AND METHODS RELATED THERETO” which claims the benefit of U.S. Provisional Application Ser. No. 60 / 519,744, filed on Nov. 12, 2003, titled “ANTIBODIES AND VARIANTS THEREOF THAT CONTAIN ALTERED CONSTANT DOMAINS.” This application also claims the benefit of U.S. Application Ser. No. 60 / 519,743, filed on Nov. 12, 2003, titled “FC RECEPTOR-BINDING POLYPEPTIDES, PH-SPECIFIC VARIANTS DERIVED BY ELECTROSTATIC OPTIMIZATION, AND USES THEREFOR.” This application also claims the benefit of U.S. Application Ser. No. 60 / 519,733, filed on Nov. 12, 2003, titled “MUTANTS DEFINED BY ELECTROSTATIC MODELING WITHIN THE HUMAN FC DOMAIN THAT CAN MODULATE HUMAN ANTIBODY HALF-LIFE.”[0002] This application is also related to PCT application PCT / US2004 / 037948, titl...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07H21/04C12P21/06C07K16/44C07K16/00
CPCC07K16/00C07K2317/24C07K2317/52C07K2317/71C07K2317/72A61P35/00A61P37/00A61P43/00C07K2317/526C07K2317/524
Inventor FARRINGTON, GRAHAM K.LUGOVSKOY, ALEXEY ALEXANDROVICHMEIER, WERNERELDREDGE, JOHN K.GARBER, ELLEN
Owner BIOGEN MA INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap