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Antigen binding molecules that bind EGFR, vectors encoding same, and uses thereof

a technology of egfr and binding molecules, applied in the field of antigen binding molecules, can solve the problems of poor prognosis of patients, induction of immune responses, and correlation or association of overexpression of egfr, and achieve the effect of enhancing the affinity and effector function of fc receptors and enhancing the efficacy of these abms

Active Publication Date: 2008-11-20
ROCHE GLYCART AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is directed to a method for producing antigen binding molecules (ABMs) that have the binding specificity of the rat ICR62 monoclonal antibody and enhanced function by glycoengineering the Fc region of the antibody. These ABMs can be used for therapeutic purposes and can be produced by recombinant DNA technology. The invention also includes a method for modulating the concentration of the ABMs for binding to their target antigen. Overall, the invention provides a way to produce highly effective ABMs for therapeutic use.

Problems solved by technology

In many of these conditions, the overexpression of EGFR correlates or is associated with poor prognosis of the patients.
A potential problem with the use of murine antibodies in therapeutic treatments is that non-human monoclonal antibodies can be recognized by the human host as a foreign protein; therefore, repeated injections of such foreign antibodies can lead to the induction of immune responses leading to harmful hypersensitivity reactions.
Furthermore, non-human monoclonal antibodies (e.g., murine monoclonal antibodies) typically lack human effector functionality, i.e., they are unable to, inter alia, mediate complement dependent lysis or lyse human target cells through antibody dependent cellular toxicity or Fc-receptor mediated phagocytosis.
Bacteria very rarely glycosylate proteins, and like other types of common hosts, such as yeasts, filamentous fungi, insect and plant cells, yield glycosylation patterns associated with rapid clearance from the blood stream, undesirable immune interactions, and in some specific cases, reduced biological activity.

Method used

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  • Antigen binding molecules that bind EGFR, vectors encoding same, and uses thereof
  • Antigen binding molecules that bind EGFR, vectors encoding same, and uses thereof
  • Antigen binding molecules that bind EGFR, vectors encoding same, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods

[0288]High Homology Acceptor Approach

[0289]The high homology antibody acceptor framework search was performed by aligning the rat ICR62 protein sequence to a collection of human germ-line sequences and choosing that human sequence that showed the highest sequence identity, while conserving all canonical residues on a functional level. Here, the sequence 1-e from the VH1 family within the VBase database was chosen as the heavy chain framework acceptor sequence, and the A30 sequence from the VK1 family of the VBase database was chosen to be the framework acceptor for the light chain. On these two acceptor frameworks the three complementarity determining regions (CDRs) and / or specificity-determining residues of those CDRs of the rat ICR62 heavy and light variable domains were grafted. Since the framework 4 region is not part of the variable region of the germ line gene, the alignment for that position was performed individually. The JH6 region was chosen for the he...

example 2

Results and Discussion

[0315]Comparison of the binding to human EGF-receptor of antibody variants I-HHA, I-HHB, I-HHC, I-HLA, I-HLB, I-HLC, I-HLA1, I-HLA2, I-HLA3, I-HLA4, I-HLA5, I-HLA6, I-HLA7, I-HLA8, I-HLA-9, I-HHD, I-HHE, I-HHF, and I-HHG, either complexed with the chimeric ICR62 light chain or with the humanized ICR62 light chains (1-KA, I-KB, or I-KC) and the parental, chimeric antibody ch-ICR62 shows that all antibodies have within one log unit similar EC50 values. Only the I-HHA has strongly diminished binding activity (see FIG. 2). FIG. 1 shows the functional activity of the individual chimeric ICR62 (ch-ICR62) polypeptide chains when combined with the humanized constructs I-HHC and I-KB, respectively. In this experiment, either the light chain, the heavy chain or both chains simultaneously of the ch-ICR62 were replaced by the above mentioned humanized constructs. This shows that the VH / VL interface formation seems to work as well in the rodent antibody as well as in the hu...

example 3

Preliminary Toxicity Study by Intravenous (Bolus) Administration to Cynomolgus Monkeys

Bioanalytical Analysis

Introduction

[0338]Glyco-Engineered Anti-EGFR Assay

[0339]This Bioanalytical Analysis describes the measurement of anti-EGFR in samples originating from cynomolgus monkeys following intravenous (bolus) administration of anti-EGFR (recombinant, glycoengineered anti-EGFR antibody produced from transfected mammalian cells in culture with antibody expression vectors harboring the heavy chain I-HHB and the light chain I-KC genes as described above, and purified as described above) as described in the protocol set forth herein below. A total of 78 monkey serum samples were stored frozen at about −20° C. until use.

[0340]The Bioanalytical methods used for the determination of anti-EGFR used an ELISA method to measure serum concentrations of anti-EGFR. Acceptance criteria were set at ±20% (±25% low QC) for precision and inaccuracy.

Materials and Methods

[0341]Objective: The objective of th...

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Abstract

The present invention relates to antigen binding molecules (ABMs). In particular embodiments, the present invention relates to recombinant monoclonal antibodies, including chimeric, primatized or humanized antibodies specific for human EGFR. In addition, the present invention relates to nucleic acid molecules encoding such ABMs, and vectors and host cells comprising such nucleic acid molecules. The invention further relates to methods for producing the ABMs of the invention, and to methods of using these ABMs in treatment of disease. In addition, the present invention relates to ABMs with modified glycosylation having improved therapeutic properties, including antibodies with increased Fc receptor binding and increased effector function.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 836,371, filed Aug. 9, 2006, the entire contents of which are hereby incorporated by reference.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to antigen binding molecules (ABMs). In particular embodiments, the present invention relates to recombinant monoclonal antibodies, including chimeric, primatized or humanized antibodies specific for human epidermal growth factor receptor (EGFR). In addition, the present invention relates to nucleic acid molecules encoding such ABMs, and vectors and host cells comprising such nucleic acid molecules. The invention further relates to methods for producing the ABMs of the invention, and to methods of using these ABMs in treatment of disease. In addition, the present invention relates to ABMs with modified glycosylation having improved therapeutic properties, including antibodies wit...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/00C12N15/13C12P21/00A61K39/395C12N1/00C12N15/63A61P35/00
CPCC07K16/2863C07K2317/24C07K2317/565C07K16/464C07K2317/72C07K2317/732C07K2317/567A61P35/00A61P43/00C07K16/28A61K39/395C12N15/11C12N15/63
Inventor UMANA, PABLOMOSSNER, EKKEHARD
Owner ROCHE GLYCART AG
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