Novel heterodimeric proteins

a heterodimer protein and protein technology, applied in the field of new heterodimer proteins, can solve the problems of affecting the production and stability of antibody fragments, unable to have the constant region of the antibody with its associated functional properties, and the binding to the new antigen is always bivalent,

Inactive Publication Date: 2014-10-02
XENCOR
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]The present invention provides isolated nucleic acids encoding the novel immunoglobulin compositions described herein. The present invention provides vectors comprising said nucleic acids, op

Problems solved by technology

While these formats can be expressed at high levels in bacteria and may have favorable penetration benefits due to their small size, they clear rapidly in vivo and can present manufacturing obstacles related to their production and stability.
A principal cause of these drawbacks is that antibody fragments typically lack the constant region of the antibody with its associated functional properties, including larger size, high stability, and binding to various Fc receptors and ligands that maintain long half-life in serum (i.e., the neonatal Fc receptor FcRn) or serve as

Method used

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Examples

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example 1

Prototype “Triple F” Bispecific Antibody

[0294]The present invention describes novel immunoglobulin compositions that co-engage a first and second antigen. One heavy chain of the antibody contains a single chain Fv (“scFv”, as defined below) and the other heavy chain is a “regular” Fab format, comprising a variable heavy chain and a light chain (see FIG. 1). This structure is sometimes referred to herein as “triple F” format (scFv-Fab-Fc). The two chains are brought together by the dimeric Fc region (see FIG. 2). The Fc region can be modified by amino acid substitution to allow for efficient purification of the “triple F” heterodimer. Further, the Fc region can be modified by amino acid substitution to promote the formation of the “triple F” heterodimer. Examples of Fc substitutions are described more fully below.

[0295]Fc substitutions can be included in the “triple F” format to allow for efficient purification of the desired “triple F” heterodimer over the undesired dual scFv-Fc and...

example 2

Multi-Specific Antibodies Derived from the “Triple F” Format

[0298]Multi-specific antibodies can be constructed by attaching additional scFv or Fab domains that bind a third antigen to the C-terminus of one of the “triple F” heavy chains. See FIG. 5 for examples. Alternatively, the C-terminal scFv or Fab may bind the first or second antigen, thus conferring bivalency and an increase in overall binding affinity for that antigen.

[0299]Multi-specific antibodies can also be constructed by coupling the scFv-Fc heavy chain of the “triple F” format may with rearranged antibody heavy chains as depicted in FIG. 6. Such rearranged heavy chains may include an additional Fv region that binds a third antigen or an additional Fv region that binds the first antigen or second antigen, thus conferring bivalency and an increase in overall binding affinity for that antigen.

example 3

Anti-CD19 Fab×Anti-CD3 scFv “Triple F” Bispecific

[0300]Amino acid sequences for anti-CD19 Fab×anti-CD3 scFv “triple F” bispecifics are listed in FIG. 7. Amino acid substitutions made to allow for efficient purification of the desired “triple F” heterodimer over the undesired dual scFv-Fc and mAb homodimers are underlined. Amino acid sequences for preferred humanized anti-CD3 variable regions are listed in FIG. 8 (with CDRs underlined). Some examples of expression and purification of the desired “triple F” species and its bioactivity are given below.

[0301]The production of XENP11874, a “triple F” bispecific with an anti-CD19 Fab and anti-CD3 scFv, is outlined in FIG. 9. In FIG. 9A, the ion exchange purification of the desired “triple F” heterodimer from the undesired dual scFv-Fc and mAb homodimers is shown. The purity of the “triple F” fraction was checked by IEF gel, shown in FIG. 9B. Finally, SEC was used to confirm the homogenous size of the “triple F” product (see FIG. 9C).

[0302...

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Abstract

The invention provides heterodimeric antibodies comprising a first heavy chain comprising a first Fc domain and a single chain Fv region that binds a first antigen. The heterodimeric antibodies also comprise a second heavy chain comprising a second Fc domain, a first variable heavy chain and a first variable light chain, wherein the first and second Fc domains are different.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. Ser. No. 14 / 155,248, filed Jan. 14, 2014, which claims priority to U.S. 61 / 780,310, filed Mar. 13, 2013, U.S. 61 / 752,349, filed on Jan. 14, 2013 and U.S. 61 / 764,954, filed on Feb. 14, 2013 which are incorporated herein in their entirety.INCORPORATION OF RELATED APPLICATIONS[0002]The following applications are incorporated by reference in their entirety, U.S. Ser. Nos. 61 / 302,707, 61 / 732,813, 61 / 598,686, 61 / 441,552, 61 / 311,472, 61 / 450,457, 61 / 545,498, 61 / 368,969, 61 / 391,509, 61 / 391,515, 61 / 439,263, 61 / 368,962 and 61 / 593,846, 61 / 515,745, 61 / 752,349, 13 / 194,904, 13 / 568,028, 13 / 648,951, 12 / 875,015, as well as US Publication Nos. 2009 / 0163,699 and 2006 / 0024298;[0003]The present invention describes novel immunoglobulin compositions that simultaneously co-engage antigens, where both of the antigens are bound monovalently. The novel immunoglobulins described preferably utilize heterodimeric Fc regions. M...

Claims

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Application Information

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IPC IPC(8): C07K16/28C12P21/00
CPCC07K16/2896C07K2317/31C12P21/00C07K16/2803C07K16/2809C07K16/468C07K16/40
Inventor MOORE, GREGORYBERNETT, MATTHEWRASHID, RUMANADESJARLAIS, JOHN
Owner XENCOR
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