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Ang-2 Binding Complexes and Uses Thereof

a technology of ang-2 and complexes, which is applied in the field of ang-2 binding complexes, can solve the problems of difficult to achieve the effect of recombinant igg-like multi-specific, multi-valent molecules, and difficult to achieve the effect of achieving the effect of reducing the number of ang-2-like ions

Inactive Publication Date: 2013-10-03
ZYNGENIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new type of antibody that contains a modular recognition domain (MRD). This MRD can be attached to the antibody at any location on the antibody. The MRD can have the same or different specificities as the antibody. The MRD-containing antibodies can be any type of antibody, including immunoglobulin molecules that bind to an antigen. The MRD-containing antibodies can be used for therapeutic or diagnostic purposes. The MRD-containing antibodies can bind to a variety of targets, such as EGFR, ErbB2, ErbB3, ErbB4, CD20, insulin-like growth factor-I receptor, VEGF, VEGF-R, and prostate specific membrane antigen. In some embodiments, the MRD-containing antibodies can be used to treat cancer or other diseases.

Problems solved by technology

Although each of these molecules may bind one or more targets, they each present challenges with respect to retention of typical Ig function (e.g., half-life, effector function), production (e.g., yield, purity), valency, and simultaneous target recognition.
Unlike their fragment counterparts, engineering and production of recombinant IgG-like multi-specific, multi-valent molecules has been, however, rather technically challenging due to their large size (150-200 kDa) and structural complexity.
Success in the field, as judged by successful application in animal models, has been very limited.
However, RGD based reporter probes are problematic due to fast blood clearance, high kidney and liver uptake, and fast tumor washout.
Metastasis is the primary cause of morbidity and mortality in cancer.
Normally, angiogenesis is tightly regulated by pro- and anti-angiogenic factors, but in the case of diseases such as cancer, ocular noovascular disease, arthritis and psoriasis, the process can go awry.
The HER2 gene is overexpressed in 25% of invasive breast cancers, and is associated with poor prognosis and altered sensitivity to chemotherapeutic agents.
In normal adult cells, few ErbB2 molecules exist at the cell surface ˜20,000 per cell thereby limiting their signaling capacity and the likelihood of forming homo- and hetero-receptor complexes on the cell surface.
HERCEPTIN® induces rapid removal of ErbB2 from the cell surface, thereby reducing its availability to multimerize and ability to promote growth.
Overexpression of EGFR or expression of mutant forms of EGFR has been observed in many tumors, particularly epithelial tumors, and is associated with poor clinical prognosis.
An obstacle in the utilization of a catalytic antibody for selective prodrug activation in cancer therapy has been systemic tumor targeting.
However, the cost of developing and producing such therapies has limited their consideration as viable treatments for most indications.

Method used

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  • Ang-2 Binding Complexes and Uses Thereof
  • Ang-2 Binding Complexes and Uses Thereof
  • Ang-2 Binding Complexes and Uses Thereof

Examples

Experimental program
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Effect test

example 1

Integrin Targeting Antibody-MRD Molecule

[0530]Novel antibody-MRD fusion molecules were prepared by fusion of an integrin αvβ33-targeting peptides to catalytic antibody 38C2. Fusions at the N-termini and C-termini of the light chain and the C-termini of the heavy chain were most effective. Using flow cytometry, the antibody conjugates were shown to bind efficiently to integrin αvβ3-expressing human breast cancer cells. The antibody conjugates also retained the retro-aldol activity of their parental catalytic antibody 38C2, as measured by methodol and doxorubicin prodrug activation. This demonstrates that cell targeting and catalytic antibody capability can be efficiently combined for selective chemotherapy.

example 2

Angiogenic Cytokine Targeting Antibody-MRD Molecules

[0531]Angiogenic cytokine targeting antibody-MRD fusion molecules were constructed. The antibody used was 38C2, which was fused with a MRD containing the 2xCon4 peptide (AQQEECEWDPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEWDPWTCEHMLE (SEQ ID NO:10)). The MRD-containing peptide was fused to either the N- or C-terminus of the light chain and the C-terminus of the heavy chain. Similar results were found with the other Ang2 MRD peptides. Additional Ang2 MRD peptides include: MGAQTNFMPMDNDELLLYEQ FILQQGLEGGSGSTASSGSGSSLGAQTNFMPMDNDELLLY (SEQ ID NO:20) (LM-2x-32); AQQEECEWDPWTCEHMG SGSATGGSGSTASSGSGSATHQEECEWDPWTCEHMLE (SEQ ID NO:10) (2xCon4); AQQEECEFAPWTCEHM (SEQ ID NO:21) ConFA; core XnEFAPWTXn where n is from about 0 to 50 amino acid residues (SEQ ID NO:22); AQQEEC EFAPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEFAPWTCEHMLE (SEQ ID NO:23) (2xConFA); AQQEECELAPWTCEHM (SEQ ID NO:24) (ConLA); XnELAPWTXn where n is from about 0 to 50 amino acid residues (SE...

example 3

Antibody-MRD Fusions with Non-Catalytic Antibodies

[0535]A humanized mouse monoclonal antibody, LM609, directed towards human integrin αvβ3 has been previously described (Rader et. al., PNAS 95:8910-5 (1998)).

[0536]A human non-catalytic monoclonal Ab, JC7U was fused to an anti-Ang2 MRD containing 2xCon4 (AQQEECEWDPWTCEHMGSGSATGGSGSTASSGSGSATHQEECE WDPWTCEHMLE (SEQ ID NO:10)) at either the N- or C-terminus of the light chain. 2xCon4 (AQQEECEWDPWTCEHMGSGSATGGSGSTASSGSGSATHQEEC EWDPWTCEHMLE (SEQ ID NO:10)) was studied as an N-terminal fusion to the Kappa chain of the antibody (2xCon-4-JC7U) and as a C-terminal fusion (JC7U-2xCon4). Both fusions maintained integrin and Ang2 binding. As shown in the left panel of FIG. 3, both antibody constructs (2xCon-4-JC7U and JC7U-2xCon4) specifically bound to recombinant Ang2 as demonstrated by ELISA studies. Binding to Ang2, however, is significantly higher with JC7U-2xCon4, which has the 2xCon4 (SEQ ID NO:10) fusion at the C-terminus of the light c...

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Abstract

Complexes containing one or more modular recognition domains (MRDs) and MRDs attached to scaffold's including antibodies are described. The manufacture of these complexes are the use of these complexes to treat and diagnose diseases and disorders are also described.

Description

[0001]Related Applications U.S. 61 / 364,764, filed Jul. 15, 2010; U.S. 61 / 364,765, filed Jul. 15, 2010; U.S. 61 / 364,766, filed Jul. 15, 2010; U.S. 61 / 364,771, filed Jul. 15, 2010; U.S. 61 / 364,774, filed Jul. 15, 2010; U.S. 61 / 383,644, filed Sep. 16, 2010; U.S. 61 / 481,063, filed Apr. 29, 2011; U.S. 61 / 485,486, filed May 12, 2011; U.S. 61 / 485,484, filed May 12, 2011; U.S. 61 / 485,502, filed May 12, 2011; U.S. 61 / 485,505, filed May 12, 2011; and U.S. Ser. No. 13 / 184,485, filed Jul. 15, 2011 are herein incorporated by reference in their entireties.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The invention relates generally to complexes containing one or more modular recognition domains and includes complexes containing a scaffold such as an antibody. The invention also relates to methods of making these complexes and methods of treatment and diagnosis using these complexes.[0004]2. Background Art[0005]The development of bispecific or multi-specific molecules that target...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/24C07K16/22
CPCA61K38/00C07K16/241A61K47/48546A61K47/48561A61K47/48584A61K47/48676C07K16/22C07K16/24C07K16/2863C07K16/2866C07K16/3046C07K16/32C07K2317/73C07K2317/77C07K2319/01C07K2319/30C12N9/0002A61K47/48415A61K47/6845A61K47/6849A61K47/6855A61K47/6879A61K47/6811A61P1/00A61P19/02A61P29/00A61P37/06C07K14/47A61K47/6843A61K47/6851A61K47/6813
Inventor ROSCHKE, VIKTORLAFLEUR, DAVIDHILBERT, DAVID M.KIENER, PETER
Owner ZYNGENIA
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