Bispecific immunobinders directed against TNF and il-17

a technology of immunobinders and il-17, which is applied in the field of bispecific immunobinders directed against tnf and il17, can solve the problems of reduced production yield, complex purification procedures, and inability to yield homogeneous preparations, and achieve the effect of reducing on

Inactive Publication Date: 2014-03-20
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0055](e) reduces one or more of IL-17-dependent cytokine production, IL-17-dependent cell killing, IL-17-dependent inflammation, IL-17-dependent bone erosion, and IL-17-dependent cartilage damage.

Problems solved by technology

The presence of mis-paired by-products, and significantly reduced production yields, means sophisticated purification procedures are required.
This approach does not yield homogeneous preparation.
Another method used to produce bispecific binding protein is the coupling of two parental antibodies with a hetero-bifunctional crosslinker, but the resulting bispecific antibodies suffer from significant molecular heterogeneity because reaction of the crosslinker with the parental antibodies is not site-directed.
But this method results in Fab′2 fragments, not full a IgG molecule.
In addition, such approach requires mutational modification of the immunoglobulin sequence at the constant region, thus creating non-native and non-natural form of the antibody sequence, which may result in increased immunogenicity, poor in vivo stability, as well as undesirable pharmacokinetics.

Method used

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  • Bispecific immunobinders directed against TNF and il-17

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Improved TNF-α Parental Binding Proteins

example 1.1

Identification of Fully Human Binding Proteins to TNF by In Vitro Display Systems

1.1.1: Antibody Selections

[0297]Fully human anti-human TNF monoclonal antibodies were isolated by in vitro display technologies from human antibody libraries by their ability to bind recombinant human TNF proteins. The amino acid sequences of the variable heavy (VH) and variable light (VL) chains were determined from DNA sequencing and listed in Table 1B in section A)I)A) above.

1.1.2: Affinity Maturation of the Fully Human Human TNF Binding Protein AE11-5

[0298]The AE11-5 human binding protein to human TNF was affinity matured by in vitro display technology. One light chain library was constructed to contain limited mutagenesis at the following residues: 28, 31, 32, 51, 55, 91, 92, 93, 95a and 96 (Kabat numbering). This library also contained framework germline back-mutations D1E, M4L, H11Q, R49K, H76N and Q103K as well as toggled residues at position 50 (R / K) and 94 (S / L) to allow for framework germlini...

example 1.2

Affinity Maturation of a Humanized Human TNF Binding Protein hMAK-195

[0301]The mouse anti-human TNF antibody MAK-195 was humanized and affinity-matured to generate a panel of humanized MAK195 variants that have cross-reactivity to cyno-TNF and improved affinity and binding kinetics against both human and cyno TNF.

[0302]To improve the affinity of hMAK195 to TNF, hypermutated CDR residues were identified from other human antibody sequences in the IgBLAST database that also shared high identity to germlines VH3-53 and IGKV1-39. The corresponding hMAK195 CDR residues were then subjected to limited mutagenesis by PCR with primers having low degeneracy at these positions to create three antibody libraries in the scFv format. The first library contained mutations at residues 31, 32, 33, 35, 50, 52, 53, 54, 56 and 58 in the VH CDR1 and 2 (Kabat numbering); the second library at residues 95 to 100, 100a, 101, and 102 in VH CDR3; and the third library at residues 28, 30, 31, 32, 50, 53, 92, 9...

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Abstract

Engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention, diagnosis, and/or treatment of disease are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Ser. No. 61 / 550,619, filed Oct. 24, 2011, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]Multivalent and multispecific binding proteins that bind TNF and IL-17, methods of making, and specifically to their uses in the, diagnosis, prevention and / or treatment of acute and chronic inflammatory diseases, cancer, and other diseases are provided.[0004]2. Background of the Invention[0005]Engineered proteins, such as multispecific binding proteins capable of binding two or more antigens are known in the art. Such multispecific binding proteins can be generated using cell fusion, chemical conjugation, or recombinant DNA techniques.[0006]Bispecific binding protein have been produced using quadroma technology (see Milstein and Cuello (1983) Nature 305(5934):537-40) based on the somatic fusion of two different hy...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/24C07K16/46
CPCC07K16/468C07K16/241C07K16/244A61K2039/505C07K2317/21C07K2317/24C07K2317/31C07K2317/33C07K2317/565C07K2317/567C07K2317/622C07K2317/64C07K2317/76C07K2317/92C07K2317/94A61P1/04A61P1/16A61P11/02A61P11/06A61P17/00A61P17/04A61P17/06A61P19/02A61P25/00A61P29/00A61P31/04A61P31/12A61P31/14A61P31/20A61P33/10A61P35/00A61P35/04A61P37/00A61P37/02A61P37/06A61P37/08A61K39/3955A61K45/06G01N33/5308
Inventor HSIEH, CHUNG-MINGPEREZ, JENNIFERBENATUIL, LORENZOKUTSKOVA, YULIYAMEMMOTT, JOHNZHONG, SUJUEATON, LUCIAHUGUNIN, MARGARETBRITO, ALYSSACLABBERS, ANCA
Owner ABBVIE INC
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