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Antibodies to lymphotoxin-alpha

A technology of lymphotoxin and antibody, applied in the direction of antibody, cytokine/lymphokine/interferon, anti-cytokine/lymphokine/interferon immunoglobulin, etc.

Inactive Publication Date: 2009-11-04
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While both classes of molecules prevent TNFα from binding to its receptors, receptor-based inhibitors such as etanercept also prevent LTα from binding

Method used

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  • Antibodies to lymphotoxin-alpha
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  • Antibodies to lymphotoxin-alpha

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0557] Example 1: Preparation of anti-human and anti-mouse LTα monoclonal antibodies and hamster-mouse chimera

[0558] Anti-human LTα monoclonal antibodies 2C8 and 3F12 were generated as follows: by injection of 5 μg / dose in DETOX TM Purified recombinant human LTα expressed in E. coli (Charles River Laboratories, Wilmington, DE) (Genentech, Inc., South San Francisco, CA; Genentech Lot.) in adjuvant (RIBI ImmunoChem Research, Inc., Hamilton, MO) # 8360-2B; see also Spriggs, "Tumor Necrosis Factor: Basic Principles and Preclinical Studies", Biologic Therapy of Cancer, DeVita et al., eds., J.B. Lippincott Company (1991) Chapter 16, pp. 354-377; Ruddle, Current Opinion in Immunology, 4:327-332 (1992); Wong et al., "Tumor Necrosis Factor", Human Monocytes, Academic Press (1989), pp. 195-215; Aggarwal et al., Cytokines and Lipocortins in Inflammation and Differentiation, Wiley-Liss , Inc. 1990, pp. 375-384; and Paul et al., Ann. Rev. Immunol., 6: 407-438 (1988)) to hyperimmunize B...

Embodiment 2

[0581] Example 2: Sequencing, humanization, and affinity maturation of anti-LTα antibody 3F12

[0582] 1. De novo sequencing of anti-LTα3F12 using LTQ-FTMS-MS / MS analysis and Edman degradation

[0583] Because the hybridoma cell line 3F 12.2D3 was lost from the frozen cell line bank, anti-LTα monoclonal antibody protein purified from ascitic fluid 3F12.2D3 was submitted for sequencing at a concentration of approximately 3.0 mg / mL in PBS. Under reducing conditions at 4-20% TRIS TM Antibodies (Ab) were separated on HCl SDS-PAGE, and each resolved separated heavy chain (HC) and light chain (LC) was subjected to N-terminal sequencing (determining the sequence of 25-30 residues) to establish monoclonality. The HC was found to be blocked by a pyroglutamyl group, making the N-terminal amino acid unavailable for Edman sequencing. The blocking group was then removed using pyroglutamate aminopeptidase (PGAP) and the HC chains were sequenced again. Both HC and LC were confirmed to be...

Embodiment 3

[0642] Example 3: Preparation and humanization of chimeric antibody 2C8

[0643] 1. Preparation of Chimeric Antibody

[0644] The heavy and light chain variable regions of murine anti-LTα antibody 2C8, which binds and neutralizes LTα3 and LTαβ, were cloned and typed as a murine / human chimeric antibody essentially as described above in Example 1 for clone S5H3.

[0645] For RT-PCR, the primers used are as follows:

[0646] 2C8 light chain:

[0647] 5' primer: GCC ATA GAT ATC GTR ATG CAN CAG TCT C (SEQ ID NO: 79)

[0648] 3' primer: TTT KAT YTC CAG CTT GGT ACC (SEQ ID NO: 80)

[0649] 2C8 heavy chain:

[0650] 5' primer: GAT CGA CGT ACG CTG AGG TYC AGC TSC AGC TSC AGC AGTCTG G (SEQ ID NO: 81)

[0651] 3' primer: ACA GAT GGG CCC TTG GTG GAG GCT GMR GAG ACD GTGASH RDR GT (SEQ ID NO: 82),

[0652] Wherein K=G or T, S=C or G, D=A or G or T, M=A or C, H=A or C or T, N is T, G, A, or C (in these four kinds any nucleic acid), R=A or G, and Y=C or T.

[0653]The light chain vari...

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PUM

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Abstract

The invention provides various antibodies that bind to lymphotoxin-alpha, methods for making such antibodies, compositions and articles incorporating such antibodies, and their uses in treating, for example, an autoimmune disorder. The antibodies include murine, chimeric, and humanized antibodies.

Description

[0001] related application [0002] This non-provisional application claims the benefit of priority to U.S. Provisional Application Serial No. 60 / 829,257, filed October 12, 2006, and U.S. Provisional Application Serial No. 60 / 938,999, filed May 18, 2007, which are hereby incorporated by reference in their entirety . field of invention [0003] The present invention relates to antibodies and their use in the treatment of autoimmune disorders. More specifically, the invention relates to antibodies that bind lymphotoxin-alpha and can also block the binding of a lymphotoxin-alpha ligand to one or more receptors. Background of the invention [0004] TNF and LT [0005] Autoimmune diseases remain clinically important human diseases. As the name suggests, autoimmune diseases work through the body's own immune system to wreak havoc. Although the mechanisms of pathology vary among the various types of autoimmune disease, one general mechanism involves the binding of certain anti...

Claims

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Application Information

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IPC IPC(8): C07K16/24A61K39/395A61P37/06C07K14/525
Inventor 卡姆利亚·W·亚当斯简·L·格罗根奥斯汀·L·格尼克丽丝塔·麦卡琴
Owner GENENTECH INC
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