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Agonistic Anti-tumor necrosis factor receptor 2 antibodies

a tumor necrosis factor and receptor 2 technology, applied in the field of agonistic antitumor necrosis factor receptor 2 antibodies, can solve the problems that the specific binding of non-human tnfr2 antibodies and antigen-binding fragments thereof may also lack specific binding to a tnfr superfamily, so as to enhance the solubility of the scfv fragment, improve the biophysical stability of the molecule, and increase the resistance of the s

Inactive Publication Date: 2019-05-09
THE GENERAL HOSPITAL CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides TNFR2 agonist antibodies and antigen-binding fragments thereof that specifically bind to TNFR2 and promote its signaling. These antibodies can be used to treat immunological diseases by administering them to patients. The antibodies recognize a specific epitope within TNFR2 and can bind to it with high specificity. They can also promote the proliferation of T-regulatory cells and the death of CD8+ T-cells. The antibodies can also be used to increase the levels of certain proteins involved in the angiogenic pathway, the NFkB pathway, and other signaling pathways.

Problems solved by technology

In addition, TNFR2 agonist antibodies and antigen-binding fragments thereof that specifically bind non-human TNFR2 may also lack specific binding to a TNFR superfamily member other than TNFR2.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

he Discrete Epitopes within TNFR2 that Interact with MR2-1

[0218]Libraries of linear, cyclic, and bicyclic peptides derived from human TNFR2 were screened for distinct sequences within the protein that exhibit high affinity for TNFR2 antibody MR2-1. In order to screen conformational epitopes within TNFR2, peptides from distinct regions of the primary protein sequence were conjugated to one another to form chimeric peptides. These peptides contained cysteine residues at strategic positions within their primary sequences (see, e.g., FIG. 2A, SEQ ID NOs: 53, 69, 75, 118, and 233). This facilitated an intramolecular cross-linking strategy that was used to constrain individual peptides to a one of a wide array of three dimensional conformations. Unprotected thiols of cysteine residues were cross-linked via nucleophilic substitution reactions with divalent and trivalent electrophiles, such as 2,6-bis(bromomethyl)pyridine and 1,3,5-tris(bromomethyl)benzene, so as to form conformationally re...

example 2

TNFR2 Antibodies Induce T-Reg Cell Proliferation

Materials and Methods

[0223]HUMAN T-REG FLOW™ Kit (BioLegend, Cat. No. 320401)[0224]Cocktail Anti-human CD4 PE-Cy5 / CD25 PE (BioLegend, Part No. 78930)[0225]ALEXA FLUOR® 488 Anti-human FOXP3, Clone 259D (BioLegend, Part No. 79467)[0226]ALEXA FLUOR® 488 Mouse IgG1, k Isotype Ctrl (ICFC), Clone MOPC-21 (BioLegend, Part No. 79486)[0227]FOXP3 Fix / Perm Buffer (4×) (BioLegend, Cat. No. 421401)[0228]FOXP3 Perm Buffer (10×) (BioLegend, Cat. No. 421402)[0229]PE anti-human CD25, Clone: BC96 (BioLegend, Cat. No. 302606)[0230]ALEXA FLUOR® 488 Anti-human FOXP3, Clone 259D (BioLegend, Cat. No. 320212)[0231]PBS pH 7.4 (1×) (Gibco Cat. No. 10010-023)[0232]HBSS (1×) (Gibco Cat. No. 14175-095)[0233]FBS (heat inactivated)[0234]15 ml tubes[0235]Bench top centrifuge with swing bucket rotor for 15 ml tubes (set speed 1100 rpm or 200 g)

[0236]Agonistic TNFR2 antibodies (MR2-1 and 8E6.D1) were tested for the ability to induce the proliferation of T-reg cells. Cu...

example 3

g Agonistic TNFR2 Antibodies by Phage Display

[0239]An exemplary method for in vitro protein evolution of agonistic TNFR2 antibodies of the invention is phage display, a technique which is well known in the art. Phage display libraries can be created by making a designed series of mutations or variations within a coding sequence for the CDRs of an antibody or the analogous regions of an antibody-like scaffold (e.g., the BC, CD, and DE loops of 10Fn3 domains). The template antibody-encoding sequence into which these mutations are introduced may be, e.g., a naive human germline sequence as described herein. These mutations can be performed using standard mutagenesis techniques described herein or known in the art. Each mutant sequence thus encodes an antibody corresponding in overall structure to the template except having one or more amino acid variations in the sequence of the template. Retroviral and phage display vectors can be engineered using standard vector construction techniqu...

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Abstract

The invention provides agonistic TNFR2 antibodies and antigen-binding fragments thereof and encompasses the use of these antibodies as therapeutics to promote the proliferation of regulatory T cells (T-reg) for the treatment of immunological diseases. Antibodies of the invention can be used to potentiate the T-reg-mediated deactivation of self- and allergen-reactive T- and B-eases. Antibodies and can thus be used to treat a wide variety of indications, including autoimmune diseases, allergic reactions, asthma, graft-versus-host disease, and allograft rejection, among others.

Description

FIELD OF THE INVENTION[0001]The invention relates to antibodies capable of potentiating tumor necrosis factor receptor 2 signalling and their use for modulating the activity of T-reg cells, and provides therapies for immunological disorders or conditions, such as multiple sclerosis, asthma, allergic reactions, graft-versus-host disease, and transplantation graft rejection.BACKGROUND OF THE INVENTION[0002]Maintaining control of the cell-mediated and humoral immune responses is an important facet of healthy immune system activity. The aberrant regulation of T-cell and B-cell driven immune reactions has been associated with a wide array of human diseases, as the inappropriate mounting of an immune response against various self and foreign antigens plays a causal role in such pathologies as autoimmune disorders, asthma, allergic reactions, graft-versus-host disease, transplantation graft rejection, and a variety of other immunological disorders. These diseases are mediated by T- and B-l...

Claims

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Application Information

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IPC IPC(8): C07K16/28G01N33/68A61K38/19A61K39/395A61P37/06
CPCC07K16/2878G01N33/6854A61K38/191A61K39/3955A61P37/06C07K2317/34C07K2317/92C07K2317/75C07K2317/622G01N2333/7151
Inventor FAUSTMAN, DENISE L.
Owner THE GENERAL HOSPITAL CORP
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