Antibody and methods for selective inhibition of T-cell responses

An antibody and cell technology, applied in chemical instruments and methods, antibodies, antibody medical components, etc., can solve the problem of not showing sufficient clinical efficacy and safety distribution at the same time

Inactive Publication Date: 2015-08-26
TOLERA THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although attempts have been made to develop certain αβTCR-specific antibodies, none have simultaneously demonstrated sufficient clinical efficacy and an acceptable safety profile

Method used

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  • Antibody and methods for selective inhibition of T-cell responses
  • Antibody and methods for selective inhibition of T-cell responses
  • Antibody and methods for selective inhibition of T-cell responses

Examples

Experimental program
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preparation example Construction

[0366] Preparation and screening of combinatorial chemical libraries is well known to those skilled in the art. Such combinatorial chemical libraries include, but are not limited to, peptide libraries (see, e.g., U.S. Patent No. 5,010,175. Peptide synthesis is by no means the only method contemplated and devised for use in the present invention. Methods for generating chemically diverse libraries can also be used. Other chemistries. Such chemistries include, but are not limited to: peptoids (PCT Publication No. WO91 / 19735, December 26, 1991), encoded peptides (PCT Publication No. WO 93 / 20242, October 14, 1993) , random bio-oligomers (PCT publication WO92 / 00091, January 9, 1992), benzodiazepines (US Patent No. 5,288,514), drivers (diversomers) such as hydantoins, benzodiazepines, and Dipeptides, ethylene analog polypeptides, non-peptide mimetics with β-D-glucose scaffolds, similar organic synthesis of small compound libraries, oligocarbamates, and / or peptidylphosphonates.Genera...

Embodiment 1

[0371] Example 1. Treatment and Evaluation of Humans Treated with TOL101 or Chimeric TOL101

[0372] TOL101 is produced by hybridoma TOL101 MCB and is a mouse IgM monoclonal antibody (specifically IgMκ) that binds to human αβTCR.

[0373] Exemplary TOL101 and TOL101 Chimeric Antibody Formulations

[0374] TOL101 and chimeric TOL101 can be produced as lyophilized preparations that are reconstituted in sterile water for injection (SWFI) and subsequently diluted in saline prior to IV administration. Vials of product can be reconstituted in 3 mL SWFI to provide 50-150 mM L-arginine (e.g. 50 mM...75 mM...100 mM...125 mM...150 mM), 1-10 mM citrate (e.g., 1.0mM...2.0mM...3.0mM...4.0mM...5.0mM...6.0mM...7.0mM...8.0mM...9.0mM...10mM), 2- 8% Mannitol (w / v) (eg, 2%...3%...4%...5%...6%...7%...or 8%), 0.005- 0.05% Tween 80, pH 7.0 (eg 0.005%...0.01%...0.02%...0.03%...or 0.05%) final formulation.

[0375] Preparation of TOL101 and chimeric TOL101

[0376] TOL101 and chimeric TOL101 can...

Embodiment 2

[0391] Example 2. Treatment of Human Transplant Patients

[0392] This example describes the treatment of human kidney transplant patients with the TOL101 monoclonal antibody, and the CD3 counts of these patients were tested at various time points. Depletion and / or modulation of T cells (as measured by the CD3 biomarker) is important in the initial stages of organ transplantation as it prevents acute rejection. Furthermore, it allows for delayed application of maintenance immunosuppressants, which are known to be toxic to transplanted organs, especially in the case of kidney transplants. Has been determined empirically by physicians, 50 (CD3+ count / mm 3 ) represents the upper threshold at which lowering of T cells is required to provide better long-term outcomes. In this example, kidney transplant patients were infused over at least 6 days according to the schedule in Table 8 below. Three different groups of two patients each were tested. Doses tested were 0.28 mg, 1.4 mg,...

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Abstract

The present invention provides compositions, methods, and assays for treating an inflammatory and / or autoimmune disease, and / or transplanted tissue rejection using anti-alphabeta TCR antibodies and antibody fragments. Anti-alphabeta TCR antibodies are antibodies which bind to a alphabeta TCR. Anti-alphabeta TCR antibodies produced by the hybridoma TOL101 MCB are also provided. Methods for treatment of an inflammatory disease, an autoimmune disease and for tissue transplant rejection using therapeutic dosing regimen of anti-alphabeta TCR antibodies and antibody fragments and for upregulating the numbers of Treg T-cells are also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Patent Application Nos: 61 / 555,335 (filed November 3, 2011); 61 / 555,344 (filed November 3, 2011); 61 / 589,715 (filed January 23, 2012); 61 / 610,348 (filed March 13, 2012) and 61 / 654,631 (filed June 1, 2012), the entire contents of each of which are hereby incorporated by reference in their entirety. [0003] Description of electronically submitted text files [0004] The content of the text file electronically filed herewith is hereby incorporated by reference in its entirety: Copy of Sequence Listing in Computer Readable Form (File Name: TLRA_001_01WO_SeqList_ST25.txt, Date of Record: November 5, 2012, File Size 20 kilowords Festival). field of invention [0005] The present invention relates to antibodies and methods for selectively inhibiting (TCR+) T cell immune responses. In particular, the invention relates to the use of anti-αβ TCR antibodies and antibody fragments in the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395
CPCC07K16/2809C07K2317/73A61K2039/545A61K39/39591A61K2039/505C07K16/2803C07K2317/622A61P1/04A61P1/16A61P11/00A61P11/06A61P13/12A61P17/00A61P17/06A61P19/00A61P19/02A61P21/00A61P21/04A61P25/00A61P27/02A61P29/00A61P37/00A61P37/06A61P37/08A61P5/00A61P9/00A61P3/10C07K2317/76C07K2317/94
Inventor D.R.盖茨J.J.赫曼J.J.普伊希斯F.J.弗克塔
Owner TOLERA THERAPEUTICS
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