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Selecting headache patients responsive to antibodies directed against calcitonin gene related peptide

A patient and antibody technology, applied in the direction of antibodies, antibody medical components, peptides, etc.

Pending Publication Date: 2019-12-27
BETH ISRAEL DEACONESS MEDICAL CENT INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, while anti-CGRP antibodies have been found to be effective in treating certain headaches, patients can respond in different ways

Method used

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  • Selecting headache patients responsive to antibodies directed against calcitonin gene related peptide
  • Selecting headache patients responsive to antibodies directed against calcitonin gene related peptide
  • Selecting headache patients responsive to antibodies directed against calcitonin gene related peptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 5

[0129] Example 5 describes the means that can be used to identify and select neurons (HT and WDR neurons) in rats. This example also describes observations made in conjunction with the activation and sensitization of each of these types of neurons following CSD induction.

[0130] Patients experiencing hyperalgesia may respond to a course of monoclonal antibodies that modulate (e.g., block, inhibit, suppress, or reduce) the CGRP pathway (e.g., longer anti-CGRP antibody courses and / or higher dose anti-CGRP antibody courses) A response, wherein the hyperalgesia is reduced (eg, reversed or eliminated) following administration of a monoclonal antibody that modulates (eg, blocks, inhibits, suppresses, or reduces) the CGRP pathway. If anti-CGRP antibodies reduce headache in hyperalgesic patients, then it is confirmed that the headache is mediated by HT neurons because, as shown in Example 5, anti-CGRP antibodies do not inhibit WDR, another class of nociceptive neurons. Example 6 de...

Embodiment 1

[0254] Example 1: Generation and Characterization of Monoclonal Antibodies Against CGRP

[0255] Generation of anti-CGRP antibodies. To generate anti-CGRP antibodies with cross-species reactivity to rat and human CGRP, adjuvants containing 25-100 μg of human α-CGRP or β-CGRP conjugated to KLH were administered at various time intervals Mice were immunized (50 μl per footpad, 100 μl total per mouse). Typically such as Geerligs HJ et al., 1989, J. Immunol. Methods 124:95-102; Kenney JS et al., 1989, J. Immunol. Methods 121:157-166; and Wicher K et al., 1989, Int. Arch. Allergy Appl. Immunizations were performed as described in Immunol. 89:128-135. Mice were first immunized with CFA (complete Freund's adjuvant) containing 50 μg of human α-CGRP or β-CGRP conjugated to KLH. After 21 days, human β-CGRP (for mice immunized for the first time with human α-CGRP) or α-CGRP (for mice immunized with human β-CGRP for the first ) IFA (incomplete Freund's adjuvant) to mice for the secon...

Embodiment 2

[0274] Example 2: Screening of anti-CGRP antagonist antibodies using in vitro assays.

[0275] Murine anti-CGRP antibodies were further screened for antagonist activity in vitro using cell-based cAMP activation assays and binding assays.

[0276] Antagonist activity measured by cAMP assay. Five microliters of human α-CGRP or rat α-CGRP (final concentration 50 nM) or rat α - CGRP or human α-CGRP (final concentration 0.1 nM-10 μM; as a positive control for c-AMP activation) was dispensed into 384-well plates (Nunc, Cat# 264657). Ten microliters of cells (human SK-N-MC if using human α-CGRP, or rat L6 from ATCC if using rat α-CGRP) in stimulation buffer (20 mM HEPES, pH 7.4 , 146mM NaCl, 5mM KCl, 1mM CaCl 2 , 1mM MgCl 2 and 500 μM 3-isobutyl-1-methylxanthine (IBMX)) were added to the wells of the plate. Plates were incubated at room temperature for 30 minutes.

[0277] After incubation, use HitHunter TM Enzyme Fragment Complementation Assay (Applied Biosystems) cAMP activ...

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Abstract

The present invention relates to methods for selecting a headache patient responsive to treatment with an anti-CGRP antibody and to methods for reducing headache frequency in the selected patient comprising administering an anti-CGRP antibody.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Application No. 62 / 466,158, filed March 2, 2017; U.S. Application No. 62 / 490,953, filed April 27, 2017; U.S. Application No. 62 / 514,346, filed June 2, 2017; and Priority benefit of U.S. Application No. 62 / 516,406, filed June 7, 2017. The contents of each of the aforementioned applications are incorporated herein by reference in their entirety. Background technique [0003] Humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have been found to be effective in reducing the frequency of chronic migraines (Dodick DW et al (2014) Lancet Neurol.13:1100-1107; Dodick DW et al (2014) Lancet Neurol.13 :885-892; Bigal ME et al. (2015) Lancet Neurol.14:1081-1090; Bigal ME et al. (2015) Lancet Neurol.14:1091-1100; and Sun H et al. (2016) Lancet Neurol.15:382-390 ). However, although anti-CGRP antibodies have been found to be effective in treating certain headaches, patients can ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/18A61P25/06
CPCA61K39/3955C07K2317/51C07K2317/515C07K2317/76A61P25/06C07K16/18A61P43/00A61P29/00C07K2317/55A61K2039/505A61K2039/54A61K2039/545A61K9/0019C07K2317/56C07K2317/565C07K2317/92C07K2317/24
Inventor R.伯斯坦
Owner BETH ISRAEL DEACONESS MEDICAL CENT INC
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