Use of semaphorin-4D binding molecules for modulation of blood brain barrier permeability

A technology combining molecules and the blood-brain barrier, applied in the direction of peptide/protein components, immunoglobulins, medical preparations containing active ingredients, etc., can solve the problem of unclear effect of signal transduction on the blood-brain barrier

Inactive Publication Date: 2014-11-26
VACCINEX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the role of SEMA4D signaling through its receptors (e.g., Plexin-B1) on angiogenesis is well established, the role of SEMA4D signaling on the blood-brain barrier (BBB) ​​remains unclear

Method used

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  • Use of semaphorin-4D binding molecules for modulation of blood brain barrier permeability
  • Use of semaphorin-4D binding molecules for modulation of blood brain barrier permeability
  • Use of semaphorin-4D binding molecules for modulation of blood brain barrier permeability

Examples

Experimental program
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Effect test

Embodiment 1

[0158] Example 1: In an in vitro DIV-BBB model, testing of anti-SEMA4D binding molecules (e.g., antibodies or antigen-binding fragments, variants or derivatives thereof), e.g., VX15 / 2503, restores BBB integrity after SEMA4D-induced BBB disruption sexual ability

[0159] experimental design. A dynamic in vitro BBB ("DIV-BBB") model was performed to study the effect of recombinant human SEMA4D (huSEMA4D-his) and VX15 / 2503 (described in detail in US2010 / 0285036A1, which is incorporated herein by reference in its entirety) on BBB integrity. influences. Two DIV-BBB boxes were tested in this model. The basic experimental design is shown in figure 1 middle. Increasing concentrations of recombinant SEMA4D (rSEMA4D) were added to the lumen at 12 hour intervals and allowed to equilibrate (approximately 12 hours / concentration). At time 0, rSEMA4D was initially added to the lumen at a concentration of 0.05 μg / ml. At each time interval, the concentration of rSEMA4D increased 10-fold,...

Embodiment 2

[0163] Example 2: In an in vitro DIV-BBB model, testing of anti-SEMA4D binding molecules (e.g., antibodies or antigen-binding fragments, variants or derivatives thereof), e.g., VX15 / 2503, restores BBB integrity following SEMA4D-induced BBB disruption sexual ability

[0164] experimental design. A second experiment using the in vitro DIV-BBB model was performed to investigate the effect of SEMA4D and VX15 / 2503 on BBB integrity. Basic experimental design and above embodiment 1 and figure 1 similar to that shown in . Over two weeks, the DIV-BBB box underwent BBB formation in the endothelial and astrocytic compartments. BBB formation as reflected by TEER is shown in image 3 and 4 middle.

[0165] rSEMA4D-induced increase in BBB permeability. After BBB formation, the effect of rSEMA4D on BBB integrity was measured by adding increasing concentrations of recombinant SEMA4D (rSEMA4D) at 12 h intervals to the lumen of the first of a set of three cassettes, allowing them to equi...

Embodiment 3

[0168] Example 3: Testing the ability of anti-plexin B1 binding molecules (e.g., antibodies or antigen-binding fragments, variants or derivatives thereof) to restore BBB integrity following SEMA4D-induced BBB disruption in an in vitro DIV-BBB model

[0169] Another study was performed to measure the effect of an anti-plexin Bl antibody (MAB37491 human plexin-Bl MAb (clone 559830), R&D Systems) on BBB integrity. This antibody blocks the binding of SEMA4D to the Plexin-B1 receptor. The results of this study were shown in Figure 5 middle. Such as Figure 5 As shown in , human endothelial cells and astrocytes in four DIV-BBB boxes underwent BBB formation similar to the experiments described above. After BBB formation, rSEMA4D was added at a concentration of 50.0 μg / ml, thereby inducing an increase in BBB permeability (ie, disruption of the BBB). Anti-Plexin-B1 antibody at a concentration of 125 μg / ml was added to two of the four boxes and VX15 / 2503 antibody at a concentration...

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Abstract

Provided herein are methods for decreasing blood-brain barrier permeability in a subject with a neuroinflammatory disorder, comprising administering to the subject an effective amount of an isolated binding molecule which specifically binds to semaphorin-4D (SEMA4D) or to its high affinity Plexin-B1 receptor.

Description

[0001] References to Sequence Listings Submitted Electronically [0002] The contents of the electronically filed Sequence Listing in the ASCII text file filed with this application (file name: "1843_068PC03_SequenceListing_ascii.txt", size: 33,807 bytes; and date created: October 10, 2012) are hereby incorporated by reference in their entirety middle. Background of the invention [0003] Semaphorin 4D (SEMA4D), also known as CD100, is a transmembrane protein belonging to the semaphorin gene family (eg, SEQ ID NO: 1 (human); SEQ ID NO: 2 (mouse)). SEMA4D is expressed on the cell surface as a homodimer, but upon cell activation, SEMA4D can be released from the cell surface via proteolytic cleavage to produce sSEMA4D, a soluble form of the protein that is also biologically active. See Suzuki et al., Nature Rev. Immunol. 3:159-167 (2003); Kikutani et al., Nature Immunol. 9:17-23 (2008). [0004] SEMA4D is expressed at high levels in lymphoid organs including spleen, thymus, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P25/00A61K38/00A61K39/395
CPCC07K16/28A61K39/3955C07K16/2803A61K2039/505C07K2317/76A61P21/00A61P21/02A61P25/00A61P25/08A61P25/16A61P25/28A61P29/00A61P43/00A61P7/10
Inventor E·S·史密斯M·佐德勒
Owner VACCINEX
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