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Pegylated tetanus neurotoxins and treatment of hypotonia

A technology of PEGylation and neurotoxins, applied in chemical instruments and methods, neuromuscular system diseases, biochemical equipment and methods, etc., can solve problems such as unused

Pending Publication Date: 2021-04-09
SNORETOX PTY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as noted above, TeNT causes muscle contraction, which precludes its use, with or without PEGylation, for the treatment of inappropriate muscle contraction disorders
[0005] Wan et al., Process Biochemistry (2017) 52:183-191 disclosed the effect of PEGylation on the anti-PEG immune response generated by administration of PEGylated proteins, but did not use its findings for any treatment

Method used

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  • Pegylated tetanus neurotoxins and treatment of hypotonia
  • Pegylated tetanus neurotoxins and treatment of hypotonia
  • Pegylated tetanus neurotoxins and treatment of hypotonia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] Embodiment 1: the preparation of PEG-TeNT-c ( figure 1 A)

[0172] In this example, TeNT-c was generated by mutating the surface serine residues to surface cysteine ​​residues to facilitate directed PEG conjugation at immunogenic epitopes. figure 1 A molecule. The mutations will be: S963C, S1041C, S1155C and S1187C.

[0173] Genes for TeNTs with surface serine→cysteine ​​substitutions S963C, S1041C, S1155C and S1187C will be synthesized by a commercial provider such as Integrated DNA Technologies. The gene was subcloned into the pRSET-A expression vector by restriction digestion to add a 6x histidine tag from the vector to the N-terminus of the mutein.

[0174] TeNTs comprising S963C, S1041C, S1155C and S1187C were expressed, PEGylated and purified according to Example 5 to generate PEG-TeNT-c.

Embodiment 2

[0175] Embodiment 2: the preparation of PEG-TeNT-HC ( figure 1 B)

[0176]In this example, TeNT-HC was generated by mutating the surface serine residues to surface cysteine ​​residues to facilitate directed PEG conjugation at immunogenic epitopes. figure 1 Molecule of B. The mutations will be: S600C, S963C, S1041C, S1155C and S1187C (Figure 24, SEQ ID NO: 16).

[0177] Genes for TeNTs with surface serine→cysteine ​​substitutions S600C, S963C, S1041C, S1155C and S1187C will be synthesized by a commercial provider such as Integrated DNA Technologies. The gene was subcloned into the pRSET-A expression vector (FIG. 25, SEQ ID NO: 17, Figure 26 ) to add a 6×histidine tag from the vector to the N-terminus of the mutein.

[0178] TeNTs comprising S600C, S963C, S1041C, S1155C and S1187C were expressed, PEGylated and purified according to Example 5 to generate PEG-TeNT-HC.

Embodiment 3

[0179] Embodiment 3: the preparation of PEG-TeNT-LC-c ( figure 1 c)

[0180] In this example, LC and c were generated by mutating the surface serine residues to surface cysteine ​​residues to facilitate directed PEG conjugation at immunogenic epitopes. figure 1 Molecules of C. The mutations are: S81C, S120C, S144C, S248C, S335C, S428C, S963C, S1041C, S1155C and S1187C (Figure 21 , SEQ ID NO: 14).

[0181] Genes for TeNTs with surface serine → cysteine ​​substitutions S81C, S120C, S144C, S248C, S335C, S428C, S963C, S1041C, S1155C and S1187C in LC and c were synthesized by a commercial provider (Integrated DNA Technologies). The gene was subcloned into the pRSET-A expression vector (FIG. 22, SEQ ID NO: 15, Figure 23 ) to add a 6×histidine tag from the vector to the N-terminus of the mutein.

[0182] TeNTs comprising S81C, S120C, S144C, S248C, S335C, S428C, S963C, S1041C, S1155C and S1187C were expressed, PEGylated and purified according to Example 5 to generate PEG-TeNT-LC-...

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Abstract

The invention relates to a composition comprising a first PEGylated tetanus neurotoxin (PEG-TeNT) comprising tetanus neurotoxin (TeNT) conjugated to polyethylene glycol (PEG) and a second TeNT. The invention also relates to various PEG-TeNTs. The invention also relates to a method of treating hypotonia using the composition or various PEG-TeNTs, and a kit comprising the composition or various PEG-TeNTs. In one embodiment, the hypotonia is obstructive sleep apnoea.

Description

technical field [0001] The present invention relates to a composition comprising: a first pegylated tetanus neurotoxin (PEG-TeNT) comprising a tetanus neurotoxin (TeNT) conjugated to polyethylene glycol (PEG) and the second TeNT. The invention also relates to a method of treating hypotonia using said composition. Background technique [0002] Tetanus neurotoxin (TeNT) is produced by Clostridium tetani. TeNT acts on the spinal cord and blocks the release of gamma-aminobutyric acid (GABA) and glycine, which are inhibitory neurotransmitters, at spinal inhibitory interneurons. Thus, TeNT can cause spastic paralysis. TeNT does not exist in multiple serotypes. [0003] Therapeutics have been proposed to exploit the biological properties of TeNT or at least TeNT fragments. However, long-term treatment with protein therapeutics often results in a targeted immune response. Since only one serotype of TeNT is known, TeNT-based therapy cannot select for serotype switching to circu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/33A61K38/16A61K47/60A61P21/00
CPCA61P21/00C07K14/33A61K47/60A61K38/00A61K39/08A61K2039/6093C12Y304/24069Y02A50/30C12Y304/24068A61K2039/6037
Inventor T·麦克林P·斯姆克L·诺伯里P·克洛伊R·孔杜伊特A·萨塞
Owner SNORETOX PTY LTD
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