A kind of polyethylene glycol-rtrail mutant trimer-dolastatin conjugate and its preparation method and application

A technology of polyethylene glycol and dolastatin, which is applied in the fields of biotechnology and medicine, can solve the problems of increased molecular weight, short half-life, and difficulty in improving the half-life of rTRAIL, and achieves reduced precipitation, long half-life, and good pharmacokinetic properties. Effect

Active Publication Date: 2018-09-28
ZHEJIANG UNIV
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  • Abstract
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Problems solved by technology

[0008] The disadvantage of this conjugate is that rTRAIL itself has a very short half-life of only 3 to 5 minutes in rodents and 23 to 30 minutes in non-human primates
After rTRAIL is coupled with dolastatin, it is difficult to improve the short half-life of rTRAIL due to the limited increase in the molecular weight of the product (1316Da)
In view of the short half-life of rTRAIL-MMAE conjugates, further modification is urgently needed to improve their pharmacokinetic properties and improve the druggability of the conjugates

Method used

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  • A kind of polyethylene glycol-rtrail mutant trimer-dolastatin conjugate and its preparation method and application
  • A kind of polyethylene glycol-rtrail mutant trimer-dolastatin conjugate and its preparation method and application
  • A kind of polyethylene glycol-rtrail mutant trimer-dolastatin conjugate and its preparation method and application

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Embodiment 1

[0061] Example 1 Preparation of polyethylene glycol-rTRAIL mutant trimer-dolastatin conjugate

[0062] 1. Preparation of PEG-rTRAIL-MMAE conjugates with different PEG / MMAE ratios (such as figure 1 )

[0063] (1) The ratio of PEG / MMAE is 0.5 (that is, the molar ratio of N109C trimer, PEG, and MMAE is 1:1:2)

[0064]A preparation method of polyethylene glycol-rTRAIL mutant trimer-dolastatin conjugate (hereinafter referred to as PEG-rTRAIL-MMAE conjugate), comprising the following steps:

[0065] ① Preparation of rTRAIL mutant N109C;

[0066] For the preparation method of the rTRAIL mutant N109C, refer to Parts 1 to 6 of the specific implementation methods in the Chinese invention patent with the authorized announcement number CN 102936281B, and its amino acid sequence is shown in SEQ ID No.1.

[0067] ② Dissolve 1mg of rTRAIL mutant N109C in 1mL PBS (pH 6.0, containing 10μM ZnCl 2 ), add 10 μL of ten-fold amount of tris(β-chloroethyl)phosphate (TCEP), and react in a water ba...

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Abstract

The invention discloses a polyethylene glycol-rTRAIL mutant tripolymer-aplysiatoxin conjugate as well as a preparation method and an application thereof. In the polyethylene glycol-rTRAIL mutant tripolymer-aplysiatoxin conjugate, the amino acid sequence of an rTRAIL mutant is shown in SEQ ID No.1; an rTRAIL mutant tripolymer is coupled with methoxy polyethylene glycol maleimide and aplysiatoxin which is provided with a connecting arm. The conjugate disclosed by the invention has higher tumor cell killing capability than an rTRAIL mutant tripolymer-aplysiatoxin conjugate and longer half-life period than an rTRAIL mutant-monomethyl polyethylene glycol maleimide conjugate; in the conjugate disclosed by the invention, the methoxy polyethylene glycol maleimide, the rTRAIL mutant tripolymer and the aplysiatoxin do not play effects independently but play a relatively high synergistic effect.

Description

technical field [0001] The invention belongs to the fields of biotechnology and medicine, and in particular relates to a polyethylene glycol-rTRAIL mutant trimer-dolastatin conjugate and a preparation method and application thereof. Background technique [0002] Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TNF related apoptosis-inducing ligand, TRAIL, or Apo2L, TNFSF10) is the third apoptosis factor of the TNF family discovered after TNF and FasL, and is an anticancer Biopharmaceuticals with promising application prospects. [0003] TRAIL is expressed in cells of the immune system, including NK cells, T cells, macrophages, and dendritic cells, and is located in the cell membrane where it can be processed into a soluble form by cysteine ​​proteases. TRAIL induces apoptosis by combining with its cell membrane receptor. Five TRAIL receptors have been discovered, including: TRAIL-R1 (DR4, TNFSF10a) and TRAIL-R2 (DR5, TNFRSF10b); TRAIL-R3 (DcR1, TNFRSF10c) and...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/525C07K1/107A61K38/19A61K47/64A61P35/00
CPCA61K38/19A61K47/60C07K14/43504C07K14/525C07K2319/00
Inventor 潘利强陈枢青
Owner ZHEJIANG UNIV
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