▌技術簡介(現況)

抗體藥物複合體(Antibody-Drug Conjugate, ADC)結合抗體藥物的高專一性與化療藥物強大的癌細胞毒殺作用,可改善傳統小分子化療藥物非專一性作用的缺點,使毒殺物質作用於腫瘤細胞,因而治療癌症之療效更佳,吸引全球市場投入開發。ADC之抗體藥物鏈結技術經多年發展已漸趨成熟,然而仍多有藥物異質性的問題,無法有效均一地接合小分子藥物至固定結合位置,使得ADC藥物穩定度無法提升。

本技術是為了開發一個高效率的專一性結合點抗體藥物共軛複合體(site specific antibody-drug conjugate)技術平台,透過特有的抗體生產細胞株或N-acetyl Glucosamidase酵素將抗體N297-Glycan切成均相三甘露醣抗體產品為原料,以MGAT-1 與MGAT-2為酵素,將Tri-mannose抗體一次性或步驟性(stepwise)轉換成帶有四個GlcNAZ G0抗體,再藉由Strain-promoted Azide-Alkyne Click Chemistry (SPAAC) 一次性或步驟性的接上4個小分子藥物,4個小分子藥物可為同種(4A)或兩種(2A及2B),轉換率為95%以上,回收率現階段達60%,1mg酵素1小時可轉換1.25g抗體,可應用於新穎或學名抗體,本開發技術已申請多國專利(WO2018126092A1, AU2017388556A1, CA3048452A1, CN110121365A, EP3568161A1, JP2020503031A和KR20190086029A),並取得台灣專利(TW:I673363B)。

 

▌技術規格

專一性接合之三甘露醣抗體藥物複合體技術平台,適合開發成抗體藥物共軛之藥物複合體

 

▌技術特色

1.Tri-mannosyl–ADC技術是藥物與此醣基結合成為專一接合藥物之位置,形成均質antibody drug conjugate (ADC) ,使ADC 的品質更專一及穩定。

2.Tri-mannosyl–ADC平台藥物連接法具有多樣性,DAR(drug antibody ratio)可以同質性的2或4,當DAR是4時連接藥物可為單種或兩種,因此有控制藥物毒性及減少抗藥性的優點。

3.藥物連接反應在水相,室溫,容易操作,轉換率高。

4.透過發酵及醣基工程細胞株可大量生產三甘露醣核心均相醣基抗體及製程轉換酵素,製成本可大幅降低。

 

▌應用範圍

多種癌症相關疾病。

 

▌接受技術者具備基礎建議(設備)

一般特殊毒化物實驗設施、分子生物學實驗設施、抗體表現與純化系統。

 

▌接受技術者具備基礎建議(專業)

抗體臨床前開發技能。

 

▌技術分類

抗體藥物共軛技術開發。

 

▌專利狀態

WO2018126092A1, AU2017388556A1, CA3048452A1, CN110121365A, EP3568161A1, JP2020503031A, KR20190086029A, TWI673363B


聯絡人林冠宗

TEL(02)7700-3800 #5239

E-mailktlin2@dcb.org.tw

最後更新日期:2020.03.30

 

 

Technology/ Title

Tri-mannosyl antibody: A versatile payload ADC platform

Technology Type

Biotechnology

□Device/Diagnostics

Pharmaceutical

□Others:_____________-

Contact Person

Name: Joseph LiuKuan-Tsung Lin

Title: Project Manager

Telephone(work): +886-02-7700-3800  ext. 5237, ext. 5239  

Email: joseph.liu@dcb.org.twktlin2@dcb.org.tw

2019 BioAsia

Information

Download

https://www.dcb.org.tw/posts/729

 

 

Technology Description

 

  • Field/Type: Linker for ADC/Platform
  • Introduction:

A high efficiency glycoengineering technology by using rabbit GnT-I (N-Acetyl glucosamine transferase I) and rat GnT-II (N-Acetyl glucosamine transferase II) to conjugate a tri-mannosyl core antibody for novel ADC has been established.   This platform converts the tri-mannosyl antibody to a tri-mannosyl-4GlcNAz antibody and then links to payloads (ex. Dibenzocyclooctyne(DBCO)-(PEG)4-DM1) to the terminal GlcNAz group at antibody’s specific sites by strain-promoted azide-alkyne click chemistry (SPAAC) reaction. The conversion efficiency is over 98%. In a dual payload ADC module, the conversion efficiency over 90%.

  1. Site specific conjugation;
  2. Homogeneous DAR (drug antibody ratio) is 2 or 4;
  3. Homogeneous payload or dual payloads can be chosen;
  4. Liquid phase, room TM and overnight manufacturing process and required materials are produced by our established cell line;
  5. Tri-mannosyl Trastuzumab-4DM1 has better PK than that of Kadcyla.
  6. Tri-mnnosyl anti mesothelin-4AZ-DBCO-vc-MMAE has better efficacy and PK than that of MMAE lysine random conjugation mesothelin ADC (DAR=4).
  • Application:

ADC for therapeutic or diagnostic purpose

Intellectual Property

PCT and TW patents applied

Business Opportunity

Antibodies are suitable as targets for ADC development