Technology/ Title

Tri-mannosyl Antibody: A Versatile Payload ADC Platform

Technology Type

Biotechnology

Device/Diagnostics

Pharmaceutical

Others:_____________-

Contact Person

Name: Joseph LiuKuantsung Lin

Title: Project Manager

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

Mobile:

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

Link

http://

 

 

Technology Description

 

Summary of Invention:

We have developed 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 and produce a novel format ADC. To validate our platform, Herceptin was sequentially digested to generate a tri-mannosyl Herceptin antibody. The tri-mannosyl ADC with DAR4 (drug-to-antibody ratio) is generated by converting the tri-mannosyl antibody to a tri-mannosyl -4GlcNAz antibody and then the Dibenzocyclooctyne (DBCO) -(PEG)4-DM1 was linked to the terminal GlcNAz group in the antibody by strain-promoted azide-alkyne click chemistry (SPAAC) reaction. Our results demonstrate that the conversion efficiency of the ADC is over 98%. We further proved the feasibility to generate a dual payload ADC with DAR4 from a tri-mannosyl antibody. Our results show that the dual payload ADC is generated with the conversion efficiency over 90%. The tri-mannosyl Herceptin ADC product not only has a similar KD to that of commercial Kadcyla, but also has cytotoxic activities to Her2/Neu medium-expression cell line HCC-1954. These studies suggest that rabbit GnT-1 and rat GnT-2 have very good potential to develop a dual payload and site-specific ADC platform when a tri-mannosyl antibody is used as a start material.

 

Advantages when compared to the existing technologies:

  1. Correct light chain and heavy chain pairing.
  2. Longer half-life.
  3. Target cancer cell-dependent T cell activation.
  4. Better anti-cancer efficacy compared to the short half-life fragment BsAb and its parental monoclonal antibody.
  5. High production yield comparable to its parental mAb.
  6. Low Immunogenicity in rodent.

Intellectual Property

PCT and TW patents applied

Key Publications

 

Business Opportunity

Antibodies are suitable as targets for ADC development.

 

 

▌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。

三甘露醣抗體藥物複合體技術平台,為一高效率之專一性結合點抗體藥物共軛複合體(site specific antibody-drug conjugate)技術平台,以N-acetyl Glucosamidase之抗體生產細胞株生產均相Tri-mannose抗體原料,再由MGAT-1 與MGAT-2酵素作用後,一次性或步驟性地接上單種(4A)或兩種(2A+2B)的 4個小分子藥物,操作容易,可於水相、室溫中反應,且現階段轉換率已達95%以上,回收率達60%,可應用於新穎或學名抗體,本開發技術已申請專利(WO2018126092A1, TW201835331A)。

 

▌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, TW201835331A


聯絡人:鍾牧樺

TEL(02)7700-3800 #5235

E-mailtony.chung@dcb.org.tw

最後更新日期:2019.03.27