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工業技術研究院

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技術名稱: Anti-EGFR 膠原蛋白支架抗體與藥物共軛

技術簡介

本技術為利用國內自主研發的「膠原蛋白支架」 (Collabody)的技術平台專利優勢,開發新穎anti- EGFR膠原蛋白支架藥物共軛複合體(CDC)技術- Collabody-drug conjugates (CDC),本技術具有 很高的細胞內噬化能力,可有效專一的將所鍵結的小分 子藥物送入腫瘤細胞中,造成腫瘤細胞的毒殺作用,目 前已在in vivo與in vitro實驗中驗證 其效果。此外為使藥廠能順利技轉此技術,各項CMC方 法學也已陸續建立,包括藥效與特性分析方法學、高表 現細胞株篩選、Collabody蛋白質純化步驟最適化、生 物反應器試量產開發與pre-formulation開發。

Abstract

We have developed a novel collabody-drug conjugate, in which a cytotoxic agent was conjugated to the collagenous motif of a trivalent anti-EGFR collabody. Due to the avidity and crosslinking effects of the trivalent nature of collabody, the anti- EGFR collabody shows a superior internalization potency to the bivalent IgG counterpart, in which 70% of the anti- EGFR collabody was internalized into the EGFR(+) tumor cell line within 5 minutes, as compared to 30% of the same anti-EGFR IgG molecule. The anti-EGFR collabody exhibits potent cytotoxicity to tumor cells both in cell-based and tumor xenograft mouse models. We conclude that collabody-drug conjugate is a good strategy in developing antibody-drug conjugate agents. For technology transfer, we have developed many methodologies about CMC including potency analytical methods, payload distribution, DAR calculation, highly-expression cell line selection, purification process development, pre- formulation development and bioreactor process development.

技術規格

1. CDC在in vitro實驗對A431腫瘤細胞的毒殺能力為 EC50 = 0.18 nM 2. CDC以HIC-HPLC分析其DAR為2.5 3. Anti-EGFR collabody產量可達0.2 g/L以上,純化 後純度可達95%以上。

Technical Specification

1. In in-vitro experiments, CDC shows the high cytotoxicity for A431 tumor cell (EC50 = 0.18 nM). 2. The DAR of CDC is 2.5 by using HIC-HPLC. 3. The yield of anti-EGFR collabody can reach 200 mg/L and the purity can reach 95% after purification.

技術特色

CDC技術現況: 目前CDC技術已驗證其高抗原結合能力、高細胞內噬能力、in-vitro腫瘤細胞毒殺能力、in vivo小鼠腫瘤模式中具有顯 著抑制效果 方法學上之建立包括: 1. In vitro potency方法學:包括腫瘤細胞毒殺測試、抗原結合能力測試、細胞內噬化能力測試 2. HIC-HPLC DAR and payload distribution方法學 3. In vitro PK方法學 4. Collabody蛋白質最佳純化方法學 CMC技術上之建立: 1. Collabody蛋白質高表現細胞株篩選完成 2. Collabody蛋白質純化最適化 3. Collabody 20~50L試量產 4. Collabody 蛋白質Pre-formulation建立 技術特色: 本技術為結合三倍體膠原蛋白支架抗體與小分子藥物共軛鍵結之技術(Collabody drug-conjugates technology),此 技術具有下列優點: 1. 可以製造雙特異性 Collabody-drug conjugates (CDCs),增加標靶選擇性,減少劑量並促進療效。 2. 藥物可以選擇性的鍵結在部位「膠原蛋白支架區間」 ,完全避開蛋白質標靶結合區間,無論在未來CMC製程開發與藥 效、毒理學皆較現階段ADC有優勢。 3. Single domain CDCs分子量低 (約50 kD, 為IgG 抗體之1/3),對solid tumor在組織穿透性佳,可有效將藥物帶 入腫瘤組織深處。 4. 標靶結合價數增加為三價較抗體IgG二價高,之前SPR證實三價型可促進標靶結合強度外,並且對於低密度的標靶分子 能有效產生 crosslinking 效應,解決誘導內噬化不佳問題。 5. 膠原蛋白支架本身已經證實不具免疫性。 6. 膠原蛋白支架氨基酸序列可增加需要鍵結小分子藥物數量,產生足夠的細胞毒性。 7. 膠原蛋白支架氨基酸序列可使用不同之化學鍵結方式,增加藥物不同種類與endosome 釋放機制。

應用範圍

大腸癌腫瘤治療

接受技術者具備基礎建議(設備)

蛋白質藥物開發之各項基礎設備

接受技術者具備基礎建議(專業)

蛋白質藥物開發之各項專業知識

技術分類 生物工程

聯絡資訊

聯絡人:周民元 標靶藥物與傳輸技術組(0W000)

電話:03-5912144 或 Email:minyuanc@itri.org.tw

客服專線:+886-800-45-8899

傳真:03-5910097

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