the New England Journal of La-Di-Science 2012;11: 008-011
Antibody-Drug Conjugates (ADCs): A Brief Introduction
Wind Chang
-----
Adapted from http://pharmastrategyblog.com/tag/t-dm1/
Source: Roche
抗體藥物複合體 (antibody-drug conjugates, ADCs) 是一種將高度細胞毒性藥物瞄準於惡性腫瘤且較不影響其他正常組織的新型態藥物。
The promise of antibody-drug conjugates (ADCs) is the specific targeting of highly potent cytotoxic agents to malignant disease without adversely affecting normal tissues.
Trastuzumab emtansine (T-DM1) 在針對帶有 HER2 過度表現，並曾使用過 trastuzumab 或 taxane 的晚期乳癌患者之 Phase III 臨床試驗 (EMILIAL trial*) 中發現，與 Lapatinib 併用 Capecitabine 的病人相較，接受 T-DM1 治療的病人擁有較長佳的 progression-free survival (T-DM1: 9.6 months; Lapatinib plus capecitabine: 6.4 months)(HR: 0.65; 95%CI: 0.55-0.77; P<0.001) 與 overall survival (T-DM1: 30.9 months; Lapatinib plus capecitabine: 25.1 months)(HR: 0.68; 95%CI: 0.55-0.85; P<0.001)。顯示了這樣的治療方式在臨床與藥理學層面都是不容忽視的進展。
A positive results of the phase III trial comparing the ADC trastuzumab emtansine (T-DM1) to the combination of lapatinib & capecitabine in women with advanced breast cancers that are strongly positive for HER2. The demonstration of significant clinical benefit (in terms of PFS [3.2 months] & OS [5.8 months] in favor of the ADC for patients whose breast cancers progressed after therapy with treatment regimens containing trastuzumab is noteworthy form both clinical & pharmacologic perspectives.
Adapted from N Engl J Med 2012; 367:1783-1791.
除了 T-DM1 之外，目前共有近 25 個 ADCs 正在進行癌症臨床試驗。而 FDA 更在 2011 年核准了 Seattle Genetics 藥廠所生產的 Brentuximab vedotin (Adcetris®) 新藥申請，核准適應症為 refractory Hodgkin's lymphoma (HL) 與另一種罕見的淋巴癌 - systemic anaplastic large-cell lymphoma (ALCL)。這個作用在 CD30 的 ADC 不僅是 FDA 自 1977 年以來第一個核准用於治療 HL 的抗癌藥，也是第一個被核准用於治療 ALCL 的藥物。Adcetris® 的核准上市以及 EMILIAL 成功的結果或許也代表著 ADCs 邁入臨床應用的開端。
There are approximately 25 ADCs in oncology clinical trials and more in preclinical development. The approval by the FDA of brentuximab vedotin (Seattle Genetics) for the treatment of refractory Hodgkin's lymphoma & systemic analpastic large-cell lymphoma and the positive outcome of the EMILIA trial may be initial output from a pipeline of ADCs that are about to reach clinical practice.
如 ADCs 慣有的天生麗質，T-DM1 的共軛節合體（Linker, 連接子）並不會影響抗體依賴性的細胞毒殺活性，也不會干擾 HER2 主導的抗體中和活性。因此，T-DM1 不僅保有 trastuzumab 本身的抗癌效力，並能使附加其上的強力細胞毒性藥物得以發揮更強的效力。
The beauty of T-DM1 is that conjugate formation does not preclude the antibody-dependent cellular cytotoxicity or HER2-neutralizing activity of the antibody; thus, T-DM1 retains the functions of trastuzumab & adds the effects of a potent cytotoxic drug.
Seek & Destroy
Ref: http://www.nature.com/news/2011/220811/full/476380a.html
ADCs 無疑是腫瘤選擇性最強大的抗癌療法，但在藥物輸送方面其表現並不亮眼，因此，ADC 需要搭載強而有力的藥物。目前較常用於與 ADCs 搭配的當屬 maytansinoids (T-DM1) 與 dolastatin 類似物 (brentuximab vedotin) 這類作用於微管且能抑制微管動力學的藥物。這類的藥物在達到皮莫爾濃度 (picomolar, pM) 時便能展現出超強的活性以抑制細胞生長；因此，ADC 以精準的將這些細胞毒性藥物「標靶式」地投入戰場中，預期將能更有效的殺敵。
ADCs are among the most tumor-selective anticancer therapeutics but are not the most efficient for drug delivery; thus potent drugs are required. The maytansinoids (such as T-DM1) & dolastatin analogues (such as brentuximab vedotin) target tubulin & suppress microtubule dynamics. These molecules have in common extreme potency with growth-inhibitory properties reached in the picomolar concentration (pM, 10−12 mol/L) range; thus, ADCs are "targeted" to deliver potent cytotoxic agents.
隨著我們逐漸了解 ADC 並將其與傳統的化療併用以治療疾病的同時，這項技術或許即將成為這場抗癌戰爭中最不可或缺的主要戰力。
With the understanding that ADCs are chemotherapeutics that will be used in combination treatment regimens, the time may have arrived for this technology to become a major contributor to improved cancer therapy.
「目前，我們正處於抗體藥物複合體的文藝復興時期。」
- 英國 曼徹斯特大學 腫瘤學家：Tim Illidge
"We're essentially in a renaissance of the antibody–drug conjugate."
- Tim Illidge, Oncologist at University of Manchester, UK.
Adapted from Nature 2011;476: 380-381.
Written by Wind Chang (MS)
27 Nov. 2012
留言列表
Apple iDevice (2)