出處：WebMD醫學新聞審閱： GaryD.Vogin,MD
June23, 2005-新英格蘭醫學期刊於6月23日刊載了一項研究結果指出， 對於早期第一型糖尿病的患者， 一種作用於CD3細胞的抗體可以保存beta(貝它)細胞的功能至18個月。
比利時布魯塞爾自由大學的BartKeymeulen醫師指出， 第一型糖尿病是T細胞的自身免疫病變，分泌胰島素的貝它細胞會因此而大量流失； 根據一項第一期臨床試驗的結果顯示，在發病之後，貝它細胞的功能會進一步衰退， 但這個現象可能可以藉由CD3單株抗體的治療予以阻止， 為了提供證據以支持這項療法的原理，研究人員於是進行了一項第二期臨床試驗， 為安慰劑控制設計，以人體化的抗體進行試驗， 這個抗體為經過aglycosylated的IgG1抗體細胞， 作用於CD3細胞(ChAglyCD3)。
本試驗在多個臨床中心進行，一共有80位第一型糖尿病的新發病例患者參與， 以隨機的方式投予安慰劑或ChAglyCD3，持續6天；在18個月的追蹤期中， 每日胰島素濃度及殘存貝它細胞的功能皆進行評估， 以葡萄糖箝制法誘發的C勝肭釋放量作指標，於升糖素服用前後進行。
試驗組(ChAglyCD3)殘存的貝它細胞功能明顯優於對照組(安慰劑)， 這個現象顯見於第6、12、18個月；使用於對照組的胰島素劑量有了增加，但試驗組並無； 80名患者中，殘存貝它細胞功能處於前半段者，ChAglyCD3最容易顯現其效果。
這一部分的試驗組患者， 第18個月的平均胰島素日劑量為0.22IU/kg的ChAglyCD3， 對照組則為0.61IU/kg；接受ChAglyCD3的16位患者中， 有12位(75%)只需要最低的胰島素劑量(不超過0.25IU/kg/日)， 對照組的21位患者卻無人可達此效果。
相關於ChAglyCD3的副作用， 皆類似於中度感冒症狀及Epstein-Barr病毒單核血球過多症的暫時症狀。
Keymeulen醫師表示，對於剛罹患第一型糖尿病的患者， 使用CD3抗體作短期治療，可以保存殘留貝它細胞功能最少達18個月； ChAglyCD3的治療潛力端視其安全性， 而注射前後的症狀相當於細胞激素的暫時釋放。
青少年糖尿病研究基金會對本研究作出資助；論文的作者群中， 有兩位為ChAglyCD3專利運用的共同發明人； ScientificResearch-Flanders(比利時)， TolerRx及Novimmune等機構，與其中的某些位作者有財務上的往來。
在期刊的評論欄中，來自西雅圖華盛頓大學的AkeLernmark醫師， 針對現行研究中的糖尿病免疫學提出討論。
經試驗證實， ChAglyCD3抗體的療效主要顯現於尚有殘存貝它細胞功能的患者身上， 這個現象顯示，可能有必要增強第一型糖尿病的免疫治療效果；Lernmark指出， 最近的第二期臨床試驗顯示，在治療潛伏自身免疫糖尿病的成人時， 使用alum配方的GAD65是一個安全的方法，對於空腹C勝肭濃度可能會有助益； 如果CD3單株抗體經證明是安全的，也許將之與誘發免疫耐受度的藥物合併使用， 可以對第一型糖尿病作更好的治療。
CD3 Antibody May Be Helpful in Recent-Onset Type 1 Diabetes
By
Medscape Medical News
June 23, 2005 — An antibody directed at CD3 can preserve beta-cell function for 18 months in patients with early stage type 1 diabetes, according to the results of a study published in the June 23 issue of the New England Journal of Medicine.
"Type 1 diabetes mellitus is a T-cell?��ediated autoimmune disease that leads to a major loss of insulin-secreting beta cells," write Bart Keymeulen, MD, PhD, from Brussels Free University–VUB in Belgium, and colleagues. "The further decline of beta-cell function after clinical onset might be prevented by treatment with CD3 monoclonal antibodies, as suggested by the results of a phase 1 study. To provide proof of this therapeutic principle at the metabolic level, we initiated a phase 2 placebo-controlled trial with a humanized antibody, an aglycosylated human IgG1 antibody directed against CD3 (ChAglyCD3).
In a multicenter trial, 80 patients with new-onset type 1 diabetes were randomized to receive placebo or ChAglyCD3 for six consecutive days. During 18-month follow-up, daily insulin needs and residual beta-cell function were evaluated with glucose-clamp–induced C-peptide release before and after glucagon administration.
Residual beta-cell function was better preserved with ChAglyCD3 than with placebo at 6, 12, and 18 months, and the insulin dose increased in the placebo group but not in the ChAglyCD3 group. This effect of ChAglyCD3 was most pronounced in patients who had initial residual beta-cell function at or above the 50th percentile of the 80 patients.
In this subgroup, the mean insulin dose at 18 months was 0.22 IU/kg per day with ChAglyCD3 and 0.61 IU/kg per day with placebo (P < .001). Twelve (75%) of 16 patients who received ChAglyCD3 required only minimal doses of insulin (not more than 0.25 IU/kg/day), as did none of the 21 patients who received placebo.
Adverse effects associated with ChAglyCD3 administration were a moderate flu-like syndrome and transient symptoms of Epstein-Barr viral mononucleosis.
"Short-term treatment with CD3 antibody preserves residual beta-cell function for at least 18 months in patients with recent-onset type 1 diabetes," the authors write. "The therapeutic potential of ChAglyCD3 will depend on its safety. Symptoms observed after the first infusions were compatible with transient cytokine release."
The Juvenile Diabetes Research Foundation supported this study. Two authors are listed as coinventors on a patent application relating to ChAglyCD3. Some of the authors report various financial arrangements with the Fund for Scientific Research–Flanders (Belgium), TolerRx, and/or NovImmune.
In an accompanying editorial, Åke Lernmark, MD, from the University of Washington in Seattle, discusses the immunology of diabetes in the context of the present study.
"The demonstration that the ChAglyCD3 antibody was effective primarily in patients with substantial residual beta-cell function suggests that it may be necessary to increase the efficacy of immunotherapy for type 1 diabetes," Dr. Lernmark writes. "A recent phase 2 study suggests that the treatment of latent autoimmune diabetes in adults with alum-formulated GAD65 is safe and may also have a beneficial effect on fasting C-peptide levels. If CD3 monoclonal antibodies are shown to be safe, perhaps their use in combination with agents for inducing immune tolerance could lead to improved therapies for type 1 diabetes."
N Engl J Med. 2005;352:2598-2608, 2642-2644
Reviewed by Gary D. Vogin, MD
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