12月26日,，以色列魏茲曼科學(xué)研究所在《自然—醫(yī)學(xué)》雜志網(wǎng)站上發(fā)表了他們最新研究成果"Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential",。科學(xué)家改變以往的治療策略,，用人工合成分子誘導(dǎo)免疫系統(tǒng)產(chǎn)生出特殊的抗體,，可封鎖在引發(fā)自身免疫疾病中起重要作用的一種酶MMP9，并在動(dòng)物實(shí)驗(yàn)中取得成功,。
新合成分子在治療克羅恩氏病等免疫系統(tǒng)疾病方面具有很大潛力,，為尋找免疫類疾病療法開(kāi)辟了新方向。
MMP是一種基質(zhì)金屬蛋白酶家族,，在細(xì)胞動(dòng)員,、分裂、傷口愈合等方面起著關(guān)鍵作用,。如果它們中的某些成員,，尤其是MMP9失控的話，就會(huì)引發(fā)自身免疫疾病和癌癥轉(zhuǎn)移,，封鎖這些蛋白質(zhì)有望找到治療自身免疫類疾病的方法,。開(kāi)始時(shí)，研究人員設(shè)計(jì)出一種直接瞄準(zhǔn)所有MMP成員的人造藥物分子,，但太過(guò)粗糙而且有很大副作用,。
研究所生物調(diào)控分部教授艾麗特·薩基解釋說(shuō),，正常情況下,，機(jī)體也能產(chǎn)生自己的MMP抑制劑，叫做TIMP,，作為一種緊縮程序來(lái)控制MMP酶,。這些自然產(chǎn)生的TIMP具有高度選擇性，由三個(gè)組氨酸多肽圍繞一個(gè)金屬鋅離子構(gòu)成,，每個(gè)手臂都極其精確,，恰好能到達(dá)MMP酶的活性位點(diǎn)凹槽,，像個(gè)軟木塞那樣堵住凹槽，使MMP失去活性,。“要想復(fù)制這種精確性是非常困難的,。”
研究人員轉(zhuǎn)而尋找另外的替代方法，不是設(shè)計(jì)一種分子,，而是直接攻擊MMP,。就像死亡病毒引發(fā)免疫系統(tǒng)生成抗體，攻擊活病毒那樣,，他們想出了一種方法,，通過(guò)MMP免疫反應(yīng)“誘騙”機(jī)體生成瞄準(zhǔn)MMP9的天然抗體，鎖住其活性位點(diǎn),。
他們?cè)贛MP9的核心活性位點(diǎn)人工合成出一種金屬鋅-組氨酸復(fù)合物,，然后把這些小分子注射到小鼠體內(nèi)，并檢查小鼠血液中抵抗MMP酶的免疫反應(yīng)信號(hào),。研究人員對(duì)所產(chǎn)生抗體的原子結(jié)構(gòu)進(jìn)行了詳細(xì)分析,，發(fā)現(xiàn)它和TIMP有所不同，但作用極其相似,，同樣能到達(dá)酶的凹槽并封鎖活性位點(diǎn),。抗體能選擇性地僅針對(duì)MMP家族中的兩個(gè)成員MMP2和MMP9,，并與它們緊密結(jié)合,。
為了檢驗(yàn)療效，他們?cè)谛∈笊砩夏M克羅恩氏病引發(fā)炎癥,，然后注射上述金屬鋅-組氨酸復(fù)合物所產(chǎn)生的抗體進(jìn)行治療,，發(fā)現(xiàn)癥狀消失。魏茲曼研究所耶達(dá)（Yeda）技術(shù)轉(zhuǎn)讓公司已經(jīng)為這種合成免疫分子及其抗體申請(qǐng)了專利,。（生物谷Bioon.com）
doi:10.1038/nm.2582
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PMID:
Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential
Netta Sela-Passwell, Raghavendra Kikkeri, Orly Dym, Haim Rozenberg, Raanan Margalit, Rina Arad-Yellin, Miriam Eisenstein, Ori Brenner, Tsipi Shoham, Tamar Danon, Abraham Shanzer & Irit Sagi
Endogenous tissue inhibitors of metalloproteinases (TIMPs) have key roles in regulating physiological and pathological cellular processes1, 2, 3. Imitating the inhibitory molecular mechanisms of TIMPs while increasing selectivity has been a challenging but desired approach for antibody-based therapy4. TIMPs use hybrid protein-protein interactions to form an energetic bond with the catalytic metal ion, as well as with enzyme surface residues5, 6, 7. We used an innovative immunization strategy that exploits aspects of molecular mimicry to produce inhibitory antibodies that show TIMP-like binding mechanisms toward the activated forms of gelatinases (matrix metalloproteinases 2 and 9). Specifically, we immunized mice with a synthetic molecule that mimics the conserved structure of the metalloenzyme catalytic zinc-histidine complex residing within the enzyme active site. This immunization procedure yielded selective function-blocking monoclonal antibodies directed against the catalytic zinc-protein complex and enzyme surface conformational epitopes of endogenous gelatinases. The therapeutic potential of these antibodies has been demonstrated with relevant mouse models of inflammatory bowel disease8. Here we propose a general experimental strategy for generating inhibitory antibodies that effectively target the in vivo activity of dysregulated metalloproteinases by mimicking the mechanism employed by TIMPs.
