AbMole小課堂丨Pegcetacoplan（APL-2）：補體C3抑制劑，在PNH、AMD、C3G模型中的應用補體系統(tǒng)在機體的免疫防御和免疫調節(jié)中發(fā)揮著關鍵作用，其過度激活與多種疾病的發(fā)生發(fā)展密切相關。Pegcetacoplan（APL-2，AbMole，M31313）作為一種新型的補體C3/C3b抑制劑，通過特異性結合C3和C3b，阻斷補體系統(tǒng)的激活，為相關疾病的研究帶來了新的思路和方向。Pegcetacoplan（APL-2）的作用機制Pegcetacoplan（APL-2，AbMole，M31313）是一種由13個氨基酸組成的聚乙二醇化環(huán)肽，其獨特的結構賦予了它與補體蛋白C3及其活化片段C3b緊密結合的能力。當Pegcetacoplan與C3/C3b結合后，能夠抑制C3轉化酶的形成與活性，從而在補體激活的關鍵節(jié)點發(fā)揮抑制作用。補體是一種關鍵的先天免疫系統(tǒng)，也是抵御病原體的第一道防線的一部分。補體系統(tǒng)由大約50種可溶性蛋白和細胞表面結合蛋白組成，這些蛋白被用于清除入侵微的生物、凋亡和壞死的細胞，以及介導T細胞和B細胞反應的調節(jié)來連接先天免疫和適應性免疫反應ADDINEN.CITEADDINEN.CITE.DATA[1,2]。補體途徑受蛋白質網絡的嚴格調節(jié)，以避免不受控制的激活，該系統(tǒng)分為三種激活途徑：經典途徑（CP）、凝集素途徑（LP）和替代途（AP）。每個通路都由不同的分子激活。上述三條途徑雖然由不同的分子激活，但經過一系列的相關蛋白的激活，都會裂解C3片段并產生不同的C5轉化酶（C5convertase），最終產生不同的效應蛋白，例如補體末端復合物（TCC），它可以插入細菌的膜中并導致細菌（革蘭氏陰性菌）死亡，其它的效應蛋白可以起到調節(jié)細胞生物反應的作用，例如吞噬作用、細胞遷移、趨化性、細胞因子產生、細胞活化等ADDINEN.CITE<EndNote><Cite><Author>Brandwijk</Author><Year>2022</Year><RecNum>517</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>517</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1752549189">517</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Brandwijk,RicardoJ.M.G.E.</author><author>Michels,MarloesA.H.M.</author><author>vanRossum,Mara</author><author>deNooijer,AlineH.</author><author>Nilsson,PerH.</author><author>deBruin,WiekeC.C.</author><author>Toonen,ErikJ.M.</author></authors></contributors><titles><title>Pitfallsincomplementanalysis:Asystematicliteraturereviewofassessingcomplementactivation</title><secondary-title>FrontiersinImmunology</secondary-title></titles><periodical><full-title>FrontImmunol</full-title><abbr-1>Frontiersinimmunology</abbr-1></periodical><volume>Volume13-2022</volume><dates><year>2022</year></dates><isbn>1664-3224</isbn><work-type>SystematicReview</work-type><urls><related-urls><url>/journals/immunology/articles/10.3389/fimmu.2022.1007102</url></related-urls></urls></record></Cite></EndNote>[3]。圖SEQ圖\*ARABIC1.補體系統(tǒng)的組成和激活途徑ADDINEN.CITE<EndNote><Cite><Author>Brandwijk</Author><Year>2022</Year><RecNum>517</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>517</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1752549189">517</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Brandwijk,RicardoJ.M.G.E.</author><author>Michels,MarloesA.H.M.</author><author>vanRossum,Mara</author><author>deNooijer,AlineH.</author><author>Nilsson,PerH.</author><author>deBruin,WiekeC.C.</author><author>Toonen,ErikJ.M.</author></authors></contributors><titles><title>Pitfallsincomplementanalysis:Asystematicliteraturereviewofassessingcomplementactivation</title><secondary-title>FrontiersinImmunology</secondary-title></titles><periodical><full-title>FrontImmunol</full-title><abbr-1>Frontiersinimmunology</abbr-1></periodical><volume>Volume13-2022</volume><dates><year>2022</year></dates><isbn>1664-3224</isbn><work-type>SystematicReview</work-type><urls><related-urls><url>/journals/immunology/articles/10.3389/fimmu.2022.1007102</url></related-urls></urls></record></Cite></EndNote>[3]補體的過度激活與某些疾病高度相關，由于C3是補體三條激活途徑的共同關鍵成分，Pegcetacoplan（APL-2，AbMole，M31313）對C3的抑制作用能夠全面阻斷補體系統(tǒng)的激活，有效阻止補體級聯反應介導的組織損傷；而且相較于大分子抗體，Pegcetacoplan較小的分子量（經PEG修飾后仍具有相對優(yōu)勢）被認為有利于其在靶組織（如視網膜、腎小球）中的滲透和分布，這為其在多種補體相關疾病中的應用提供了堅定的基礎。Pegcetacoplan（APL-2）的科研應用Pegcetacoplan用于陣發(fā)性睡眠性血紅蛋白尿癥（PNH）模型的研究PNH是一種罕見的獲得性造血干細胞基因突變導致的溶血性（紅細胞破裂或壽命縮短）疾病，其發(fā)病機理是由于磷脂酰肌醇聚糖錨生物合成A類基因突變，該基因負責表達GPI錨生物合成相關的加工蛋白，GPI錨的缺乏將導致紅細胞表面缺少補體調節(jié)蛋白CD55和CD59，使得紅細胞對補體介導的溶血異常敏感ADDINEN.CITE<EndNote><Cite><Author>Brandwijk</Author><Year>2022</Year><RecNum>517</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>517</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1752549189">517</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Brandwijk,RicardoJ.M.G.E.</author><author>Michels,MarloesA.H.M.</author><author>vanRossum,Mara</author><author>deNooijer,AlineH.</author><author>Nilsson,PerH.</author><author>deBruin,WiekeC.C.</author><author>Toonen,ErikJ.M.</author></authors></contributors><titles><title>Pitfallsincomplementanalysis:Asystematicliteraturereviewofassessingcomplementactivation</title><secondary-title>FrontiersinImmunology</secondary-title></titles><periodical><full-title>FrontImmunol</full-title><abbr-1>Frontiersinimmunology</abbr-1></periodical><volume>Volume13-2022</volume><dates><year>2022</year></dates><isbn>1664-3224</isbn><work-type>SystematicReview</work-type><urls><related-urls><url>/journals/immunology/articles/10.3389/fimmu.2022.1007102</url></related-urls></urls></record></Cite></EndNote>[3]。在針對PNH的研究中，Pegcetacoplan（APL-2，AbMole，M31313）展現出了顯著的抑制效果。通過構建PNH疾病動物模型，發(fā)現給予Pegcetacoplan干預后，能夠有效減少紅細胞的溶血現象ADDINEN.CITE<EndNote><Cite><Author>Brandwijk</Author><Year>2022</Year><RecNum>517</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>517</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1752549189">517</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Brandwijk,RicardoJ.M.G.E.</author><author>Michels,MarloesA.H.M.</author><author>vanRossum,Mara</author><author>deNooijer,AlineH.</author><author>Nilsson,PerH.</author><author>deBruin,WiekeC.C.</author><author>Toonen,ErikJ.M.</author></authors></contributors><titles><title>Pitfallsincomplementanalysis:Asystematicliteraturereviewofassessingcomplementactivation</title><secondary-title>FrontiersinImmunology</secondary-title></titles><periodical><full-title>FrontImmunol</full-title><abbr-1>Frontiersinimmunology</abbr-1></periodical><volume>Volume13-2022</volume><dates><year>2022</year></dates><isbn>1664-3224</isbn><work-type>SystematicReview</work-type><urls><related-urls><url>/journals/immunology/articles/10.3389/fimmu.2022.1007102</url></related-urls></urls></record></Cite></EndNote>[3]。Pegcetacoplan和Ravulizumab（AbMole，M21383）、Eculizumab（AbMole，M1598）等是PNH研究領域中重要的生物活性分子。圖SEQ圖\*ARABIC2.補體抑制劑在陣發(fā)性睡眠性血紅蛋白尿癥中的作用機制ADDINEN.CITE<EndNote><Cite><Author>Brandwijk</Author><Year>2022</Year><RecNum>517</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>517</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1752549189">517</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Brandwijk,RicardoJ.M.G.E.</author><author>Michels,MarloesA.H.M.</author><author>vanRossum,Mara</author><author>deNooijer,AlineH.</author><author>Nilsson,PerH.</author><author>deBruin,WiekeC.C.</author><author>Toonen,ErikJ.M.</author></authors></contributors><titles><title>Pitfallsincomplementanalysis:Asystematicliteraturereviewofassessingcomplementactivation</title><secondary-title>FrontiersinImmunology</secondary-title></titles><periodical><full-title>FrontImmunol</full-title><abbr-1>Frontiersinimmunology</abbr-1></periodical><volume>Volume13-2022</volume><dates><year>2022</year></dates><isbn>1664-3224</isbn><work-type>SystematicReview</work-type><urls><related-urls><url>/journals/immunology/articles/10.3389/fimmu.2022.1007102</url></related-urls></urls></record></Cite></EndNote>[3]Pegcetacoplan（APL-2）用于年齡相關性黃斑變性（AMD）和模型的研究AMD是一種常見的導致老年個體視力喪失的眼部疾病。補體系統(tǒng)的異常激活在AMD的發(fā)病機制中起著重要作用，研究發(fā)現補體激活產物在視網膜下的沉積加速了AMD的惡化，并且與晚期干性AMD（又稱地理性萎縮，GA）高度相關。在對AMD疾病模型的研究中，發(fā)現Pegcetacoplan能夠通過玻璃體內注射的方式，有效遞送至眼部病變部位。與Pegcetacoplan（APL-2，AbMole，M31313）起到類似作用的Iptacopan則是與補體旁路途徑的因子B結合，進而調節(jié)C3的裂解，同樣也備受關注ADDINEN.CITE<EndNote><Cite><Author>Girgis</Author><Year>2023</Year><RecNum>518</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>518</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1752557132">518</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Girgis,S.</author><author>Lee,L.R.</author></authors></contributors><auth-address>CityEyeCentre,Brisbane,Australia. RoyalBrisbaneandWomen'sHospital,Brisbane,Australia. FacultyofMedicine,UniversityofQueensland,SaintLucia,Queensland,Australia.</auth-address><titles><title>Treatmentofdryage-relatedmaculardegeneration:Areview</title><secondary-title>ClinExpOphthalmol</secondary-title><alt-title>Clinical&experimentalophthalmology</alt-title></titles><periodical><full-title>ClinExpOphthalmol</full-title><abbr-1>Clinical&experimentalophthalmology</abbr-1></periodical><alt-periodical><full-title>ClinExpOphthalmol</full-title><abbr-1>Clinical&experimentalophthalmology</abbr-1></alt-periodical><pages>835-852</pages><volume>51</volume><number>8</number><edition>2023/09/22</edition><keywords><keyword>Humans</keyword><keyword>*GeographicAtrophy/therapy</keyword><keyword>*MacularDegeneration/drugtherapy</keyword><keyword>AngiogenesisInhibitors/therapeuticuse</keyword><keyword>IntravitrealInjections</keyword><keyword>*WetMacularDegeneration/drugtherapy</keyword><keyword>age-relatedmaculardegeneration(AMD)</keyword><keyword>complementinhibitors</keyword><keyword>dryage-relatedmaculardegeneration</keyword></keywords><dates><year>2023</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1442-6404</isbn><accession-num>37737509</accession-num><urls></urls><electronic-resource-num>10.1111/ceo.14294</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[4]。圖SEQ圖\*ARABIC3.年齡相關性黃斑變性的發(fā)病機制和相關抑制劑ADDINEN.CITE<EndNote><Cite><Author>Girgis</Author><Year>2023</Year><RecNum>518</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>518</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1752557132">518</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Girgis,S.</author><author>Lee,L.R.</author></authors></contributors><auth-address>CityEyeCentre,Brisbane,Australia. RoyalBrisbaneandWomen'sHospital,Brisbane,Australia. FacultyofMedicine,UniversityofQueensland,SaintLucia,Queensland,Australia.</auth-address><titles><title>Treatmentofdryage-relatedmaculardegeneration:Areview</title><secondary-title>ClinExpOphthalmol</secondary-title><alt-title>Clinical&experimentalophthalmology</alt-title></titles><periodical><full-title>ClinExpOphthalmol</full-title><abbr-1>Clinical&experimentalophthalmology</abbr-1></periodical><alt-periodical><full-title>ClinExpOphthalmol</full-title><abbr-1>Clinical&experimentalophthalmology</abbr-1></alt-periodical><pages>835-852</pages><volume>51</volume><number>8</number><edition>2023/09/22</edition><keywords><keyword>Humans</keyword><keyword>*GeographicAtrophy/therapy</keyword><keyword>*MacularDegeneration/drugtherapy</keyword><keyword>AngiogenesisInhibitors/therapeuticuse</keyword><keyword>IntravitrealInjections</keyword><keyword>*WetMacularDegeneration/drugtherapy</keyword><keyword>age-relatedmaculardegeneration(AMD)</keyword><keyword>complementinhibitors</keyword><keyword>dryage-relatedmaculardegeneration</keyword></keywords><dates><year>2023</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1442-6404</isbn><accession-num>37737509</accession-num><urls></urls><electronic-resource-num>10.1111/ceo.14294</electroni