作者：寵物醫(yī)師網(wǎng)編委會

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看著愛寵被關(guān)節(jié)炎折磨得步履蹣跚，因過敏反復(fù)抓撓潰爛的皮膚，或是忍受化療的副作用對抗癌癥——這些場景是否讓你揪心？

單抗療法：一針導(dǎo)航，直搗病根。

摘要

近四十年來，單克隆抗體（Monoclonalantibodies，mAbs）廣泛應(yīng)用于人類醫(yī)療保健領(lǐng)域，犬貓與人類共享90%以上慢性病類型（如癌癥、關(guān)節(jié)炎、過敏癥以及慢性疼痛等慢性疾病），但過去治療常依賴激素、止痛藥，長期使用易引發(fā)胃腸損傷、免疫力下降，mAb療法則對小動物的這些疾病提供新的靶向治療方法。

本綜述旨在探究mAb療法在小動物醫(yī)學(xué)中的治療潛力，重點(diǎn)關(guān)注目前已獲批的產(chǎn)品，包括它們的作用機(jī)制、臨床療效以及安全方面的問題。

關(guān)鍵詞：檢單克隆抗體；免疫療法；慢性疾病；淋巴瘤；骨關(guān)節(jié)炎；特應(yīng)性皮炎；寵物

一、引言

單克隆抗體（mAbs）在治療癌癥、自身免疫性疾病以及其他病癥（如傳染病、炎癥性疾病和過敏癥）中展現(xiàn)不可估量的價值[1]。

單克隆抗體目前正被用于治療犬和貓的慢性疾病。在這篇綜述文章中，我們回顧了單克隆抗體在獸醫(yī)領(lǐng)域作為生物治療藥物的應(yīng)用情況，重點(diǎn)關(guān)注已獲批且在市場上可購買到的產(chǎn)品。

圖1獸醫(yī)學(xué)中單克隆抗體的時間表

表1 批準(zhǔn)用于伴侶動物的獸醫(yī)單克隆抗體簡介（按時間順序）

美國農(nóng)業(yè)部有條件許可證

二、治療犬特應(yīng)性皮炎的單抗體

用于治療犬特應(yīng)性皮炎（AD）的單克隆抗體--塞妥敏

特應(yīng)性皮炎是一種慢性、復(fù)雜的疾病，其特征為皮膚發(fā)炎和瘙癢；

過敏性皮炎更寬泛，指的是由各種過敏原（如食物、跳蚤叮咬或化學(xué)物質(zhì)）引起的皮膚炎癥。

總體而言，特應(yīng)性皮炎影響著10%-15%的犬，并且具有遺傳易感性[39]。犬的特應(yīng)性皮炎需要終生管理，而且在大多數(shù)患病犬中，都需要長期治療[40]。

抗IL-31單克隆抗體被設(shè)計用于中和主要由T淋巴細(xì)胞產(chǎn)生的游離IL-31。它的研發(fā)源于對IL-31參與犬骨關(guān)節(jié)炎的認(rèn)識[42]。抗IL-31單克隆抗體（塞妥敏）的作用機(jī)制如圖3所示。

美國農(nóng)業(yè)部于2016年12月批準(zhǔn)了首個用于治療犬特應(yīng)性皮炎和過敏性皮炎的單克隆抗體，這是一種犬源化的抗IL-31單克隆抗體。塞妥敏（Librela?）最初的標(biāo)簽適應(yīng)癥是用于治療體重3kg及以上、任何年齡的犬與特應(yīng)性皮炎相關(guān)的臨床癥狀。

圖2.塞妥敏阻斷瘙癢循環(huán)的機(jī)制

注：塞妥敏阻斷瘙癢循環(huán)的機(jī)制至靶向犬白細(xì)胞介素31（IL-31），IL-31在患有特應(yīng)性皮炎的犬的瘙癢發(fā)展過程中起著關(guān)鍵作用。通過中和IL-31，洛維單抗能有效減輕瘙癢，并有助于最大程度減少炎癥性皮膚損傷。

三、控制犬貓?zhí)弁吹膯慰?/strong>

用于控制犬貓?zhí)弁吹目股窠?jīng)生長因子的單克隆抗體---夫盧維單抗和貝汀維單抗

骨關(guān)節(jié)炎（OA）相關(guān)的疼痛管理仍然頗具挑戰(zhàn)，也是導(dǎo)致犬貓安樂死的常見原因[45]。

犬貓骨關(guān)節(jié)炎疼痛管理的傳統(tǒng)療法包括：減重、運(yùn)動、針灸、按摩，以及藥物治療。

藥物包括：非甾體抗炎藥（NSAIDs）、加巴噴丁和曲馬多。

目前，非甾體抗炎藥中，尤其是環(huán)氧化酶-2（COX-2）抑制劑，常用于犬貓的疼痛控制。但長期使用可能引起不良反應(yīng)，如胃腸道刺激、腎功能障礙和肝毒性[20,46]。此外，單獨(dú)使用非甾體抗炎藥可能無法完全緩解疼痛[47]。

神經(jīng)生長因子（NGF）對于感覺神經(jīng)元和交感神經(jīng)元的生長及維持至關(guān)重要[48]。抗NGF療法是一種對抗慢性疼痛的新型療法[20]。人們對各種針對該途徑的單克隆抗體療法展開了研究，以開發(fā)治療慢性疼痛的藥物療法。這些單克隆抗體針對犬貓?zhí)禺愋訬GF[49]。

圖3 神經(jīng)生長因子（NGF）在骨關(guān)節(jié)炎的疼痛感知和神經(jīng)系統(tǒng)可塑性中起關(guān)鍵作用

犬骨關(guān)節(jié)炎（Caninestiflejoint with OA）：展示了患有骨關(guān)節(jié)炎的犬膝關(guān)節(jié)，關(guān)節(jié)處軟骨等結(jié)構(gòu)出現(xiàn)病變，釋放神經(jīng)生長因子（NGF）。

NGF與TrkA受體結(jié)合：NGF從病變關(guān)節(jié)釋放，與感覺神經(jīng)纖維上的TrkA受體結(jié)合。

同時，炎癥/免疫細(xì)胞釋放組胺等物質(zhì)，參與這一過程。

受體/離子通道的局部調(diào)節(jié)：NGF/TrkA復(fù)合物逆向運(yùn)輸至背根神經(jīng)節(jié)（DRG）。

這導(dǎo)致相關(guān)物質(zhì)轉(zhuǎn)錄增加，包括P物質(zhì)（SP）、瞬時受體電位香草酸亞型1（TRPV1）、降鈣素基因相關(guān)肽（CGRP）、腦源性神經(jīng)營養(yǎng)因子（BDNF）、酸敏感離子通道3（ASIC3）等。

還會對鈉離子（Na+）、鈣離子（Ca2+）、鉀離子（K+）通道，以及緩激肽受體2（BR2）等進(jìn)行局部調(diào)節(jié)。

背角突觸：

初級傳入神經(jīng)釋放SP、BDNF、CGRP等神經(jīng)遞質(zhì)。

這些神經(jīng)遞質(zhì)作用于二級神經(jīng)元上的相應(yīng)受體，如CGRP受體（CGRPR）、NK-1受體、N-甲基-D-天冬氨酸受體（NMDA）、α-氨基-3-羥基-5-甲基-4-異惡唑丙酸受體（AMPA）等。

引發(fā)一系列離子流動（如Ca2+、Na+、Mg2+），信號進(jìn)一步向大腦傳遞，產(chǎn)生疼痛感覺。

注：由軟骨細(xì)胞釋放的NGF與感覺纖維和免疫細(xì)胞上的原肌球蛋白受體激酶A（TrkA）結(jié)合，促使炎癥介質(zhì)/自體活性物質(zhì)（如組胺和血清素）的釋放。NGF/TrkA復(fù)合物被轉(zhuǎn)運(yùn)至背根神經(jīng)節(jié)（DRG），增加疼痛相關(guān)受體和離子通道（如瞬時受體電位香草酸亞型1（TRPV1）、酸敏感離子通道（ASIC）、電壓門控鈉通道（Nav））的表達(dá)，從而導(dǎo)致外周敏化。NGF還會增強(qiáng)促傷害感受性神經(jīng)遞質(zhì)（P物質(zhì)（SP）、降鈣素基因相關(guān)肽（CGRP）、腦源性神經(jīng)營養(yǎng)因子（BDNF））的產(chǎn)生，這些神經(jīng)遞質(zhì)釋放后會刺激二級神經(jīng)元，有可能引起中樞敏化。這個過程放大了從外周（如關(guān)節(jié)）到大腦的疼痛信號傳導(dǎo)[20]。

縮寫：5-HT：血清素；AMPA：α-氨基-3-羥基-5-甲基-4-異惡唑丙酸；ASIC：酸敏感離子通道；BDNF：腦源性神經(jīng)營養(yǎng)因子；BR2：緩激肽受體2；Cav：鈣通道；CGRP：降鈣素基因相關(guān)肽；DRG：背根神經(jīng)節(jié)；K：鉀通道；Nav：鈉通道；NMDA：N-甲基-D-天冬氨酸受體；NGF：神經(jīng)生長因子；SP：P物質(zhì)；TrkA/B：原肌球蛋白受體激酶A/B。

夫盧維單抗（Solensia?）是一種貓?jiān)椿?/strong>的免疫球蛋白G（IgG）單克隆抗體，它能與神經(jīng)生長因子（NGF）結(jié)合，阻斷其在貓體內(nèi)的致痛作用。當(dāng)夫盧維單抗與NGF結(jié)合時，它會阻止疼痛信號傳至大腦。夫盧維單抗在貓體內(nèi)耐受性良好；在誘發(fā)炎癥后長達(dá)7d的時間里，它能顯著減輕跛行癥狀。

貝地維單抗（Librela?）是一種犬源化IgG單克隆抗體，其可變區(qū)由B淋巴細(xì)胞表達(dá)，并通過中國倉鼠卵巢（CHO）細(xì)胞中的重組DNA技術(shù)進(jìn)行生產(chǎn)。貝地維單抗每月皮下注射一次，靶向NGF。Librela?是美國首個也是唯一獲批用于控制犬骨關(guān)節(jié)炎疼痛的注射用單克隆抗體治療藥物。

四、治療犬免疫抑制性癌癥的單抗

用于治療犬免疫抑制性癌癥的單克隆抗體--吉維單抗

肥大細(xì)胞瘤（MCTs）和黑色素瘤是犬中最常見的癌癥類型，分別占皮膚癌病例的20%[50]和所有惡性腫瘤的7%[51]，此外它們還具有免疫抑制性[52]。這些腫瘤的免疫抑制特性為探索靶向這些檢查點(diǎn)分子的療法（如抗PD-1單克隆抗體）提供了理論依據(jù)，目的是重新激活免疫反應(yīng)并增強(qiáng)抗腫瘤免疫力。

在獸醫(yī)腫瘤學(xué)領(lǐng)域，研究越來越側(cè)重于開發(fā)犬特異性抗體，抗PD-1和抗PD-L1療法展現(xiàn)出顯著潛力，這反映了人類癌癥治療領(lǐng)域所取得的進(jìn)展（圖4）[54,55]。這兩種單克隆抗體都被證明具有獨(dú)特的功能性阻斷能力[56]。

圖4.癌癥治療中的PD-1抑制劑通過阻斷PD-L1/PD-1通路發(fā)揮作用，從而在兩個關(guān)鍵點(diǎn)重新激活免疫系統(tǒng)的抗腫瘤反應(yīng)：淋巴結(jié)中的識別階段和腫瘤微環(huán)境中的效應(yīng)階段。這些抑制劑包括抗PD-1和抗PD-L1抗體，它們有效地破壞了使腫瘤能夠逃避免疫檢測的信號傳導(dǎo)。

注：腫瘤細(xì)胞或免疫細(xì)胞表面表達(dá)程序性死亡配體1（PD-L1），T細(xì)胞表面表達(dá)程序性死亡受體1（PD-1）。PD-L1與PD-1結(jié)合，抑制T細(xì)胞活性（Deactivation of Tcellactivity），使腫瘤細(xì)胞能夠逃避免疫監(jiān)視。主要涉及的分子還有主要組織相容性復(fù)合體（MHC）和T細(xì)胞受體（TCR），MHC負(fù)責(zé)呈遞抗原給TCR，但PD-L1/PD-1結(jié)合阻礙了T細(xì)胞正常功能的發(fā)揮。

抗PD-L1抗體（Anti PD-L1 Antibody）與腫瘤細(xì)胞或免疫細(xì)胞表面的PD-L1結(jié)合，抗PD-1抗體（Anti PD-1 Antibody）與T細(xì)胞表面的PD-1結(jié)合。這兩種抗體的結(jié)合阻斷了PD-L1與PD-1的相互作用，激活T細(xì)胞活性（Activation of Tcellactivity）。活化的T細(xì)胞能夠識別并殺傷腫瘤細(xì)胞（Tumor Cell Death），重新啟動免疫系統(tǒng)對腫瘤細(xì)胞的攻擊，發(fā)揮抗腫瘤作用。

吉維單抗是專門為犬治療而開發(fā)的犬源化IgG單克隆抗體，也是一種檢查點(diǎn)抑制劑，它特異性靶向PD-1，重新激活犬的免疫系統(tǒng)以識別并對抗癌細(xì)胞。它是一種針對I期、II期和III期MCT以及III期黑色素瘤犬的全身性治療選擇。吉維單抗與犬PD-1結(jié)合，阻斷PD-L1/L2與PD-1之間的相互作用[59]，從而增強(qiáng)免疫反應(yīng)以對抗這些癌癥[60]。不良反應(yīng)主要包括嗜睡和食欲不振/胃腸道紊亂[58]，通常是輕微的。吉爾維單抗于2023年10月13日獲得美國農(nóng)業(yè)部（USDA）有條件批準(zhǔn)，用于治療患有MCT或黑色素瘤的犬[62]。

五、犬細(xì)小病毒單克隆抗體

犬細(xì)小病毒（CPV）是全球范圍內(nèi)導(dǎo)致犬患病和死亡的常見原因。其高度傳染性、致命性會損害腸道內(nèi)壁對營養(yǎng)的吸收，增加細(xì)菌感染的風(fēng)險[63,64]。CPV是最具傳染性和危險性的犬類病毒之一，感染率高達(dá)91%，死亡率也極高[65]。盡管接種疫苗能顯著降低CPV感染風(fēng)險，但對于已感染的犬，目前尚無完全有效的治療選擇。據(jù)估計，美國每年約有33萬例CPV感染病例有待治療[66]。

犬細(xì)小病毒單克隆抗體（CPMA）是美國農(nóng)業(yè)部于2023年5月2日有條件批準(zhǔn)的，用于治療8周齡及以上犬首次感染CPV的單劑量療法。給接觸過CPV的未接種疫苗幼犬注射該產(chǎn)品后，可降低發(fā)病率、加速臨床癥狀緩解并縮短住院時間。臨床試驗(yàn)表明，CPMA單次靜脈注射在治療這種致命疾病方面具有針對性療效。

六、小結(jié)

全球已有超過160種單克隆抗體被批準(zhǔn)用于治療人類疾病，如腫瘤、傳染病、慢性炎癥性疾病和心血管疾病等[71]。單克隆抗體療法有望為獸醫(yī)學(xué)中眾多未得到滿足的疾病治療需求提供解決方案。

治療性抗體在人類和動物健康領(lǐng)域都取得了巨大成功。治療性單克隆抗體為伴侶動物等小型動物疾病（如炎癥、腫瘤、自身免疫和傳染病）提供了精準(zhǔn)的治療選擇。與傳統(tǒng)藥物不同，單克隆抗體具有特異性，可制定個性化治療策略，最大限度減少對健康組織的不良反應(yīng)。隨著單克隆抗體研究和制造技術(shù)的進(jìn)步，獸用單克隆抗體的療效和安全性有望逐步提高。未來，持續(xù)的研究和開發(fā)將在維持和改善伴侶動物健康和福祉方面發(fā)揮重要作用。

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