毛孩子的慢性病有救了？神奇的一针！
作者：宠物医师网编委会
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看着爱宠被关节炎折磨得步履蹒跚，因过敏反复抓挠溃烂的皮肤，或是忍受化疗的副作用对抗癌症——这些场景是否让你揪心？
单抗疗法：一针导航，直捣病根。
摘要
近四十年来，单克隆抗体（Monoclonalantibodies，mAbs）广泛应用于人类医疗保健领域，犬猫与人类共享90%以上慢性病类型（如癌症、关节炎、过敏症以及慢性疼痛等慢性疾病），但过去治疗常依赖激素、止痛药，长期使用易引发胃肠损伤、免疫力下降，mAb疗法则对小动物的这些疾病提供新的靶向治疗方法。
本综述旨在探究mAb疗法在小动物医学中的治疗潜力，重点关注目前已获批的产品，包括它们的作用机制、临床疗效以及安全方面的问题。
关键词：检单克隆抗体；免疫疗法；慢性疾病；淋巴瘤；骨关节炎；特应性皮炎；宠物
一、引言
单克隆抗体（mAbs）在治疗癌症、自身免疫性疾病以及其他病症（如传染病、炎症性疾病和过敏症）中展现不可估量的价值[1]。
单克隆抗体目前正被用于治疗犬和猫的慢性疾病。在这篇综述文章中，我们回顾了单克隆抗体在兽医领域作为生物治疗药物的应用情况，重点关注已获批且在市场上可购买到的产品。
图1兽医学中单克隆抗体的时间表
表1 批准用于伴侣动物的兽医单克隆抗体简介（按时间顺序）
美国农业部有条件许可证
二、治疗犬特应性皮炎的单抗体
用于治疗犬特应性皮炎（AD）的单克隆抗体--塞妥敏
特应性皮炎是一种慢性、复杂的疾病，其特征为皮肤发炎和瘙痒；
过敏性皮炎更宽泛，指的是由各种过敏原（如食物、跳蚤叮咬或化学物质）引起的皮肤炎症。
总体而言，特应性皮炎影响着10%-15%的犬，并且具有遗传易感性[39]。犬的特应性皮炎需要终生管理，而且在大多数患病犬中，都需要长期治疗[40]。
抗IL-31单克隆抗体被设计用于中和主要由T淋巴细胞产生的游离IL-31。它的研发源于对IL-31参与犬骨关节炎的认识[42]。抗IL-31单克隆抗体（塞妥敏）的作用机制如图3所示。
美国农业部于2016年12月批准了首个用于治疗犬特应性皮炎和过敏性皮炎的单克隆抗体，这是一种犬源化的抗IL-31单克隆抗体。塞妥敏（Librela®）最初的标签适应症是用于治疗体重3kg及以上、任何年龄的犬与特应性皮炎相关的临床症状。
图2.塞妥敏阻断瘙痒循环的机制
注：塞妥敏阻断瘙痒循环的机制至靶向犬白细胞介素31（IL-31），IL-31在患有特应性皮炎的犬的瘙痒发展过程中起着关键作用。通过中和IL-31，洛维单抗能有效减轻瘙痒，并有助于最大程度减少炎症性皮肤损伤。
三、控制犬猫疼痛的单抗
用于控制犬猫疼痛的抗神经生长因子的单克隆抗体---夫卢维单抗和贝汀维单抗
骨关节炎（OA）相关的疼痛管理仍然颇具挑战，也是导致犬猫安乐死的常见原因[45]。
犬猫骨关节炎疼痛管理的传统疗法包括：减重、运动、针灸、按摩，以及药物治疗。
药物包括：非甾体抗炎药（NSAIDs）、加巴喷丁和曲马多。
目前，非甾体抗炎药中，尤其是环氧化酶-2（COX-2）抑制剂，常用于犬猫的疼痛控制。但长期使用可能引起不良反应，如胃肠道刺激、肾功能障碍和肝毒性[20,46]。此外，单独使用非甾体抗炎药可能无法完全缓解疼痛[47]。
神经生长因子（NGF）对于感觉神经元和交感神经元的生长及维持至关重要[48]。抗NGF疗法是一种对抗慢性疼痛的新型疗法[20]。人们对各种针对该途径的单克隆抗体疗法展开了研究，以开发治疗慢性疼痛的药物疗法。这些单克隆抗体针对犬猫特异性NGF[49]。
图3 神经生长因子（NGF）在骨关节炎的疼痛感知和神经系统可塑性中起关键作用
（上下滑动查看）
注：由软骨细胞释放的NGF与感觉纤维和免疫细胞上的原肌球蛋白受体激酶A（TrkA）结合，促使炎症介质/自体活性物质（如组胺和血清素）的释放。NGF/TrkA复合物被转运至背根神经节（DRG），增加疼痛相关受体和离子通道（如瞬时受体电位香草酸亚型1（TRPV1）、酸敏感离子通道（ASIC）、电压门控钠通道（Nav））的表达，从而导致外周敏化。NGF还会增强促伤害感受性神经递质（P物质（SP）、降钙素基因相关肽（CGRP）、脑源性神经营养因子（BDNF））的产生，这些神经递质释放后会刺激二级神经元，有可能引起中枢敏化。这个过程放大了从外周（如关节）到大脑的疼痛信号传导[20]。
缩写：5-HT：血清素；AMPA：α-氨基-3-羟基-5-甲基-4-异恶唑丙酸；ASIC：酸敏感离子通道；BDNF：脑源性神经营养因子；BR2：缓激肽受体2；Cav：钙通道；CGRP：降钙素基因相关肽；DRG：背根神经节；K：钾通道；Nav：钠通道；NMDA：N-甲基-D-天冬氨酸受体；NGF：神经生长因子；SP：P物质；TrkA/B：原肌球蛋白受体激酶A/B。
夫卢维单抗（Solensia®）是一种猫源化的免疫球蛋白G（IgG）单克隆抗体，它能与神经生长因子（NGF）结合，阻断其在猫体内的致痛作用。当夫卢维单抗与NGF结合时，它会阻止疼痛信号传至大脑。夫卢维单抗在猫体内耐受性良好；在诱发炎症后长达7d的时间里，它能显著减轻跛行症状。
贝地维单抗（Librela®）是一种犬源化IgG单克隆抗体，其可变区由B淋巴细胞表达，并通过中国仓鼠卵巢（CHO）细胞中的重组DNA技术进行生产。贝地维单抗每月皮下注射一次，靶向NGF。Librela®是美国首个也是唯一获批用于控制犬骨关节炎疼痛的注射用单克隆抗体治疗药物。
四、治疗犬免疫抑制性癌症的单抗
用于治疗犬免疫抑制性癌症的单克隆抗体--吉维单抗
肥大细胞瘤（MCTs）和黑色素瘤是犬中最常见的癌症类型，分别占皮肤癌病例的20%[50]和所有恶性肿瘤的7%[51]，此外它们还具有免疫抑制性[52]。这些肿瘤的免疫抑制特性为探索靶向这些检查点分子的疗法（如抗PD-1单克隆抗体）提供了理论依据，目的是重新激活免疫反应并增强抗肿瘤免疫力。
在兽医肿瘤学领域，研究越来越侧重于开发犬特异性抗体，抗PD-1和抗PD-L1疗法展现出显著潜力，这反映了人类癌症治疗领域所取得的进展（图4）[54,55]。这两种单克隆抗体都被证明具有独特的功能性阻断能力[56]。
图4.癌症治疗中的PD-1抑制剂通过阻断PD-L1/PD-1通路发挥作用，从而在两个关键点重新激活免疫系统的抗肿瘤反应：淋巴结中的识别阶段和肿瘤微环境中的效应阶段。这些抑制剂包括抗PD-1和抗PD-L1抗体，它们有效地破坏了使肿瘤能够逃避免疫检测的信号传导。
（上下滑动查看）
注：肿瘤细胞或免疫细胞表面表达程序性死亡配体1（PD-L1），T细胞表面表达程序性死亡受体1（PD-1）。PD-L1与PD-1结合，抑制T细胞活性（Deactivation of Tcellactivity），使肿瘤细胞能够逃避免疫监视。主要涉及的分子还有主要组织相容性复合体（MHC）和T细胞受体（TCR），MHC负责呈递抗原给TCR，但PD-L1/PD-1结合阻碍了T细胞正常功能的发挥。
吉维单抗是专门为犬治疗而开发的犬源化IgG单克隆抗体，也是一种检查点抑制剂，它特异性靶向PD-1，重新激活犬的免疫系统以识别并对抗癌细胞。它是一种针对I期、II期和III期MCT以及III期黑色素瘤犬的全身性治疗选择。吉维单抗与犬PD-1结合，阻断PD-L1/L2与PD-1之间的相互作用[59]，从而增强免疫反应以对抗这些癌症[60]。不良反应主要包括嗜睡和食欲不振/胃肠道紊乱[58]，通常是轻微的。吉尔维单抗于2023年10月13日获得美国农业部（USDA）有条件批准，用于治疗患有MCT或黑色素瘤的犬[62]。
五、犬细小病毒单克隆抗体
犬细小病毒（CPV）是全球范围内导致犬患病和死亡的常见原因。其高度传染性、致命性会损害肠道内壁对营养的吸收，增加细菌感染的风险[63,64]。CPV是最具传染性和危险性的犬类病毒之一，感染率高达91%，死亡率也极高[65]。尽管接种疫苗能显著降低CPV感染风险，但对于已感染的犬，目前尚无完全有效的治疗选择。据估计，美国每年约有33万例CPV感染病例有待治疗[66]。
犬细小病毒单克隆抗体（CPMA）是美国农业部于2023年5月2日有条件批准的，用于治疗8周龄及以上犬首次感染CPV的单剂量疗法。给接触过CPV的未接种疫苗幼犬注射该产品后，可降低发病率、加速临床症状缓解并缩短住院时间。临床试验表明，CPMA单次静脉注射在治疗这种致命疾病方面具有针对性疗效。
六、小结
全球已有超过160种单克隆抗体被批准用于治疗人类疾病，如肿瘤、传染病、慢性炎症性疾病和心血管疾病等[71]。单克隆抗体疗法有望为兽医学中众多未得到满足的疾病治疗需求提供解决方案。
治疗性抗体在人类和动物健康领域都取得了巨大成功。治疗性单克隆抗体为伴侣动物等小型动物疾病（如炎症、肿瘤、自身免疫和传染病）提供了精准的治疗选择。与传统药物不同，单克隆抗体具有特异性，可制定个性化治疗策略，最大限度减少对健康组织的不良反应。随着单克隆抗体研究和制造技术的进步，兽用单克隆抗体的疗效和安全性有望逐步提高。未来，持续的研究和开发将在维持和改善伴侣动物健康和福祉方面发挥重要作用。
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