lbk60ox 发表于 2024-5-21 10:11:37

治疗性癌症疫苗的研发发展

<span style="color: black;"><span style="color: black;"><img src="https://mmbiz.qpic.cn/sz_mmbiz_png/oZAqKz8bY0HicGMSwiaHOibEvh30lnBia6viaxpLic3uzib4yJd9gRBjfib3PFdH2mXY55Lf5YibUgobtRH5LLicCFJL2YgQ/640?wx_fmt=other&amp;from=appmsg&amp;wxfrom=5&amp;wx_lazy=1&amp;wx_co=1&amp;tp=webp" style="width: 50%; margin-bottom: 20px;"></span></span><span style="color: black;"><span style="color: black;">癌症是一种慢性<span style="color: black;">疾患</span>，虽</span><span style="color: black;"><span style="color: black;">然对癌症的病因、诊断、新的治疗性生物标志物和靶点<span style="color: black;">已然</span>进行了广泛的<span style="color: black;">科研</span>，但癌症仍与高死亡率和高患病率密切<span style="color: black;">关联</span>。</span>2015<span style="color: black;">年世界卫生组织的数据报告<span style="color: black;">表示</span><span style="color: black;">全世界</span>有</span>760<span style="color: black;">万人死于癌症。</span></span><strong style="color: blue;"><span style="color: black;"><span style="color: black;">按照</span></span></strong><strong style="color: blue;"><span style="color: black;">2005</span></strong><strong style="color: blue;"><span style="color: black;">年</span></strong><strong style="color: blue;"><span style="color: black;">-2020</span></strong><strong style="color: blue;"><span style="color: black;">年我国癌症死亡和<span style="color: black;">包袱</span><span style="color: black;">状况</span><span style="color: black;">科研</span>报告结果<span style="color: black;">表示</span>，癌症<span style="color: black;">关联</span>死亡人数和早死寿命损失年分别增长了</span></strong><strong style="color: blue;"><span style="color: black;">21.6%</span></strong><strong style="color: blue;"><span style="color: black;">和</span></strong><strong style="color: blue;"><span style="color: black;">5.0%</span></strong><strong style="color: blue;"><span style="color: black;">，肺癌、肝癌和胃癌仍是前三位死因。</span></strong><span style="color: black;"><span style="color: black;"><span style="color: black;">因此呢</span>，<span style="color: black;">必要</span>在寻找<span style="color: black;">能够</span>预防和</span>/<span style="color: black;">或治疗这一<span style="color: black;">全世界</span>健康问题的新<span style="color: black;">办法</span>上进行<span style="color: black;">靠谱</span>的投资。</span></span></span><span style="color: black;"><span style="color: black;"><span style="color: black;">治疗性癌症疫苗是一种免疫疗法，<span style="color: black;">能够</span></span><span style="color: black;">“</span><span style="color: black;">培养</span><span style="color: black;">”</span><span style="color: black;">免疫系统识别和消除癌细胞。</span></span><span style="color: black;"><span style="color: black;">有别于<span style="color: black;">能够</span>预防癌症的疫苗，如</span><span style="color: black;">HPV</span><span style="color: black;">疫苗，接种后在机体产生中和抗体，当有</span><span style="color: black;">HPV</span><span style="color: black;">感染宫颈破损部位时<span style="color: black;">能够</span>有效清除感染，阻断<span style="color: black;">疾患</span>自然进程，从而预防癌症；又如乙肝疫苗、<span style="color: black;">开发</span>中的幽门螺旋杆菌疫苗等。但</span>传统的癌症治疗<span style="color: black;">方法</span>并不完善，为了<span style="color: black;">加强</span>抗癌<span style="color: black;">药品</span>的效果并将其运送到靶点，治疗性癌症疫苗应运而生。癌症疫苗被认为是大<span style="color: black;">都数</span>实体瘤的潜在可行性治疗<span style="color: black;">办法</span>，疫苗<span style="color: black;">经过</span><span style="color: black;">包括</span>的肿瘤抗原、核酸、全细胞和多肽刺激抗肿瘤免疫。</span><strong style="color: blue;"><span style="color: black;">设计<span style="color: black;">能够</span>诱导长期抗肿瘤记忆，消瘤，清除微小残留病灶；并预防非特异性或不良反应的癌症疫苗，这些疫苗有助于清除身体<span style="color: black;">各样</span>器官或器官系统的癌细胞，把肿瘤复发或转移的</span></strong></span><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">危害</span></span></strong><strong style="color: blue;"><span style="color: black;">降到最低</span></strong><strong style="color: blue;"><span style="color: black;">。</span></strong></span><img src="https://mmbiz.qpic.cn/mmbiz_png/KWiaWAKG5wETxVSns2qJia57LfY9IW77b6bc9FepWSyaxgwGMEJITFvrUibBOdATxaFCbTZciaEjTDvXRdZ7ah6n8A/640?wx_fmt=png&amp;from=appmsg&amp;tp=webp&amp;wxfrom=5&amp;wx_lazy=1&amp;wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><span style="color: black;"><span style="color: black;">因为</span>癌细胞更像正常的健康细胞，<span style="color: black;">研发</span>有效的癌症疫苗仍然难以捉摸，极具挑战性。<span style="color: black;">因为</span>每一个肿瘤在某种程度上都是独一<span style="color: black;">没</span>二的，有它自己特异性的抗原，<span style="color: black;">咱们</span>需要采取更<span style="color: black;">繁杂</span>、更个性化和更有针对性的<span style="color: black;">办法</span>。<span style="color: black;">日前</span>在动物模型和人类志愿者的异种移植物中<span style="color: black;">已然</span>进行了<span style="color: black;">海量</span>的癌症<span style="color: black;">科研</span>，目的是<span style="color: black;">研发</span><span style="color: black;">经过</span>刺激免疫系统识别和根除肿瘤来治疗癌症的疫苗。</span></span><span style="color: black;"><span style="color: black;"><span style="color: black;">美国</span>FDA</span><span style="color: black;"><span style="color: black;">已然</span><span style="color: black;">准许</span>了三款治疗性肿瘤疫苗，</span><span style="color: black;">Sipuleucel-T</span><span style="color: black;">（</span><span style="color: black;">Provenge</span><span style="color: black;">®</span><span style="color: black;">）</span><span style="color: black;"><span style="color: black;">是一种由<span style="color: black;">病人</span><span style="color: black;">自己</span>树突状细胞活化<span style="color: black;">形成</span>的疫苗，用于治疗<span style="color: black;">少许</span>基本<span style="color: black;">没</span>症状的转移性去势抵抗性前列腺癌；<span style="color: black;">另一</span>两种</span>FDA<span style="color: black;"><span style="color: black;">准许</span>的癌症疫苗是治疗<span style="color: black;">初期</span>膀胱癌的活卡介苗（</span><span style="color: black;">Bacillus calmette - gusamrin</span><span style="color: black;">）和治疗黑色素瘤的</span><span style="color: black;">Talimogene laherparepvec</span></span><span style="color: black;">®</span><span style="color: black;"><span style="color: black;">。</span></span></span><span style="color: black;">虽然我国仍未有<span style="color: black;">获准</span>的癌症治疗性疫苗，但有不少<span style="color: black;">公司</span><span style="color: black;">已然</span>在<span style="color: black;">开发</span>中，<span style="color: black;">咱们</span><span style="color: black;">一块</span>看一看<span style="color: black;">日前</span>国内<span style="color: black;">公司</span><span style="color: black;">发展</span>较快的两款癌症治疗性疫苗的<span style="color: black;">开发</span><span style="color: black;">发展</span>。</span><img src="https://mmbiz.qpic.cn/mmbiz_png/KWiaWAKG5wETxVSns2qJia57LfY9IW77b6rD1QzPJiaKA7mEFxEGdl6dia8hsK5mUsNhszcAbRxsq3A993hXicyrt4w/640?wx_fmt=png&amp;from=appmsg&amp;tp=webp&amp;wxfrom=5&amp;wx_lazy=1&amp;wx_co=1" style="width: 50%; margin-bottom: 20px;"><img src="https://mmbiz.qpic.cn/mmbiz_png/KWiaWAKG5wETxVSns2qJia57LfY9IW77b6XA0AjaagGmMGMK1fzDvovFdeOFys0MaXvMxw2ia9E0EHuSy38jX3NxQ/640?wx_fmt=png&amp;tp=webp&amp;wxfrom=5&amp;wx_lazy=1&amp;wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><span style="color: black;"><span style="color: black;">嘉晨西海生物技术有限<span style="color: black;">机构</span>自主<span style="color: black;">开发</span>的创新<span style="color: black;">药品</span></span>JCXH-211<span style="color: black;">注射液，于</span>22<span style="color: black;">年底<span style="color: black;">得到</span>中国国家<span style="color: black;">药物</span>监督管理局（</span>NMPA<span style="color: black;">）<span style="color: black;">准许</span>开展</span><span style="color: black;">I</span><span style="color: black;">期临床<span style="color: black;">实验</span>，用于晚期恶性实体瘤治疗。<span style="color: black;">按照</span>其官方<span style="color: black;">网</span><span style="color: black;">表示</span>，<span style="color: black;">机构</span>共有三款肿瘤治疗性疫苗在<span style="color: black;">开发</span>中，其中</span>JCXH-211<span style="color: black;">不仅在我国<span style="color: black;">得到</span>临床批件，</span></span><span style="color: black;"><span style="color: black;">亦</span>同步在美国开展</span><span style="color: black;">IIT</span><span style="color: black;">（由<span style="color: black;">科研</span>者发起的）<span style="color: black;">科研</span>。<span style="color: black;">另外</span></span><span style="color: black;">JCXH-212</span><span style="color: black;"><span style="color: black;">亦</span><span style="color: black;">经过</span></span><span style="color: black;">IIT</span><span style="color: black;">形式在我国开展了</span><span style="color: black;">I/II<span style="color: black;">期临床试</span></span><span style="color: black;">验。</span></span><span style="color: black;">JCXH-211</span><span style="color: black;">是一款基于自复制</span><span style="color: black;">RNA</span><span style="color: black;">（</span><span style="color: black;">srRNA</span><span style="color: black;">）技术平台打造，编码人源白细胞介素</span><span style="color: black;">-12</span><span style="color: black;">（</span><span style="color: black;">IL-12</span><span style="color: black;">），</span><span style="color: black;"><span style="color: black;">由脂质纳米颗粒递送的，用于多种实体肿瘤治疗的新型<span style="color: black;">药品</span>。</span></span><span style="color: black;"><span style="color: black;"><span style="color: black;">在大<span style="color: black;">都数</span>生物系统中，外源性</span>mRNA<span style="color: black;">的半衰期有限，尤其是在快速分裂的细胞中。相比之下，病毒</span><span style="color: black;">RNA</span><span style="color: black;"><span style="color: black;">能够</span><span style="color: black;">经过</span>在宿主内主动复制来延长其寿命。<span style="color: black;">因此呢</span>，它们<span style="color: black;">常常</span><span style="color: black;">做为</span>设计合成</span><span style="color: black;">srRNA</span><span style="color: black;">的框架，</span></span><strong style="color: blue;"><span style="color: black;">srRNA<span style="color: black;">能够以<span style="color: black;">自己</span>的</span><span style="color: black;">RNA</span><span style="color: black;">序列为模板进行自我复制，它的<span style="color: black;">重点</span><span style="color: black;">优良</span>在于<span style="color: black;">能够</span>用很低的剂量达到与传统</span><span style="color: black;">mRNA</span><span style="color: black;">相同的蛋白表达水平</span></span></strong><strong style="color: blue;"><span style="color: black;">。</span></strong></span><img src="https://mmbiz.qpic.cn/mmbiz_png/KWiaWAKG5wETxVSns2qJia57LfY9IW77b6KqnXl49jNdF4ujgxaCqQBYze5FCqTOegwH1O4YqtI9nIQJYTfibzddg/640?wx_fmt=png&amp;from=appmsg&amp;tp=webp&amp;wxfrom=5&amp;wx_lazy=1&amp;wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><span style="color: black;">IL-12<span style="color: black;">是一种天然存在的细胞因子，在机体对癌症的免疫反应中起着<span style="color: black;">重要</span><span style="color: black;">功效</span>。</span></span><strong style="color: blue;"><span style="color: black;"><span style="color: black;">尽管在多项临床前<span style="color: black;">科研</span>中，</span>IL-12<span style="color: black;">始终<span style="color: black;">表示</span>出有效的抗肿瘤活性，但在人体可耐受剂量下，重组</span>IL-12<span style="color: black;">蛋白<span style="color: black;">没</span>法<span style="color: black;">表示</span>其应有的临床治疗效果。</span>IL-12<span style="color: black;">疗法的<span style="color: black;">重要</span>性挑战在于其在人<span style="color: black;">身体</span>短的半衰期以及高频率重复给药所带来的全身系统免疫毒性。</span></span></strong><span style="color: black;"><span style="color: black;"><span style="color: black;">运用</span>新的</span>IL-12<span style="color: black;"><span style="color: black;">药品</span>形式，如编码</span>IL-12<span style="color: black;">的</span>srRNA<span style="color: black;">，<span style="color: black;">能够</span>克服<span style="color: black;">以上</span><span style="color: black;">阻碍</span>，充分释放</span>IL-12<span style="color: black;">疗法的治疗<span style="color: black;">潜能</span>。</span>JCXH-211<span style="color: black;">在多项临床前动物源肿瘤模型以及人源性肿瘤异种移植模型给药<span style="color: black;">实验</span>中，均展现出良好的安全性和优异的肿瘤清除效力，<span style="color: black;">显著</span>优于<span style="color: black;">运用</span>其他分子形式的</span>IL-12</span><span style="color: black;"><span style="color: black;">药品</span>（重组蛋白</span><span style="color: black;"><span style="color: black;">、</span>DNA</span><span style="color: black;">质粒以及非自复制</span><span style="color: black;">mRNA</span><span style="color: black;">等）。</span></span><img src="https://mmbiz.qpic.cn/mmbiz_png/KWiaWAKG5wETxVSns2qJia57LfY9IW77b6jHJxooscdXY7Diaobm0Z5a1y2ZX24BUo4eYwiaDnxg79HRzoDpNJ6P5g/640?wx_fmt=png&amp;from=appmsg&amp;tp=webp&amp;wxfrom=5&amp;wx_lazy=1&amp;wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><span style="color: black;"><span style="color: black;">斯微生物的编码新生抗原</span>mRNA</span><span style="color: black;">个性化肿瘤疫苗（</span><span style="color: black;">SWP1001</span><span style="color: black;">）在</span><span style="color: black;">2022<span style="color: black;">年初<span style="color: black;">得到</span>澳洲</span>I<span style="color: black;">期临床批件，并<span style="color: black;">已然</span>完成</span><span style="color: black;">50ug</span><span style="color: black;">剂量组爬坡入组工作。<span style="color: black;">日前</span>，该疫苗已同步在国内多家医院开展</span><span style="color: black;">IIT</span><span style="color: black;"><span style="color: black;">科研</span>，近期与复旦大学<span style="color: black;">附庸</span>中山医院合作的项目是国产</span><span style="color: black;">mRNA</span><span style="color: black;">个性化肿瘤疫苗在肝癌术后的临床<span style="color: black;">科研</span>。</span></span></span><img src="https://mmbiz.qpic.cn/mmbiz_png/KWiaWAKG5wETxVSns2qJia57LfY9IW77b6n8T4DuBYuiawujevicpJrHptb7W4AaDehJJcGjDTnws5FAtSWZ6lGUmg/640?wx_fmt=png&amp;from=appmsg&amp;tp=webp&amp;wxfrom=5&amp;wx_lazy=1&amp;wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><span style="color: black;">随着对癌症的<span style="color: black;">科研</span>深入，尤其是测序技术和生信的发展，<span style="color: black;">经过</span>对肿瘤组织的基因测序，<span style="color: black;">能够</span>检测到<span style="color: black;">海量</span>的基因突变。</span><strong style="color: blue;"><span style="color: black;">基因突变能产生<span style="color: black;">仅在</span>肿瘤中表达的新抗原</span></strong><strong style="color: blue;"><span style="color: black;">（</span></strong><strong style="color: blue;"><span style="color: black;">neoantigens</span></strong><strong style="color: blue;"><span style="color: black;">），这些新抗原<span style="color: black;">能够</span>被人体的</span></strong><strong style="color: blue;"><span style="color: black;">T</span></strong><strong style="color: blue;"><span style="color: black;">细</span></strong><strong style="color: blue;"><span style="color: black;">胞识别，从而<span style="color: black;">导致</span>免疫反应。<span style="color: black;">因此呢</span>，这些新抗原是理想的癌症疫苗靶点。每种肿瘤都有自己独特的突变<span style="color: black;">构成</span>，<span style="color: black;">仅有</span>一小部分在<span style="color: black;">病人</span>之间共享，<span style="color: black;">因此呢</span>利用这些基因突变信息<span style="color: black;">能够</span>设计个性化肿瘤疫苗。</span></strong><span style="color: black;">随着基因组学、数据科学和癌症免疫治疗方面的技术进步，<span style="color: black;">此刻</span><span style="color: black;">能够</span>快速绘制基因组内的突变图谱，<span style="color: black;">恰当</span><span style="color: black;">选取</span>疫苗靶点，并<span style="color: black;">按照</span><span style="color: black;">病人</span>的个体肿瘤定制治疗<span style="color: black;">方法</span>。相比传统<span style="color: black;">药品</span>，个性化肿瘤疫苗的<span style="color: black;">优良</span>在于<span style="color: black;">能够</span>在局部和外周免疫系统中激活特异性抗肿瘤</span><span style="color: black;">T</span><span style="color: black;">细胞免疫，<span style="color: black;">诱发</span>特异性</span><span style="color: black;">T</span><span style="color: black;">细胞克隆扩增，对肿瘤组织和细胞进行浸润和杀伤，从而<span style="color: black;">掌控</span>和缩小肿瘤。另一方面，个性化肿瘤疫苗<span style="color: black;">倘若</span>和</span><span style="color: black;">PD-1/L1</span><span style="color: black;">等抗体<span style="color: black;">药品</span>联用，<span style="color: black;">亦</span>许能产生更好的治疗效果。</span></span><img src="https://mmbiz.qpic.cn/mmbiz_png/KWiaWAKG5wETxVSns2qJia57LfY9IW77b6saib7yZQHANjrAXVlSFSTazV9pa4WDC2DvYMBaLxibcwOQmEiaBdVLjRQ/640?wx_fmt=png&amp;from=appmsg&amp;tp=webp&amp;wxfrom=5&amp;wx_lazy=1&amp;wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><span style="color: black;"><span style="color: black;">肝癌术后复发率高，<span style="color: black;">同期</span>缺少有效的治疗<span style="color: black;">办法</span>，<span style="color: black;">因此呢</span>需探索有效的术后新辅助手段，基于</span>mRNA<span style="color: black;">平台的个性化肿瘤疫苗利用手术组织来进行测序，特异性高、安全性</span></span><span style="color: black;">相对较好</span><span style="color: black;"><span style="color: black;">。斯微生物</span>mRNA<span style="color: black;">个性化肿瘤疫苗在肝癌术后的临床<span style="color: black;">科研</span>中，<span style="color: black;">经过</span><span style="color: black;">针对</span><span style="color: black;">病人</span>的肿瘤组织以及血液样本开展高深度的全外显子以及</span><span style="color: black;">RNA-seq</span><span style="color: black;">的测序，再利用斯微生物搭建的</span><span style="color: black;">AI</span><span style="color: black;">预测平台</span><span style="color: black;">-SmartNeo</span><span style="color: black;">，预测每一位<span style="color: black;">病人</span>的个性化肿瘤新抗原，并<span style="color: black;">经过</span>设计和优化<span style="color: black;">得到</span>个性化的<span style="color: black;">制品</span>序列，经过质粒以及原液快速生产。<span style="color: black;">最后</span><span style="color: black;">经过</span>纳米材料（</span><span style="color: black;">Lipopolyplex, LPP</span><span style="color: black;">）递送平台系统包裹</span><span style="color: black;">mRNA</span><span style="color: black;">，多点注射的方式递送到<span style="color: black;">病人</span><span style="color: black;">身体</span>，从而有效的激活<span style="color: black;">病人</span>特异性免疫。在临床前<span style="color: black;">科研</span>中，斯微生物编码新生抗原</span><span style="color: black;">mRNA</span><span style="color: black;">个性化肿瘤疫苗<span style="color: black;">针对</span>肝癌</span></span><span style="color: black;">术后<span style="color: black;">病人</span>取得了良好的效果。</span></span><span style="color: black;"><strong style="color: blue;"><span style="color: black;">结语</span></strong></span><span style="color: black;"><span style="color: black;">初期</span>癌症较为隐匿，难以<span style="color: black;">发掘</span>，中晚期癌症癌细胞在人体多处转移，<span style="color: black;">引起</span>手术等局部治疗<span style="color: black;">没</span>法彻底清除，加上肿瘤的异质性和变化性的特点，使得<span style="color: black;">无</span>一种<span style="color: black;">药品</span>能够涵盖所有不同生物学特性的并且<span style="color: black;">持续</span>变化的肿瘤细胞。纵使是乔布斯<span style="color: black;">这般</span>惊才绝艳之人，有能力享受到世界最顶尖的治疗<span style="color: black;">方法</span>，<span style="color: black;">亦</span>不得不饮恨西去。疫苗的<span style="color: black;">功效</span>在传<span style="color: black;">患病</span><span style="color: black;">行业</span>、以及预防部分癌症中至关<span style="color: black;">要紧</span>，随着新技术的<span style="color: black;">持续</span>迭代，治疗性癌症疫苗有望和<span style="color: black;">药品</span>联合<span style="color: black;">运用</span>，彻底治愈癌症，但<span style="color: black;">这里</span>之前<span style="color: black;">咱们</span>仍有很长的路要走。</span><span style="color: black;">参考<span style="color: black;">源自</span>：</span>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">https://mp.weixin.qq.com/s?__biz=MzA3OTE0ODU3NQ==&amp;mid=2650000128&amp;idx=2&amp;sn=323dfe70d082be9ed5e21bd35595417c&amp;chksm=87b08870b0c701660de43adbccda435650b45d3c1d014dd3320e60807c071402a84b70cb8e2f&amp;scene=27</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">https://www.stemirna.com/CompanyDynamics/info.aspx?itemid=413</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">https://www.immorna.com/cn/pipeline.html</span></p><strong style="color: blue;">识别<span style="color: black;">微X</span>二维码，可添加<strong style="color: blue;">药时空</strong><span style="color: black;">博主</span></strong><span style="color: black;"><strong style="color: blue;">请注明：姓名+<span style="color: black;">科研</span>方向！</strong></span><img src="https://mmbiz.qpic.cn/sz_mmbiz_png/EAiav8ncGU6aicLHQaUDGiaD2AsksovxMuiczeIGp7kGJwoiap107cnZYHibia5BzP0nrQm7NtvZUXyTazibY0M4BLLjkA/640?wx_fmt=other&amp;from=appmsg&amp;wxfrom=5&amp;wx_lazy=1&amp;wx_co=1&amp;tp=webp" style="width: 50%; margin-bottom: 20px;"><strong style="color: blue;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><img src="https://mmbiz.qpic.cn/sz_mmbiz_png/EAiav8ncGU6aUfAjmAydX4DFib0OXWxhCcJzeBaHMVG0VsyY218NaW7orvHFXBtER55ZPOHRCJ96E86P1NEvrQFQ/640?wx_fmt=other&amp;wx_co=1&amp;wxfrom=5&amp;wx_lazy=1&amp;tp=webp" style="width: 50%; margin-bottom: 20px;"></span></strong></span></strong>




听听海 发表于 2024-8-23 08:50:06

外链论坛的成功举办，是与各位领导、同仁们的关怀和支持分不开的。在此，我谨代表公司向关心和支持论坛的各界人士表示最衷心的感谢！

huijie168 发表于 2024-9-9 23:16:40

在遇到你之前，我对人世间是否有真正的圣人是怀疑的。

4lqedz 发表于 2024-10-12 10:25:23

对于这个问题，我有不同的看法...

4lqedz 发表于 2024-11-14 12:57:28

你的努力一定会被看见，相信自己，加油。
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