Background: Soft tissue sarcoma (STS) treatment has made limited progress in the past four decades due to various challenges, with doxorubicin (DOX) as one of the main treatment options. Methods: Our recently developed single-protein-encapsulated DOX nanodrug, SPEDOX-6, provides a novel approach for improving DOX’s efficacy and reducing its side effects. Furthermore, SPEDOX-6 may be used to target cancer cells with low neonatal Fc receptor (FcRn) levels based on the FcRn-aided human serum albumin (HSA) cellular recycling mechanism. Results: A toxicokinetic study in Sprague–Dawley (SD) rats indicates that the total exposure for SPEDOX-6 increases 7–17 times depending on the dosage, compared to the equivalent amount of DOX. Cardiotoxicity in SD rats from a high dose of 50 mg/kg of GLP-grade SPEDOX-6 was undetectable, in contrast to observable cardiotoxicity from a single dose of 5–10 mg/kg DOX. Non-GLP-grade SPEDOX-6 at cumulative doses of 52.5 mg/kg was well tolerated by mice and no more toxic than DOX at its MTD (10 mg/kg cumulative dose). SPEDOX-6 remarkably suppresses HT-1080 (fibrosarcoma cell line STS model but recently reclassified as dedifferentiated chondrosarcoma due to characteristic IDH1 mutation, with the lowest FcRn expression level among cancer cell lines), with 3 out of 10 mice attaining tumor-free status. GLP-grade SPEDOX-6 at 30 mg/kg is significantly better than Doxil at 4 mg/kg (MTD) and DOX at 3.5 mg/kg (MTD) in inhibiting SK-ES-1 (Ewing sarcoma model, with the highest FcRn expression level among cancer cell lines) tumor growth, but SPEDOX-6 has less efficacy against SK-ES-1, relative to HT-1080. Conclusions: Combined with our earlier study on a TNBC (triple-negative breast cancer) mouse model (MB-MDA-231 with a medium FcRn expression level), SPEDOX-6’s antitumor efficacy displays an inverse relationship with the FcRn expression level in three different tumor mouse models, thereby providing a potential mechanism for SPEDOX-6 to effectively target tumors with low FcRn expression levels. With “Orphan Drug Designation” status, SPEDOX-6’s current human phase Ib/IIa clinical trials for treating STS underway will provide more information on establishing the correlation between antitumor efficacy of SPEDOX-6 and FcRn expression levels of cancer tissues. If validated by clinical trial data, SPEDOX-6 may become the first targeted cancer therapy based on the FcRn expression level, leading to the development of more FcRn-targeted cancer therapeutics with improved efficacy and reduced toxicity.
背景：过去四十年间，软组织肉瘤的治疗因多种挑战进展有限，阿霉素是主要治疗方案之一。方法：我们近期研发的单蛋白包裹阿霉素纳米药物SPEDOX-6，为提升阿霉素疗效并降低其副作用提供了新途径。该药物基于新生儿Fc受体介导的人血清白蛋白细胞循环机制，可靶向低表达新生儿Fc受体的癌细胞。结果：Sprague-Dawley大鼠毒代动力学研究表明，相较于等效剂量的阿霉素，SPEDOX-6的总暴露量随剂量不同可提高7-17倍。给予50 mg/kg GLP级SPEDOX-6的大鼠未检测到心脏毒性，而单次给予5-10 mg/kg阿霉素则出现明显心毒性。累计52.5 mg/kg的非GLP级SPEDOX-6在小鼠体内耐受性良好，其毒性不高于最大耐受剂量（累计10 mg/kg）的阿霉素。SPEDOX-6对HT-1080（纤维肉瘤细胞系STS模型，因特征性IDH1突变近期被重新归类为去分化软骨肉瘤，其FcRn表达水平在癌细胞系中最低）具有显著抑制作用，10只小鼠中有3只达到无瘤状态。在抑制SK-ES-1（尤文肉瘤模型，FcRn表达水平在癌细胞系中最高）肿瘤生长方面，30 mg/kg GLP级SPEDOX-6的疗效显著优于4 mg/kg（最大耐受剂量）的多柔比星脂质体与3.5 mg/kg（最大耐受剂量）的阿霉素，但相对于HT-1080模型，SPEDOX-6对SK-ES-1的疗效较弱。结论：结合我们前期在三阴性乳腺癌小鼠模型（MB-MDA-231，FcRn表达水平中等）中的研究，SPEDOX-6在三种不同肿瘤小鼠模型中的抗肿瘤疗效与FcRn表达水平呈负相关，这为SPEDOX-6有效靶向低FcRn表达肿瘤提供了潜在机制依据。凭借"孤儿药认定"资格，SPEDOX-6目前针对软组织肉瘤治疗的人体Ib/IIa期临床试验正在进行，将为建立该药物抗肿瘤疗效与癌组织FcRn表达水平的相关性提供更多依据。若经临床试验数据验证，SPEDOX-6可能成为首个基于FcRn表达水平的靶向癌症疗法，从而推动更多以FcRn为靶点、兼具增效减毒特性的癌症治疗药物的开发。
肿瘤(癌症)患者之家