肿瘤细胞治疗研究
英文原题：RO4, a high-affinity humanized antibody against the juxtamembrane region of mesothelin for targeted cancer therapy.
用 hRO4 靶向 MSLN 的非脱落表位，克服了传统 MSLN 靶向疗法的关键局限。
背景：间皮素（MSLN）是在间皮瘤、卵巢癌和胰腺癌等多种实体瘤中高表达的表面抗原。然而，脱落型MSLN（SM）可作为可溶性诱饵在肿瘤微环境中积聚，减少抗体与肿瘤细胞表面的结合，因而常削弱MSLN靶向药物的治疗效果。 方法：为克服这一障碍，研究者使用涵盖主要切割位点的肽段免疫兔，制备靶向MSLN膜近端、不会脱落区域的抗体。从200个B细胞克隆中筛得14种特异性结合MSLN近膜区的抗体。领先候选抗体RO4随后接受详细表征和人源化改造，以提高临床适用性。 结果：人源化RO4（hRO4）对MSLN的结合亲和力增强，并可特异识别肿瘤相关、非脱落表位。结构分析证实其精确结合切割位点附近的表位。hRO4能有效抑制体外间皮素脱落；将其表达于嵌合抗原受体（CAR）T细胞后，可在NOD scid gamma小鼠模型中有效清除肿瘤。 结论：利用hRO4靶向MSLN非脱落表位，可克服传统MSLN靶向疗法的一项关键局限。通过避免诱饵干扰并增强肿瘤特异性靶向，基于hRO4的治疗方案有望改善MSLN阳性癌症患者结局。
BACKGROUND: Mesothelin (MSLN) is a surface antigen highly expressed in several solid tumors, including mesothelioma, ovarian, and pancreatic cancers. However, therapeutic efficacy of MSLN-targeted agents is often compromised by shed MSLN (SM), which acts as a soluble decoy and accumulates in tumor microenvironments, reducing antibody engagement at the tumor surface. METHODS: To overcome this barrier, we generated antibodies targeting the membrane-proximal, non-shed region of MSLN using a peptide encompassing major cleavage sites for rabbit immunization. From 200 B-cell clones, 14 antibodies specific to the juxtamembrane region of MSLN were identified. The lead candidate, RO4, underwent detailed characterization and humanization to improve clinical applicability. RESULTS: Humanized RO4 (hRO4) exhibited enhanced binding affinity to MSLN and specifically recognized tumor-associated, non-shed epitopes. Structural analysis confirmed precise epitope engagement near the cleavage site. hRO4 effectively inhibited mesothelin shedding in vitro and enabled potent tumor eradication when expressed in chimeric antigen receptor (CAR) T cells in NOD scid gamma mouse models. CONCLUSIONS: Targeting a non-shed epitope of MSLN with hRO4 overcomes a critical limitation of conventional MSLN-directed therapies. By avoiding decoy interference and enhancing tumor-specific targeting, hRO4-based therapeutics offer promising clinical potential for improving outcomes in MSLN-positive cancers.
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