Antibody-based therapies designed for human use frequently fail to cross-react with the murine isoform of their target. Because of this problem, preclinical studies of antibody-based mesothelin (Msl)-targeted therapeutics in immunocompetent systems have been limited by the lack of suitable mouse models. Here, we describe two immunocompetent humanized mesothelin transgenic mouse lines that can act as tolerant hosts for C57Bl/6-syngeneic cell lines expressing the human isoform of mesothelin. Thyroid peroxidase (TPO) mice have thyroid-restricted human mesothelin expression. Mesothelin (Msl) mice express human mesothelin in the typical serosal membrane distribution and can additionally be utilized to assess on-target, off-tumor toxicity of human mesothelin–targeted therapeutics. Both transgenic strains shed human mesothelin into the serum like human mesothelioma and patients with ovarian cancer, and serum human mesothelin can be used as a blood-based surrogate of tumor burden. Using these models, we examined the on-target toxicity and antitumor activity of human mesothelin–targeted recombinant immunotoxins. We found that immunotoxin treatment causes acute and chronic histologic changes to serosal membranes in Msl mice, while human mesothelin-expressing thyroid follicular cells in TPO mice are resistant to immunotoxin despite excellent drug delivery. Furthermore, poor delivery of immunotoxin to syngeneic orthotopic human mesothelin-expressing pancreatic adenocarcinoma limits antitumor activity both alone and in combination with immune checkpoint inhibition. In summary, we have developed two high-fidelity, immunocompetent murine models for human cancer that allow for rigorous preclinical evaluation of human mesothelin–targeted therapeutics.

中文翻译：

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新型表达人源化间皮素的基因工程小鼠模型强调了向胰腺癌提供复杂疗法的挑战

为人类使用而设计的基于抗体的疗法经常无法与其靶标的鼠亚型发生交叉反应。由于这个问题，免疫活性系统中基于抗体的间皮素 (Msl) 靶向治疗的临床前研究因缺乏合适的小鼠模型而受到限制。在这里，我们描述了两种具有免疫能力的人源化间皮素转基因小鼠系，它们可以作为表达人类间皮素亚型的 C57Bl/6 同源细胞系的耐受宿主。甲状腺过氧化物酶 (TPO) 小鼠具有甲状腺限制的人类间皮素表达。间皮素 (Msl) 小鼠在典型的浆膜分布中表达人类间皮素，还可用于评估人类间皮素靶向治疗的靶向、非肿瘤毒性。两种转基因菌株都将人类间皮素释放到血清中，如人类间皮瘤和卵巢癌患者，血清人类间皮素可用作肿瘤负荷的血液替代物。使用这些模型，我们检查了人间皮素靶向重组免疫毒素的靶向毒性和抗肿瘤活性。我们发现免疫毒素治疗会导致 Msl 小鼠浆膜发生急性和慢性组织学变化，而 TPO 小鼠中表达人间皮素的甲状腺滤泡细胞尽管具有出色的药物递送能力，但对免疫毒素具有抗性。此外，免疫毒素对同源原位表达人间皮素的胰腺癌的不良递送限制了单独和与免疫检查点抑制结合的抗肿瘤活性。综上，我们开发了两种高保真，