一种靶向MUC1-C的ADC在完整和睾酮耗竭的临床前模型中均对神经内分泌前列腺癌表现出强效抗肿瘤活性

Background: Prostate cancer (PC) is one of the most frequently diagnosed malignancies in men and remains the second leading cause of cancer-related mortality. The castration-resistant and neuroendocrine variants (CRPC/NEPC) are especially challenging to treat, as these tumors often lose dependence on androgen receptor signaling and become refractory to androgen-targeted therapies. Although prostate-specific membrane antigen (PSMA) is a valuable surface target in many forms of PC, its absence in PSMA-negative tumors necessitates alternative therapeutic markers. One such marker is MUC1, whose expression becomes markedly upregulated in PSMA-negative disease. Notably, aberrant MUC1 expression is a hallmark of CRPC/NEPC and is strongly associated with aggressive tumor behavior and poor clinical outcomes. Methods: In-vitro cytotoxic activity of MUC1-C targeting ADC (XYA02-8) was evaluated in a series of prostate cancer cell lines. Preclinical antitumor activity was evaluated in-vivo in both intact and castrated nude mice to model androgen replete and depleted states in PC patients. Results: We find that the MUC1-C mAb 7B8 * binds to ~90% cells compared to isotype control in CRPC/NEPC in-vitro. To develop multiple ADC formulations and to optimize the candidate, Quality by Design (QbD, FDA) approach was utilized, leveraging the Design of Experiments (DOE) statistical framework. XYA02-8-ADC exhibits efficient internalization at 3 hours at 37 o C in multiple CRPC/NEPC cell lines and displayed potent cytotoxicity in in-vitro. Both intact and castrated nude mice with established tumor xenografts were treated with 7.5 mg/kg QW x 3 i.v. and monitored for over two-month post treatment. Significant (~70%) tumor growth inhibition was observed with XYA02-8-ADC without an accompanying weight loss and/or tissue toxicity. Interestingly, the antitumor activity persists in both intact and castrated nude mice xenografts demonstrating that targeting MUC1-C present a unique opportunity for tumor abrogation downstream of androgen signaling. Conclusions: XYA02-8-ADC demonstrates strong antitumor activity with a favorable safety profile in CRPC/NEPC models. Notably, its ability to retain efficacy even under testosterone-replete conditions highlights an important therapeutic opportunity: targeting MUC1-C with XYA02-8-ADC without relying on androgen-deprivation strategies. These findings open a promising avenue for developing effective treatments that avoid the systemic adverse effects associated with hormonal deprivation.* https://patents.google.com/patent/US20230265208A1/en