A MUC1-C-targeting ADC exhibits potent antitumor activity against neuroendocrine prostate cancer in both intact and testosterone-depleted preclinical models

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