Antibody-drug Conjugates Research, ,

Hormone receptor-positive, HER2-negative breast cancer (HR+/HER2- BC) represents a significant fraction of all breast cancer diagnoses. While conventional treatment with endocrine therapy (ET) and CDK4/6 inhibitors has improved clinical outcomes, the development of therapeutic resistance remains an inevitable and limiting factor for long-term survival in many patients. This pleiotropic drug resistance, often involving multiple mechanisms without a single common pathway, creates a profound unmet need for new therapeutic strategies.

A crucial breakthrough in addressing this challenge lies in identifying a common dependency shared by all treatment-refractory HR+/HER2- BC cells. Recent research has powerfully established the oncogenic protein MUC1-C as a critical common effector and, consequently, a compelling target for the advanced precision medicine offered by antibody-drug conjugates (ADCs).

The Rationale: MUC1-C as the Central Vulnerability

ADCs are a class of targeted therapy already validated and approved for the treatment of metastatic breast cancer. The success of an ADC hinges on selecting a tumor-specific cell surface target (the antigen) that is highly expressed on cancer cells but minimally on healthy tissue. The MUC1-C protein fits this profile, as its expression is upregulated across the entire surface of depolarized breast cancer cells compared to lower apical expression in normal epithelia.

The core rationale for an ADC targeting MUC1-C stems from its indispensable role in maintaining cancer cell viability and drug resistance. MUC1-C acts as a central hub, governing the signaling pathways that sustain tumor growth, particularly through the estrogen receptor (ER).

Research shows that MUC1-C achieves this by regulating two critical ER coactivators:

  • Steroid Receptor Coactivator 3 (SRC-3): MUC1-C forms nuclear complexes with ER and SRC-3. MUC1-C is necessary for SRC-3 expression, which it regulates via the kinase MK2.
  • Mediator Subunit 1 (MED1): MUC1-C is also integral to the complex involving ER and MED1. It regulates the stabilization of MED1 through the activation of CDK7.

In both scenarios, genetically or pharmacologically targeting MUC1-C is sufficient to suppress the expression of these coactivators, thereby crippling the ER signaling required for tumor cell proliferation and survival. This fundamental dependency makes MUC1-C a universal upstream target against core tumor processes.

Engineering the Targeted Delivery Platform

To translate this vulnerability into a viable therapy, an ADC platform was developed. The foundational component is a monoclonal antibody engineered to specifically recognize and bind to the MUC1-C epitope found on the surface of breast cancer cells.

This antibody component is chemically linked to a highly potent cytotoxic payload—the ‘drug’—via a specially designed cleavable linker. The linker is designed to remain stable in the systemic circulation but efficiently release the toxic payload once the ADC is internalized by the cancer cell and trafficked to the lysosome. This mechanism ensures the selective delivery of the cytotoxic agent, maximizing efficacy against the tumor while minimizing systemic exposure and potential off-target toxicity.

The resulting ADC was synthesized with an optimal drug-to-antibody ratio (DAR) of approximately ~4, representing a balance of target binding and therapeutic potency. Initial testing confirmed its selective activity, showing it was active against MUC1-positive breast cancer cells but not MUC1-negative cells.

Preclinical Validation: Broad Efficacy Against Resistance

The true therapeutic potential of this ADC platform was demonstrated in its activity against the various forms of acquired drug resistance plaguing HR+/HER2- BC patients:

  1. ER-Mutant Resistance: ESR1 mutations, such as Y537S and D538G, confer resistance to ET. The anti-MUC1-C antibody demonstrated comparable cell surface expression and cell killing efficacy (IC-50) in both wild-type and ESR1 mutant cell lines. Critically, ESR1 mutant cells, which are dependent on MUC1-C for ER signaling, were effectively inhibited by the ADC.
  2. CDK4/6 Inhibitor Resistance: Cell lines engineered to be resistant to the CDK4/6 inhibitor abemaciclib (AR cells) were shown to have a marked upregulation of MUC1-C expression, confirming MUC1-C’s involvement in resistance mechanisms. Despite this acquired resistance, the AR cells showed comparable surface expression of the MUC1-C epitope and similar sensitivity to the ADC when compared to their parental counterparts. This suggests the ADC can bypass the established resistance pathway.

Importantly, the anti-MUC1-C ADC was highly effective at inhibiting the self-renewal capacity (tumorsphere formation efficiency) of cancer stem cells (CSCs) across all wild-type, ER-mutant, and CDK4/6 inhibitor-resistant models. This ability to target the root CSC population is vital for achieving durable, long-term therapeutic responses.

Fig.1 CDK4/6 inhibitor resistant HR+/HER2− BC cells are MUC1-C-dependent.1

Translating to Tumor Regression and Safety

The exceptional preclinical efficacy was successfully translated into in vivo tumor regression models:

  • Xenograft Model: Treatment with the anti-MUC1-C ADC in a mouse xenograft model of HR+/HER2- BC resulted in complete and durable tumor regressions. All tumors became unmeasurable early in the treatment course, and the therapeutic effect was significantly different from the vehicle control group.
  • Patient-Derived Xenograft (PDX) Model: The ADC was tested against a challenging PDX model (PDX1415) derived from a patient whose HR+/HER2- BC was refractory to multiple prior treatments, including ET and various chemotherapies. Treatment with the ADC suppressed tumor growth in this heavily pretreated model, demonstrating a significantly better outcome compared to the control.

Crucially, in both the xenograft and PDX models, treatment with the ADC was well-tolerated and was not associated with significant body weight loss or other overt toxicities, underscoring the success of the ADC design in achieving selective tumor targeting.

Conclusion: A New Horizon for Refractory BC

The identification of MUC1-C as a critical and common dependency in treatment-resistant HR+/HER2- BC provides a robust foundation for a new therapeutic path. The data on the anti-MUC1-C ADC—demonstrating broad efficacy across all major resistance mechanisms, the ability to eliminate cancer stem cells, and potent anti-tumor activity in vivo with a favorable safety profile—positions this platform as a strong candidate for addressing this refractory disease.

MUC1-C is widely expressed in HR+/HER2- BCs that harbor ESR1 mutations, as well as those refractory to CDK4/6 inhibitors. The clinical data and robust preclinical success underscore the importance of this MUC1-C targeted ADC as a promising, urgently needed therapeutic option for patients with limited choices.

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Reference

  1. Nakashoji, Ayako, et al. “MUC1-C dependency in drug resistant HR+/HER2− breast cancer identifies a new target for antibody-drug conjugate treatment.”NPJ Breast Cancer1 (2025): 39. CC BY 4.0. https://doi.org/10.1038/s41586-025-09626-3