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Membrane Protein Degraders: A New Therapeutic Strategy for Auto Immune Disease​

  • Therapeutics
  • 2024

Xin Zhou, PhD, Assistant Professor of Cancer Biology at Dana-Farber and Biological
Chemistry and Molecular Pharmacology at Harvard Medical School, focuses on cellular
signal perception in cancer and immunological diseases. Her lab is developing novel
technologies to degrade cell surface proteins involved in these conditions and applying
these new therapeutic approaches to address unmet biomedical needs.
Initially designed for targeting cancer cells, Zhou’s membrane protein degradation
technology is now being adapted to immune modulation and autoimmune diseases, for
which she has received Dana-Farber Accelerator funding.

Targeted Proteins are Captured then Destroyed

Zhou’s technology, Transferrin Receptor Targeting Chimera (TransTAC), offers a novel cancer-targeting approach by directing cancer-driver membrane proteins for degradation. Membrane proteins play crucial roles in cellular activities, including signal transduction and cell communication. Misregulation of membrane proteins are drivers of many diseases. However, some of these proteins are considered “undruggable” due to their complex structures and functions. TransTAC circumvents these challenges by inducing the internalization of target proteins with bifunctional antibodies and their degradation in lysosomes.

As described in a recent Nature1 paper, in cancer, TransTAC exploits the high expression
of Transferrin Receptor 1 (TfR1) on cancer cells to degrade its target. Zhou’s team is now
adapting a novel membrane protein degradation technology for targeting immune cells and
addressing autoimmune conditions.

Focus on a Key Autoimmune Receptor

Developing this technology to target the immune system is a natural extension of its earlier
success in cancer. By leveraging a protein expressed in immune cells and specifically degrading key surface receptors that regulate immune signaling, this new approach could
highly effectively inhibit receptors that were previously difficult to block. This targeted
approach promises to both enhance efficacy and avoid the side effects associated with
broad immune suppressive therapies, offering patients a safer and more effective
treatment option.

Zhou’s first target is a well-validated drug target in various autoimmune conditions and has
been extensively explored in drug discovery; however, both small molecule and antibody
approaches have failed in the past due to either limited efficacy or toxicity issues. This
makes it an ideal candidate for Zhou’s targeted degradation approach. Early experiments
have shown promising results, with significant downregulation of the receptor and complete
inhibition of its functional activity. The Dana-Farber Accelerator funding is providing critical
support for the team to fully establish the method and build intellectual property around this
technology.

The team’s work on its initial target is just the beginning, and future studies will explore
other targets that have been considered “undruggable” proteins. Zhou’s vision extends
beyond autoimmune diseases. The platform’s versatility suggests potential Jun Huh, PhD
Associate Professor, Harvard Medical School Jhoely Duque-Jimenez Former Research Technician/Lab Manager, Zhou Lab, Dana-Farber Current MD Student, BU Kaitlin Rhee Graduate Student, Zhou Lab, DanaFarber Aoxing Cheng, PhD Postdoctoral Fellow, Zhou Lab, Dana-Farber applications in other fields, such as immunotherapy for targeting cancer, or other non-oncology indications such as pain management and rare diseases. In addition to Dana-Farber Accelerator funding, Zhou’s lab research is supported by a National Institutes of Health Director’s New Innovator Award, a National Institute of Biomedical Imaging and Bioengineering R00 Award, and a
Dana-Farber Helen Gurley Brown Presidential Initiative Helen Trailblazer Award.

The most well-studied approach for restoring p53 has been by inhibiting the MDM2 protein. However, clinical trials of at least ten MDM2 inhibitors show that while they increase p53 levels, that increase has been too toxic for the body. Therefore, the identification of targets that activate p53 without boosting their levels remains a competitive area of drug discovery and one with potentially significant promise in treating many cancers.  

Several years ago, Dr. Chowdhury and his team discovered TIRR, a novel p53-associated protein, but they were not aware of its mechanism of action on p53 at the time. Since then, the team discovered that TIRR inhibition activates the tumor suppressor functions of normal, wild-type p53 leading to cancer cell death. Since half of all cancers retain at least one copy of wild-type p53 this therapeutic strategy may be widely applicable to multiple tumor types, and a potential approach that avoids the toxicity seen with previously developed MDM2 inhibitors.  

Team Members: Xin Zhou, PhD, Jun Huh, PhD, Jhoely Duque-Jimenez, Kaitlin Rhee, Aoxing Cheng, Dingjingyu Zhou, Itay Algov, Lawrence Shue

Team Members

Xin Zhou, PhD

Assistant Professor of Cancer Biology, Dana-Farber

Assistant Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School