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TransTAC: Next-Generation Targeted Protein Degradation Technology

TransTAC, a novel technology developed in the lab of Prof. Xin Zhou, PhD, is a next generation protein degradation approach for reaching previously ‘undruggable’ targets in cancer while minimizing treatment toxicity.  

Therapeutics

Project Overview

Protein degradation approaches have greatly expanded what is considered druggable inside of cells. However, these approaches are not amenable for targeting the extracellular proteome, where many of the high value targets are in oncology and other diseases.
The Transferrin Receptor-Mediated TArgeting Chimeras (TransTAC) technology platform was engineered as a highly specific way to degrade difficult-to-target receptors or other proteins on the surface of the cancer cell, resulting in cell death.
Dana-Farber is seeking partners to create a new company around this technology or to license it for development to the clinic.

Technology

Protein degradation is a natural process by which cells break down proteins that are damaged or no longer needed so they can be recycled or disposed of. One of the earliest protein degradation strategies – PROteolysis TArgeting Chimeras (PROTAC) technology – degrades proteins contained within a cell but it is challenging to target proteins on the surface or outside of the cell.

In contrast, TransTAC targets disease-specific proteins on the surface of cells, including cancer cells. This is because the collection of external proteins on the surface of cells – the proteome – constitutes approximately 40 percent of all protein-encoding genes and plays key roles in health and disease.  Therefore, developing a universal strategy for regulating extracellular proteins would be of exceptional interest for both therapeutic intervention and basic research. TransTAC was designed as this type of strategy.

TransTAC molecules hijack the lysosomal degradation pathway of cells by removing specific disease-associated membrane-bound proteins from the surface of cells, many of which cannot be targeted and inhibited with other methods, like blocking antibodies or small molecules. The degradation approach offers a new way to entirely capture these previously ‘undruggable’ targets by internalizing them inside the cell where they – and the cancer cell – are destroyed. The technique mitigates the toxicities associated with many other cancer treatments which often harm healthy tissue. And it overcomes the limitations with other targeted strategies, including blocking antibodies or small molecules, which often cannot effectively bind a target or otherwise cannot effectively inhibit its activity.

As described in a recent Nature paper, the heart of the TransTAC technology is the transferrin receptor-1 (TfR1 or CD71), a pivotal protein which is overexpressed in various malignant tumor types such as brain, liver, breast, lung, pancreas, stomach, and blood cancers. TfR1 is responsible for facilitating the uptake of iron to fuel cancer cell rapid proliferation and dissemination, shuttling iron molecules into cancer cells at a rate of 500 receptors per second, then quickly returning to the cell surface for another round. Cancer cells overexpress TfR1 because of its elevated reliance on iron for rapid growth and spread. For this reason, the TransTAC platform preferentially targets cancer cells.

Bi-specific molecules, those that bind to two compounds, are central to the TransTAC platform. The TransTAC molecule consists of a TfR1-antibody fragment and a second antibody fragment engineered to target a specific protein of interest (POI), also present on the surface of the cancer cell. Examples include EGFR, PD-L1, or CD20 – three well-known proteins that are overexpressed in many cancer types. Once bound to TfR1, a TransTAC molecule can now enter the cell, along with its tethered protein of interest. The TransTAC molecular design ensures that the target protein stays inside the cell where it will be destroyed while the transferrin receptor recycles.

Other protein targeted strategies, including blocking antibodies and small molecules, are often limited because either the structure or activity of the target receptor is considered unreached or impossible to target. TransTAC overcomes these limitations with its bi-specific approach.

TransTAC induces close proximity of TfR and a protein of interest (POI) at the cell surface, leading to co-internalization of the complex where an enzyme cleaves TransTAC and separates the POI from the TfR. The POI then traffics to lysosomes for degradation, while TfR is recycled back to the cell surface.

Team Members: Xin Zhou, PhD, Pasi Jänne, MD, PhD, Kaitlin Rhee, Jhoely Duque-Jimenez, Francesco Facchinetti, MD, PhD

Source: Zhang, D., Duque-Jimenez, J., Facchinetti, F. et al. Transferrin receptor targeting chimeras for membrane protein degradation. Nature (2024).

Applications

TransTAC technology represents a highly versatile and modular approach for precise manipulation of cell surface targets, with broad potential applications in research and therapy, including activity against oncology and non-oncology targets that have diverse structures and functions. 

The technology’s potential has been validated through the design, purification, and successful testing of multiple TransTAC degrader molecules, including an EGFR-targeting TransTAC for lung cancer developed in collaboration with the Dana-Farber laboratory of Pasi Jänne MD, PhD, and a PD-L1 molecule.  The technology’s efficacy in degrading a diverse range of cancer membrane proteins establishes new possibilities for targeted precision cancer therapy.

Opportunities

Dana-Farber welcomes discussions with interested parties to accelerate the development of the TransTAC program to the clinic.

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