Targeted protein degradation (TPD) is an attractive concept that has been studied and refined over the past two decades. It leverages cells’ existing “infrastructure” to signal specifically targeted disease-causing proteins for degradation. This can be via:
- A “molecular glue” – directly engages the signalling moiety with the protein of interest (POI)
- A heterobifunctional molecule – a ligand to the POI connected by a linker to the degradation signalling moiety
The most well-explored mechanism is the E3 ligases and the ubiquitin-proteasome. The beauty of these interactions is that they work by proximity and do not require a high specificity of binding to the POI.
This is especially encouraging for diseases where developing drugs to inhibit aberrant proteins have been unsuccessful. For example, prior to the entry of Lumakras™ and Krazati® in the last few years, KRAS mutations were considered “undruggable.” Even now, the clinical data has not lived up to the expectations set by other biomarker segments within non-small cell lung cancer (such as EGFRm).
However, it is only within the last couple of years that enthusiasm for TPD has intensified, as a deeper understanding of the complexities involved has allowed teams to overcome hurdles in discovery and development to translate interesting molecules into viable drugs.
This year, ESMO held a dedicated session for protein degraders, where the speakers sought not only to educate the audience, but to showcase a variety of potential uses for TPD. The proprietary technologies discussed covered degradation of transcription factors and transmembrane proteins, going beyond oncology into the immunology sphere.
Professor Madelon Maurice, Ph.D., (Professor of Molecular Cell Biology at UMC Utrecht and Principal Investigator at Oncode Institute), presented data for SureTACs (Surface removal Targeting Chimeras) where one end of the molecule binds to a membrane-bound protein and brings it into proximity with a transmembrane ligase. With this mechanism, there is exciting potential to remove cancer-promoting receptors, such as PD-1, altogether.
However, no innovation comes without obstacles. First, the large size of these heterobifunctional proteins or proteolysis-targeting chimeras (PROTACs) creates challenges when developing orally bioavailable compounds, although the degraders under clinical assessment have been able to circumvent Lipinski’s “rule of 5”.
Second, Dr. David Spiegel from Yale, who spoke to the potential for TPD in the field of autoimmune diseases, highlighted the “prozone” effect. This is a concentration-dependent effect on protein degraders that can limit the formation of the necessary complexes and protect the POI from degradation. This will prove a challenge when identifying optimal dosing regimens during clinical development.
These challenges may have dampened the speed at which this field has advanced. However, they have not decreased the appetite for exploration, from biotechs with novel platforms to entrenched biopharma players. There are more than 100 companies actively research TPD, with 20+ molecules in clinical development and an unknown number in in the preclinical stage.
With so much that can be said about TPD—and at the risk of doing it injustice—I want to touch on just three examples to highlight the spectrum of activities and interest.
From the biotech angle, Arvinas (now in partnership with Pfizer) has the most advanced degrader in clinical development and first coined the term PROTAC. They presented Phase 1/2 data for vepdegestrant (ARV-471 – currently in Phase 3 for ER+/HER2- advanced or metastatic breast cancer) at an ESMO poster session. It showed favourable tolerability and an ORR of 11.5% in heavily pre-treated metastatic breast cancer patients.
After the first regulatory approvals come in the next few years, many expect that the relative risk of TPD will decrease, and interest will increase with more companies looking to fill that “TPD-shaped hole” in their pipelines.
That said, many biopharma companies are already exploring TPD as its functionality naturally aligns with their established expertise. For example, BeiGene has a second generation BTKi, and can build on this experience with BGB-16673, a BTK-targeting CDAC (chimeric degradation activation compound) currently in Phase 1 for B-cell malignancies.
However, the most ambitious appears to be BMS. Having in-house expertise with the acquisition of Celgene and their molecular glues, and the domain “targetedproteindegraders.com,” they have looked to further expand their reach by acquiring Orum Therapeutics (6th November 2023) into their already extensive TPD armoury. Interestingly, Orum’s technology seeks to combine two innovative technologies, TPD and antibody-drug conjugates (ADCs):
“Orum’s unique Dual-Precision Targeted Protein Degradation approach…improve the therapeutic window and realize the full potential of targeted protein degraders through precision delivery to cancer cells via antibody drug conjugates” – Sung Joo Lee, Ph.D., CEO of Orum Therapeutics
We will cover the advance of ADCs as part of another Blue Matter thought piece soon.
Overall, there is a lot to keep watch on in the field of TPD. And further down the line, the technology looks to encompass protein homeostasis more broadly as the next logical step, enabling protein stabilisation as well as degradation.
