David O’Connell, director of scientific affairs at PCI Pharma Services, explores how enabling technologies are helping targeted protein degraders (TPDs) overcome their biggest challenge.
PCI Pharma Services
Nothing vast enters the realm of mortals without a curse. Targeted protein degraders (TPDs) are a case in point. As one of the fastest-growing frontiers in oral solid dose development, these molecules hold great therapeutic promise, yet their delivery challenges remain formidable.
First described in the early 2000s, TPDs – including proteolysis-targeting chimeras (PROTACs) and molecular glues – were conceived as elegant ways to eliminate disease-causing proteins rather than inhibit them. Although conceptually powerful, early molecules were too large, unstable, and poorly permeable to advance into patient therapies. Over the past decade, progress in structural biology, computational chemistry, and clinical validation has shifted the debate from if TPDs work to how to deliver them effectively.
The bioavailability challenge
TPDs are often dubbed “brick dust” compounds, reflecting their poor solubility and limited permeability. Even when dissolution occurs in the gastrointestinal tract, bulky structures restrict absorption, resulting in low systemic bioavailability. This paradox—potent therapeutics unable to reach sufficient circulation—presents a fundamental barrier to their clinical success.
The role of CDMOs
Over the past twenty years, contract development and manufacturing organisations (CDMOs) have significantly advanced in expertise and infrastructure. Many have experience with highly potent compounds and possess a deep understanding of development and scale-up processes. Yet not all CDMOs can independently provide the enabling technologies required to enhance TPD bioavailability. Capabilities such as spray drying, hot-melt extrusion, and nanomilling demand specialist expertise and investment.
Building strategic partnerships
An emerging solution is the adoption of strategic partnerships across the pharmaceutical supply chain. Instead of attempting to internalise every advanced capability, CDMOs are increasingly forming collaborations with technology specialists. This approach preserves their strengths in process development, technical transfer, regulatory and analytical services, and commercial supply, while providing access to best-in-class formulation technologies.
A single-point-of-contact (SPOC) model offers further advantages. By coordinating communications and technical exchanges between partners, the CDMO ensures seamless integration of enabling technologies into development programmes, minimising delays and avoiding data gaps that can hinder downstream manufacture. Ultimately, such collaborations place the needs of the patient first, ensuring promising compounds can move into the clinic efficiently.
Enabling technologies in focus
Several technologies are proving critical for advancing oral TPD delivery:
- Spray drying creates amorphous solid dispersions, enhancing dissolution of hydrophobic molecules by embedding them in a polymer matrix.
- Hot-melt extrusion blends drug substances with carriers under controlled heat and shear, forming solid dispersions that can improve solubility and permeability without solvents.
- Nanomilling reduces particle size to the nanometre scale, dramatically increasing surface area and dissolution rates for otherwise intractable compounds.
Each technology offers different strengths, and selecting the optimal approach requires case-by-case evaluation.
Looking ahead
The TPD field is expanding rapidly, with market forecasts projecting annual growth of more than 20% to 2035, outpacing even biologics. This growth underscores the urgency of overcoming solubility and permeability barriers. Collaboration between CDMOs and formulation specialists, coupled with ongoing innovation in enabling technologies, represents the most pragmatic route forward.
For patients, these advances are more than operational efficiencies; they represent a tangible bridge from laboratory discoveries to accessible treatments for cancer and other serious diseases. Two decades after their inception, the curse of poor delivery that once overshadowed TPDs is steadily being lifted, unlocking their potential as a transformative therapeutic class.