Expanding the Therapeutic Potential of Protein Degraders Through Alternative Delivery Routes

On February 21, scientists from Genentech, Merck & Co., Inc., and Pfizer, Inc. jointly published a review article in Nature Reviews Drug Discovery, exploring strategies to expand the scope of action of protein degradation drugs through different routes of administration.

Currently, several bivalent PROTAC protein degraders have entered clinical trials. Researchers often aim to design these drug molecules for oral administration. However, due to the large molecular weight of such drugs, developing them into oral medications requires simultaneous optimization of parameters like potency, selectivity, metabolic stability, and cell permeability, making the structural optimization process quite demanding. Therefore, the development path of oral administration may limit the future prospects of protein degraders.

Discovery Patterns of Protein Degraders (Source: Nature Reviews Drug Discovery)

Classification of Protein Degraders

Protein degraders with different structures have varying "drug-like" properties and face distinct biological barriers that need to be overcome. Therefore, it is necessary to classify protein degraders.

• Class I barely exceeds the "Rule of 5" for proteolysis-targeting chimeras: The design strategy of such drugs focuses on using low molecular weight target protein ligands and E3 ligase ligands, minimizing the number of hydrogen bond donors as much as possible, while employing short-chain rigid linker groups.

• Class II Protein Degraders Exceeding the "Rule of 5 for Drugs": This class of protein degraders has a broader selection space for target protein ligands, E3 ligase ligands, and linker groups. Their permeability is lower than that of Class I, making them less likely to have sufficient gastrointestinal permeability and poor bioavailability, which are the main focus of this review.

• Class III Far Exceeds "Rule of 5" Protein Degraders: Such drugs may be designed based on peptides, proteins, or oligonucleotides and are generally used for target proteins (such as transcription factors) that lack obvious binding sites. Due to their poor cell permeability, they need to be administered through delivery carriers outside the gastrointestinal tract to reach the site of action.

  
  

Classification of Protein Degraders (Source: Nature Reviews Drug Discovery)

Oral Administration of Class I and Class II Protein Degraders

Oral administration remains the preferred route for many diseases. However, as the molecular weight of protein degraders increases, achieving a balance between gastrointestinal permeability and solubility becomes increasingly challenging.

• Increase Solubility：Amorphous solid dispersions can enhance the solubility of lipophilic degraders, but this technology may lead to a decrease in drug loading per tablet, thereby increasing the frequency of daily medication.

• Enhance Permeability: The permeability of protein degraders can be enhanced through chemical modification or nanoparticle delivery. Medium-chain fatty acids represent the most advanced class of chemical modification methods, but the oral bioavailability of the modified drugs remains low, and there is significant variability in pharmacokinetic parameters among subjects. This strategy may require an increase in the daily dosage or frequency of administration, making it suitable for protein degraders with good tolerability and low dose requirements. Oral nanoparticles encapsulate protein degraders within their cavities, with the permeability of the formulation achieved by the surface chemistry of the nanoparticles. This approach improves the oral bioavailability of protein degraders, but each nanoparticle has a limited payload, and there is variability in individual absorption.

Parenteral Administration of Class II Protein Degraders

Shifting from oral administration to parenteral administration provides a broader design space for protein degraders. This development strategy needs to be considered from scientific research, patient, and commercialization perspectives.

• Parenteral Administration Relaxes the "Drug-Likeness" Restrictions on Protein Degraders: For example, compared with VHL ligands, CRBN ligands have smaller molecular weight and better drug-like properties, so CRBN ligands are more commonly used in current PROTAC molecule design. However, CRBN ligands may bring off-target effects and teratogenic risks. Although VHL ligands have a larger molecular weight, they exhibit consistent degradation activity across different tumor cell lines, with fewer off-target effects, making them suitable for protein degraders administered via parenteral routes.

• PK-PD Model Assists in Using Appropriate Delivery Strategies: PThe K-PD model can help researchers balance different parameters and predict the drug dosage required to achieve the desired level of degradation for various administration methods.

PK-PD Considerations for Extragastric Administration of Degraders (Source: Nature Reviews Drug Discovery)

• Intravenous Administration: In the early stage of drug development, detailed research should be conducted on the clinical needs and care standards for treating diseases to determine the future acceptance by doctors and patients as well as the commercial performance after the drug is marketed. For example, for cancer patients without effective treatment options, developing intravenous protein degraders is feasible. If a certain protein degradation therapy requires long-term intravenous injection, reducing the frequency of administration needs to be considered. Based on PK-PD relationship considerations, this may require extending the drug's half-life. Nanoparticles can influence the pharmacokinetics, tissue distribution, and cellular uptake pathways of drugs, which can help protein degraders prolong systemic circulation time. To further enhance the tissue targeting of protein degraders, lesion-targeting moieties can be attached to the surface of nanoparticles, overcoming the poor permeability issue of Class II degraders and increasing the accumulation of protein degraders in target cells.

• Subcutaneous Formulation: The strategy of subcutaneous administration reduces patients' medication costs and improves compliance. However, due to the low bioavailability of subcutaneous administration, achieving the desired level of protein degradation may require increased dosing frequency.

• Long-acting Injectable: The release rate and mechanism of action of long-acting injectables depend on the structure and composition of the formulation, as well as factors such as the injection site and dosage. This route of administration requires attention to toxicity issues caused by transient peak drug concentrations.

Parenteral Administration of Class III Protein Degraders

Due to the lack of suitable small molecule binding sites, many target proteins are difficult to develop Class I and Class II protein degraders. Class III protein degraders can avoid the need to search for small molecule ligands for target proteins and bypass the time-consuming structural optimization required for Class I and Class II degraders. However, the structure of Class III degraders differs significantly from that of small molecule degraders, resulting in reduced gastrointestinal and cellular permeability, necessitating the use of delivery systems to enhance bioavailability.

• Peptide-based degraders: Such degraders are often a "last resort" due to the lack of suitable binding ligands, with poor cell permeability and reliance on cell-penetrating peptides to enter cells. Some have suggested using nucleic acid delivery systems to enhance lesion targeting of peptide degraders, but the physicochemical properties of peptides themselves require adjustments to the delivery system to ensure effective drug encapsulation and intracellular release.

• Protein-based degraders: Since protein-based degrader molecules have a larger molecular weight, using LNPs to deliver mRNA and translate complete protein molecules inside cells to achieve target protein degradation is a feasible strategy. However, LNPs currently mainly target liver tissue, and future research needs to focus on how to achieve extrahepatic targeting of mRNA. Additionally, the manufacturing and storage of LNPs are also issues that need to be considered for this technology.

• Oligonucleotide-based protein degradersDouble-stranded oligonucleotides with a length of 15-19 nucleotides can be used as target protein ligands for transcription factors and other targets that lack clear binding sites. These degraders can be delivered using LNPs or antibodies. However, the synthesis of antibody-delivered oligonucleotides and their in vivo PK parameters are highly challenging.

Summary

Over the past 20 years, protein degradation has evolved from concept validation to clinical development. The outcomes of protein degraders currently in clinical trials hold significant implications for future capital and industrial investment in this field, with these drugs primarily belonging to Class I degraders. If these degraders succeed in clinical settings, they could yield substantial profits for investors, enabling the technology to gradually transition toward Class II and Class III degraders, offering genuine hope to patients with unmet medical needs. In this process, non-oral drug delivery strategies are a critical component for success.

References:

[1]Matthew N. O’Brien Laramy et al. Delivering on the promise of protein degraders. Nature Reviews Drug Discovery. 2023.

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