Release date:2022/11/24 14:00:15

Peptide-drug conjugates (PDCs) are the next generation of targeted therapeutics after antibody-drug conjugates (ADCs), and their core advantages are enhanced cell permeability and improved drug selectivity. So far, two PDC drugs have been approved for marketing in the world, namely Lutathera developed by Novartis in 2018 and Pepaxto developed by Oncopeptipes in 2021.

Chemical structure of Lutathera and Pepaxti
Figure 1. Chemical structure of marketed PDC drugs Lutathera and Pepaxti

Compared with ADC drugs, PDC drugs have the advantages of small molecular weight, strong tumor penetration, low immunogenicity and low production cost. PDC drugs are expected to become a new generation of targeted anticancer drugs after small molecule drugs, monoclonal antibodies and ADC drugs. Over the past few years, several pharmaceutical companies have been working to develop PDC drugs as targeted therapeutic candidates for diseases such as cancer, COVID-19, and metabolic diseases. This article introduces the development status and future development direction of PDC drugs, hoping to bring reference value for PDC drug research and development.

Peptides play a variety of functions in human life, such as repairing cells, improving cell metabolism and preventing cell degeneration, etc. Peptides have biological activity and good targeted transport ability. This property makes it suitable not only for oncology, but also for targeted therapies of COVID-19, diabetes, rheumatism and rheumatoid arthritis.

Studies have shown that PDC drugs have wider applications than ADC drugs. In addition to cancer treatment, PDCs can be applied to many other diseases, such as COVID-19. As a means of anticancer drug delivery, PDC has the advantage of covalently modifying ligand peptides that can target specific cell surface receptors or biomarkers at tumor sites for long-lasting efficacy and thus confer overall desirable pharmacokinetic characteristics. This allows sufficient quantities of the drug to be delivered to the cancer site while minimizing exposure to healthy tissue and reducing toxicity.

Cancer is the second leading cause of death and a major public health problem in the world. Depending on the patient's stage and tumor type, the patient received one or more of the following treatments: surgery, radiation therapy, or chemotherapy. Since the end of 2019, as the COVID-19 pandemic has swept the world, many new drug treatment strategies have emerged. However, drug therapy has varying degrees of toxicity and side effects, and some serious toxicity and side effects are the direct cause of limiting drug dosage or use.

Usually, chemotherapy inhibits cell mitosis rapidly, with serious side effects. Even if the tumor is successfully eradicated, healthy tissue may be affected by chemotherapy. Fortunately, drug-targeted therapy can effectively distinguish the characteristics of tumor cells (including cell pH, cell GSH content, cell morphology, and enzyme expression differences), so as to improve the poor prognosis of patients and reduce toxicity. As an emerging targeted anticancer therapy, PDCs drive the accumulation of toxic payloads in tumor stem cells, enabling precise drug therapy. However, the biggest challenge of PDC drugs is their unstable transport in vivo, resulting in low bioavailability.

Comparison of ADCs and PDCs

The structure of PDC is similar to that of ADC, but the difference is the targeting unit. The targeting unit of ADC is an antibody, while PDC is a peptide (Figure 1). PDC is mainly composed of polypeptide, link chain and cytotoxin. The mechanism of action of PDC is also similar to that of ADC. The targeting polypeptide and cytotoxin are covalently linked through the decomposable linking chain in the cell, precisely targeting the specific receptor of tumor cells, and the cytotoxin is released in a controlled manner, thereby killing tumor cells. PDC has a small molecular weight, so it shows better membrane penetration. At the same time, PDC is more easily cleared and metabolized by the kidney, which is critical for reducing toxicity to liver and bone tissue. In addition, PDC has lower production cost and a wider variety of drug loading. Therefore, PDC is a kind of targeted therapeutic drug with great research and development prospect and market prospect.

 Comparison of PDC and ADC

Figure 2. Comparison of PDC and ADC

Peptide-drug conjugates (PDCs)

PDC is a targeted therapeutic drug with a structure and function similar to ADC, which is composed of different types of peptides linked to drugs. PDC consists of three important components: homing peptides, linker chains and cytotoxic drugs. These three components work synergistically to deliver chemotherapeutic drugs by targeting receptors on tumor cells to amplify their therapeutic effects.

 PDC structure illustration

Figure 3. PDC structure illustration

1. Homing peptide

The peptides in PDC are mainly cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs). At present, the uptake mechanism of cell-penetrating peptides on the cell membrane is unclear and the cell specificity is low, which limits the application of cell-penetrating peptides. On the contrary, cell-targeting peptides are ideal carriers, which can specifically bind to tumor cell surface receptors (Figure 3) and transport drugs. Common cell-targeting peptides include: bombesin analogs, GnRH analogs, growth hormone inhibition analogues, RGD peptides, PEGA, etc.

 Common peptides targeting receptors

Figure 4. Common Peptide Targeting Receptors

1. Selection of targeting peptides

Studies have shown that different peptides affect the efficiency of drug endocytosis in PDC, and have significant effects on efficacy, pharmacokinetic/pharmacodynamic characteristics, and therapeutic indicators. In general, ideal PDCs peptides should have strong target binding affinity, high stability, low immunogenicity, efficient internalization, and long plasma half-life. Homing peptides can target specific overexpressed protein receptors in tumor tissues, which directly deliver drug delivery to target cells and limit off-target delivery of chemotherapeutic agents. These homing peptides typically have a high binding affinity for the target at nanomolar concentrations.

In addition, the secondary structure of homing peptides significantly affected their binding affinity. It was found that the linking chain can improve the binding affinity of homing peptide to the target by stabilizing the secondary structure. In addition to their targeting properties, some peptides can also act as cell-penetrating peptides (CPPs), which exhibit properties such as hydrophobicity, amphiphilicity, and negative charges that facilitate transmembrane penetration. Cell-penetrating peptides can deliver drugs to target tissues and mediate drug internalization in cells. However, positively charged CPPs have some disadvantages, such as unstable target selectivity, resulting in nonspecific cellular uptake. Therefore, negatively charged cpps are often used in PDCs to improve tumor cell specificity.

Peptides and small molecules have significantly different pharmacokinetic properties. Among them, the biggest disadvantage of peptide drugs is their low bioavailability and drug uptake, and peptides are usually not able to be administered orally. Therefore, rapid renal clearance and short half-life hinder the study of peptides in vivo, as well as factors affecting their drug-forming properties. There are several ways to improve the ADMTE properties of peptides:

1) Increase cell permeability.

2) Enhance chemical stability and anti-proteolytic ability.

3) Reduce renal clearance rate and prolong circulatory half-life.

2. Strategies to improve the stability and cell permeability of peptides

At present, common strategies to improve peptide stability and cell permeability mainly include the following (Figure 4):

1) Cyclic modification of peptide. Cyclization reactions are widely used in the synthesis of peptides, including head-to-tail cyclization, head-to-tail cyclization, side-chain cyclization, side-chain and side-chain cyclization. Peptide anastomosis is often used to determine the secondary structure of peptides, such as α-helix and β-folding, which can improve the binding affinity of peptides to their targets and increase their ADME.

2) Amino acid modification. Another way to increase peptide stability is to use D-configuration amino acids instead of L-configuration amino acids. This reduces the amino acid sequence, substrate recognition and binding affinity of the proteolytic enzyme.

3) Modifications combined with chemical macromolecules. The charge of the peptide is associated with renal clearance. Negatively charged peptides have a longer half-life than positively charged peptides. Peptides with higher molecular weight (>450 kDa) can increase the lipophilicity of the peptide. In addition, modification methods such as PEG chain modification, PSA modification, HES modification, and fatty chain modification can also increase the half-life of the polypeptide.

4) Change the dosage form. Intracellular protein delivery systems typically rely on the fusion of genetic proteins with membrane-penetrating tags and protein-encapsulating carriers based on cationic liposomes, polymers, and inorganic nanomaterials. Several approaches have been reported to enhance the oral bioavailability of peptide therapeutics through dosage forms, such as adding penetration enhancers and acid-resistant coatings, etc.

 Modification strategies of peptides

Figure 5. Modification strategies of peptides

Link chain

The selection of connecting chains is one of the key factors in the design of PDC. It is necessary to consider the microenvironment of PDC so as not to interfere with the binding affinity of peptide and its receptor and drug efficacy. Different types of linkers are used in PDCs according to their properties such as length, stability, release mechanism, functional groups, hydrophilicity/hydrophobicity, etc. Linking chains used in PDCs must exhibit stability to prevent premature and nonspecific drug release.

The link chains are divided into two main categories, cleavable or non-cleavable (Figure 5). Cleavable link chains can be cleaved enzymatically or chemically. Among them, chemically cleavable linker chains include: PH-sensitive linker chains, disulfide-bonded linker chains, and exogenous stimulus cleaved linker chains. The non-cleavable linker chains cannot be activated by external stimuli, and the non-cleavable linker chains act after the payload is released by peptide metabolism. While cleavable linkers are more advantageous in the development of targeted therapeutics, non-cleavable linkers are more stable in the in vivo metabolic cycle. Therefore, the choice of cleavable or non-cleavable linkers depends on the design of the targeted therapeutic agent and the need for a mode of action.

 Types of link chains

Figure 6. Types of link chains

Type of drug loading

Toxic drugs are an integral part of the process of killing tumors. After PDC enters cells, toxin drugs are the factors that eventually lead to the death of target cells. Therefore, the toxicity and physicochemical properties of toxic drugs can directly affect the ability of drugs to kill tumors, thus affecting their efficacy. In general, cytotoxins must have four requirements: clear mechanism of action, small molecular weight, high cytotoxicity, and retention of antitumor activity after chemical conjugation with peptides. However, each toxic drug usually has its limitations, such as poor pk properties, etc. In addition, the non-selectivity of toxic drugs is the biggest disadvantage, causing serious side effects. Since chemotherapy drugs are attached to peptides, lower cytotoxic doses are required. Therefore, the selected chemotherapeutic drugs usually have strong anti-proliferation activity. Chemotherapeutic drugs for PDC include doxorubicin, paclitaxel, camptothecin, etc. It also includes the radionuclide, 177Lu-dotatate.  

 Types of drug loading in PDC

Figure 7. Types of drug loading in PDC

Latest research progress of PDC

To date, two PDC drugs have been developed and marketed worldwide: Lutathera, approved by Novartis in 2018, and Pepaxto, developed by Oncopeptipes in 2021. Lutathera is the first globally approved PDC drug developed by Novartis, which belongs to the emerging peptide receptor radionuclide therapy (PRRT). In a narrow sense, the drug can also be classified as a radionuclide-drug conjugate (RDC). Pepaxto is a first-in-class peptide-conjugated drug, strictly speaking, it is the first approved PDC drug. Unfortunately, on October 22 of the same year, Oncopetides announced the withdrawal of Pepaxto in the US market, mainly because in the confirmatory phase III OCEAN study, Pepaxto failed to reduce the risk of death in the ITT population. In addition, there are several PDCs in the clinical trial stage, and the competition in the PDC track is fierce.

 PDC drugs in clinical trials

Figure 8. PDC drugs in clinical trials and approved for marketing


PDC is a combination of peptides and chemotherapeutic drugs, which combines the selectivity of peptides and the high inhibitory activity of chemotherapeutic drugs. By modifying the amino acid sequence of the peptide, PDC can change the hydrophobic and ionizing properties of the conjugate, solve problems such as poor water solubility and metabolism, and at the same time promote cell permeability, which is helpful for further clinical development. In addition, lower molecular weight PDCs are easier to purify.

PDC can significantly improve the therapeutic effect, but also reduce toxicity, improve the therapeutic window, and has a broader application prospect in tumor treatment. Although peptides have a smaller molecular weight and faster renal clearance, these issues have been effectively addressed by several approaches, including chemical modification and physical techniques (cyclization, binding peptides, dosage forms).

PDC is a new research field of anticancer, but there are still many problems to be solved. Fortunately, based on the successful development of adc drugs, PDC research may have some shortcuts and fewer detours. At the same time, with the innovation of research and development technology, PDC research will gradually be validated clinically, thus promoting the development of the field and bringing more treatment options.

As a leading PEG derivatives supplier, Biopharma PEG is dedicated to being your most reliable partner to provide a variety of PEG linkers to facilitate antibody-drug conjugate (ADC) development projects. We are committed to promoting the progress of your ADC discovery and development projects.

Peptide-drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?
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