 Home > Active Ingredient News > Drugs Articles > After ADC, can PDC become a new direction for targeted therapy?

After ADC, can PDC become a new direction for targeted therapy?

 Last Update: 2022-11-26
 Source: Internet
 Author: User

Tags

limestone ph

ph meter definition

Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com

Peptide-drug conjugates (PDCs) It is the next generation of targeted therapy drugs after antibody-drug conjugates (ADCs), and its core advantages are enhanced cell permeability and improved drug selectivity
.
So far, a total of two PDC drugs have been approved for marketing
worldwide.

Its core advantages are enhanced cell permeability and improved drug selectivity

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

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

Studies have shown that PDCs drugs have a wider range of applications
than ADC drugs.
In addition to cancer treatment, PDCs can be applied to many other diseases, such as COVID-19
.
As an anti-cancer drug delivery modality, PDCs have the advantage of covalently modifying a ligand peptide that can target specific cell surface receptors or biomarkers at the tumor site for long-lasting efficacy, thereby imparting an overall desirable pharmacokinetic profile
.
This allows a sufficient amount of the drug to be delivered to the cancer site while minimizing contact with healthy tissue and reducing toxicity
.

As an anti-cancer drug delivery modality, PDCs have the advantage of covalently modifying a ligand peptide that can target specific cell surface receptors or biomarkers at the tumor site for long-lasting efficacy, thereby imparting an overall desirable pharmacokinetic profile
.

Worldwide, cancer is the second leading cause of death and a major public health problem
.
Depending on the patient's stage and tumor type, the patient receives one or more of the following treatments: surgery, radiation, or chemotherapy
.

Since the end of 2019, the new crown pneumonia epidemic has swept the world, and many new drug treatment strategies
have emerged.
However, drug therapy has varying degrees of toxicity and side effects, and some serious toxicities and side effects are the direct cause
of limiting the dose or use of drugs.

Chemotherapy usually rapidly suppresses cell mitosis, 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 tumor cell characteristics (including differences in cell pH, cell GSH content, cell morphology, and enzyme expression) to improve poor prognosis and reduce toxicity
.
As an emerging targeted anti-cancer therapy, PDC drives the accumulation of toxic payloads in cancer stem cells to achieve precise treatment
of drugs.
However, the biggest challenge for PDC drugs is their instability in transport in the body, resulting in problems such as
low bioavailability.

As an emerging targeted anti-cancer therapy, PDC drives the accumulation of toxic payloads in cancer stem cells to achieve precise treatment of drugs

1 Comparison of ADC and PDC

The structure of the PDC is similar to that of the ADC, except that the target unit of the ADC is an antibody and the PDC is a peptide (Figure 1).

PDC is mainly composed of
three parts: peptide, linkage chain and cytotoxin.
The mechanism of action of PDC is also similar to that of ADC, which covalently links targeted peptides and cytotoxins through decomposable linkage chains in cells, precisely targets specific receptors of tumor cells, and can control the release of cytotoxins, thereby killing tumor cells
.
PDCs have a small molecular weight and therefore exhibit better membrane permeability
.
At the same time, PDCs are also more easily cleared and metabolized by the kidneys, which is essential
for reducing toxicity to liver and bone tissue.
In addition, PDCs are cheaper to produce and have a wider range of
drug loads.
Therefore, PDC is a targeted therapy drug
with great R&D prospects and market prospects.

The structure of PDC is similar to that of ADC, except in the targeting unit, where the target unit of the ADC is an antibody and the PDC is a polypeptide

Figure 1.
PDC compared to ADC

2 PDCs (peptide conjugates)

PDC is a targeted therapeutic drug that is similar in structure and function to ADCs
.
It is made up of connections between different types of
peptides and drugs.
PDCs consist of three important components: homing peptides, linkage chains, and cytotoxic drugs
.
These three parts synergistically deliver chemotherapy drugs by targeting receptors on tumor cells, amplifying their therapeutic effects
.

PDCs consist of three important components: homing peptides, linkage chains, and cytotoxic drugs
.

Figure 2.
Schematic diagram of PDC drugs

Homing peptides

The peptide part in PDC mainly includes cell-penetrating peptides (CPPs) and cell-targeted peptides (CTPs), and the current uptake mechanism of cell-penetrating peptides on cell membranes is unclear and the cell specificity is low, which limits the application of cell-penetrating peptides
.
On the contrary, cell-targeted peptides are ideal carriers, which can specifically bind to and transport drugs with tumor cell surface receptors (Figure 3), and common cell-targeted peptides include: frocetin analogues, GnRH analogues, growth hormone inhibition analogues, RGD peptides, PEGA, etc.
;

Figure 3.
Common peptide-targeting receptors

1.
Selection of targeted peptides

Studies have shown that different peptides affect the efficiency of drug endocytosis in PDCs and have a significant impact
on efficacy, pharmacokinetic/pharmacodynamic profile, and therapeutic indicators.
In general, the ideal PDC peptide should have a strong target binding affinity, high stability, low immunogenicity, efficient internalization, and long plasma half-life
.
Homing peptides can target specific overexpression protein receptors in tumor tissues, which directly deliver the drug carrier to the target cell, limiting off-target delivery
of chemotherapy drugs.
These homing peptides typically have a high binding affinity
for target targets at nanomolar concentrations.

In addition, the secondary structure of homing peptides significantly affects their binding affinity
.
It has been found that the linkage chain can improve the binding affinity
of homing peptides to targets by stabilizing the secondary structure.
In addition to their targeting properties, some peptides act as cell-penetrating peptides (CPPs), which exhibit properties such as hydrophobicity, amphiphilicity, and negative charges that favor transcellular membranes
.
Cell-penetrating peptides can deliver drugs to target tissues and mediate the internalization of
drugs in cells.
However, positively charged CPPs have some drawbacks, such as target selectivity instability, leading to non-specific 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 intake, and peptides are often 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
that affect their drug-forming properties.
There are several ways to improve the ADMTE properties of peptides:

1) Increase cell permeability
.

2) Enhance chemical stability and resistance to protein hydrolysis
.

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

2.
Improve the stability and cell permeability strategy of peptides

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

1) Cyclization modification
of peptides.
Cyclization reactions are widely used in peptide synthesis, including head-tail cyclization, head-tail cyclization, side-chain cyclization, side-chain and side-chain cycling
.
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 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 proteolytic enzyme affinity for amino acid sequence, substrate recognition, and binding
.

3) Modification
in combination with chemical macromolecules.
The charge of the peptide is related to
kidney clearance.
Negatively charged peptides have longer
half-lives than positively charged peptides.
Peptides with a larger molecular weight (>450 KDA) can increase the lipophilicity
of peptides.
In addition, PEG chain modification, PSA modification, HES modification, fat chain modification and other modifications can also increase the half-life of polypeptides
.

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

Figure 4.
Modification strategy for peptides

Connection chain

The choice of linkage chain is one of the key factors in designing PDCs, and the microenvironment in which the PDC is located needs to be considered so as not to interfere with the binding affinity of peptides and their receptors and drug efficacy
.
Different types of linkers
are used in PDCs due to their characteristics such as length, stability, release mechanism, functional group, hydrophilicity/hydrophobicity, etc.
The ligation chains used in PDCs must demonstrate stability to prevent premature and non-specific drug release
.

Connection chains are divided into two main categories: cuttable or non-cuttable (Figure 5).

The cleavage chain can be enzymatically or chemically lycaed
.
Among them, chemically lypable linkage chains include: PH-sensitive linkage, disulfide bonding chain, and exogenous stimulus cleavage linkage
.
The non-cleaved linker cannot be activated by an external stimulus, and the non-cleavage link does not work
until the peptide metabolism releases the payload.
While cleavetable chains are more advantageous in developing targeted therapeutics, non-cleavetable chains are more stable
in the metabolic cycle in vivo.
Therefore, the choice of lysable or non-lysocus linker depends on the design and mode of action of the targeted therapy drug as required
.

Figure 5.
Types of connection chains

Type of drug

Toxin drugs are an integral part of
the process of killing tumors.
After the PDC enters the cell, the toxin drug is the factor that ultimately leads to the
death of the target cell.
Therefore, the toxicity and physicochemical properties of toxin drugs can directly affect the ability of drugs to kill tumors, thereby affecting their efficacy
.
In general, cytotoxins must have four requirements: a clear mechanism of action, small molecular weight, high cytotoxicity, and maintaining antitumor activity
after chemical coupling to peptides.
However, each toxic drug usually has its limitations, such as undesirable PK properties
.
In addition, the non-selectivity of toxic drugs is the biggest drawback, causing serious side effects
.
Since chemotherapy drugs attach to peptides, lower cytotoxic doses
are required.
Therefore, the chemotherapy drugs selected usually have strong anti-value-added activity
.
Chemotherapy drugs for PDC include doxorubicin, paclitaxel, camptothecin and so on
.
Also included is radionuclide, 177Lu-dotatate
.

Figure 6.
The type of drug loaded in PDC

3 Recent research progress in PDC

So far, two PDC drugs have been developed and marketed around the world, namely Lutathera, which was approved by Novartis in 2018, and Pepaxto
, which was developed by Oncopeptipes, in 2021.
Lutathera is the world's first approved PDC drug developed by Novartis and is part of the emerging peptide receptor radionuclide therapy (PRRT).

In a narrow sense, the drug can also be classified as a nuclear conjugate drug (RDC).

Pepaxto is a first-of-its-kind peptide conjugate drug that is technically 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 Pepaxto failed to reduce the risk
of death in people with ITT in the confirmatory phase III OCEAN study.
In addition, there are multiple PDCs in the clinical trial stage, and the competition in the PDC track is intense
.

Figure 7.
PDC drugs in clinical trials and approved for marketing

Figure 8: Chemical structure of the PDC drugs Lutathera and Pepaxti

4 Summary

PDC is a combination of peptide and chemotherapy drugs, which combines peptide selectivity and high inhibitory activity
of chemotherapy drugs.
By modifying the amino acid sequence of the peptide, PDCs can change the hydrophobic and ionizing properties of the conjugation, solve problems such as poor water solubility and metabolism, and 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 treatment window, and have broader application prospects
in tumor treatment.
Although the molecular weight of polypeptides is small and the renal clearance rate is faster, these problems have been effectively solved
by several methods such as chemical modification and physical techniques (cyclization, binding peptides, dosage forms).

PDC is an emerging research field in anti-cancer, but there are still many problems to be solved
.
Fortunately, based on the successful development experience of ADC drugs, PDC research may have some shortcuts and fewer detours
.
At the same time, with the innovation of R&D technology, the research of PDC will gradually be clinically verified, thereby promoting the development of this field and bringing more options
for treatment.

References:

1、Peptide-drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope? doi.
org/10.
1016/j.
apsb.
2022.
07.
020

2、Tsomaia N.
Peptide therapeutics: targeting the undruggable space.
Eur J Med Chem 2015; 94:459e70.

3、Peptide\u2012drug conjugate: a novel drug design approach.
Curr Med Chem 2017; 24: 3373e96.

4、Protein- and peptide\u2012drug conjugates: an emerging drug delivery technology.
Adv Protein Chem Struct Biol 2015; 98:1e55

5、Design and evaluation of a novel peptide\u2012drug conjugate covalently targetingSARS-CoV-2 papain-like protease.
J Med Chem 2022; 65:876e84.

This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.