PEG & ADC

The list of PEGylated drugs approved by FDA Up to 2022

Polyethylene glycol (PEG) is a polymer material that is widely used for covalent modification of biopolymers such as proteins and peptides. PEGylation is a drug technology that covalently binds PEG to a drug to improve the pharmacokinetics, pharmacodynamics and immunological properties of the drug, thereby enhancing its therapeutic effect.

PEG has the advantages of non-toxicity, non-immunogenicity, non-antigenicity and good water solubility, and is one of the most commonly used polymer materials today. PEGylation changes the physicochemical properties of drugs, including conformation, electrostatic binding, and hydrophobicity. These physical and chemical changes increase the in vivo retention time of the drug, increase the plasma half-life, prolong the absorption time, and also affect the binding affinity of the drug to cellular receptors, improving tumor targeting. PEG-modified drugs can reduce the number of administrations, improve efficacy, improve tolerability, reduce severity and the incidence of adverse events. At the same time, PEG can also increase the solubility and stability of proteins, which is also beneficial to the production and storage of drugs. Therefore, PEG is often used as a drug delivery and drug modification technology, which can be directly coupled with drugs, or attached to the surface of drugs and encapsulated in nanomaterials.

Pegylation has been the most clinically established half-life extension technology since the early 1990s, and has demonstrated safety in humans for over 30 years. PEGylated drugs have been approved by authorities in most countries for human intravenous, oral, and dermal use. Currently, PEGylation can be used to modify proteins, polypeptides, oligonucleotides, antibody fragments, small organic molecules, and nanoparticles.

I. Structure of PEG-modified drugs

PEG polymers are polymerized from ethylene oxide and can form linear or branched structures. The molecular formula of linear PEG is H-(O-CH2-CH2)n-OH, and only 2 ends can be used to modify the novel conjugated drug, so the drug load is low. The branched structure has functional groups on one or more ends, such as branched PEG, forked PEG and multi-armed PEG with a branched structure at the end, thereby realizing various conjugation possibilities and greatly increasing the drug loading.

PEGylated drugs generally include PEG, coupled drugs and/or linkers and other parts. PEGylation is the optimization of drug solubility, immunogenicity and biological function through various conjugated chemistries and/or linkers. The versatility of PEG conjugation comes from the use of stable or hydrolyzable linkages.

PEGylation technology appeared in the 1970s, initially using succinimidyl succinate (ss) as Linker, and later evolved into a variety of PEG Linkers. In recent years, with the continuous deepening of research and development, new PEGylated drugs such as PEG bifunctional heteroterminal modified drugs (heterobifunctional PEG, X-PEG-Y) have appeared.

II. Classification of PEG-modified drugs

The applications of PEGylation modification in medicine are mainly PEGylated protein drugs, PEGylated peptide chain compounds, PEGylated small molecule drugs, PEGylated liposomes and so on.

1. PEGylated protein drugs

The modification pathways of PEGylated protein drugs mainly include amino modification (including acylation modification of N-terminal amino group, acylation modification of lysine side chain amino group, alkylation modification of N-terminal amino group), carboxyl modification, sulfhydryl modification, etc. The research of PEGylated protein drugs mainly focuses on adenosine deaminase, asparaginase, interferon, granulocyte colony stimulating factor, interleukin and so on. PEGylated macromolecular drugs are currently mainly used for the treatment of cancer, chronic kidney disease, hepatitis, multiple sclerosis, hemophilia and gastrointestinal diseases.

2. PEGylated peptide-based compounds

Polypeptides generally have a short plasma half-life and low oral bioavailability, which is due to the presence of a large number of peptidases and their excretion mechanisms in the body, which inactivate and clear the peptides. This instability allows the body to rapidly adjust hormone levels to maintain homeostasis, but is detrimental to many therapeutic developments. In addition, the low bioavailability of oral peptides is due to the fact that digestive enzymes in the oral cavity can decompose the amide bonds of ingested proteins, and can also effectively cut the same bonds of peptide hormones. At the same time, the high polarity and large molecular weight of peptides also severely limit intestinal permeability. sex. Chemical modification of peptides with PEG can improve various physicochemical and pharmacokinetic properties of peptides with minimal increase in manufacturing costs. The effect of PEGylation on peptide pharmacokinetics has potentially beneficial biodistribution changes, including avoidance of Reticuloendothelial System (RES) clearance, reduced immunogenicity, and reduced enzymatic and renal filtration loss. These effects can significantly increase the half-life of the peptide in vivo and indirectly improve the bioavailability without adversely affecting the binding and activity of the peptide to the ligand. Compared with the parent drug, PEGylated peptide chain compounds, such as channel calcitonin and epidermal growth factor, have longer half-life and higher biological activity. Especially in the site-directed modification of PEG, peptide compounds are more readily available than proteins. The most common application in PEGylation studies of polypeptide compounds is mPEG.

3. PEGylated small molecule drugs

At present, many small molecules, especially antitumor drugs, can be modified by PEGylation. PEG-loaded small molecules can transfer many of their excellent properties to the conjugates, making polymers with good biocompatibility. Not only can their solubility and biodistribution be improved, but their metabolism and toxicity can be reduced by altering the drug’s exposure to enzymes and vital organs. Many antitumor drugs are modified by high molecular weight PEG to achieve targeted drug delivery to tumor tissue. Small molecule antitumor drugs such as irinotecan, camptothecin, doxorubicin, paclitaxel, etc. are prepared into prodrugs by PEG modification, and their solubility, circulation half-life in vivo, adverse reactions, etc. have been greatly improved, and at the same time, they have significantly enhanced Penetration and retention effects, targeting of tumor tissue are also improved.

Despite the remarkable success of PEGylated proteins and peptides, limited progress has been made in the development of PEGylated small-molecule drugs. This may be due to problems such as loss of biological activity of natural medicines, difficulties in chemical coupling and purification, and adverse reactions. For example, PEGylated camptothecin, Enzon Pharmaceuticals announced in 2005 that it would stop further development of this drug based on the data of Phase 2b clinical trials. Clinical trial results showed that the conjugate was highly tolerated with significantly reduced toxicity compared to the commercial formulation. However, the rapid hydrolysis of this conjugate in vivo resulted in toxicity parallel to that of the natural drug, leading to the failure of drug development of this conjugate.

4. PEGylated liposomes

Lipids are amphiphilic molecules with two parts, hydrophilic and hydrophobic. When lipids come into contact with water, the unfavorable interaction of the hydrophobic segment of the molecule with the solvent leads to the self-assembly of the lipids, usually in the form of liposomes. Liposomes are spherical self-enclosed structures formed by one or more concentric lipid bilayers, with an aqueous phase wrapped between the center and the bilayers, and are composed of natural or synthetic lipids. In the 1960s, Alec D Bangham of the Babraham Institute of Cambridge University first discovered liposomes and proposed the idea of ​​using liposomes as drug delivery vehicles. Liposomes are promising drug delivery systems with many advantages due to their size, hydrophobic and hydrophilic properties (in addition to biocompatibility). Liposomes can improve the therapeutic index of new or marketed drugs by changing drug absorption, reducing metabolism, prolonging biological half-life or reducing toxicity. Drug distribution is mainly controlled by the properties of the carrier, not just the physicochemical properties of the drug substance.

Liposomes also have many disadvantages, such as high production cost, easy leakage and fusion when encapsulating drugs/molecules, and phospholipids sometimes undergo oxidation and hydrolysis reactions. The main defect of liposomes is that they are rapidly captured by RES, resulting in short half-life, low solubility, and short stability period. And PEGylated liposomes (PEGylated long-circulating liposomes) can solve these problems. After PEGylation, the PEG chain increases the hydrophilicity of the liposome surface by establishing a hydrophilic protective film on the surface of the liposome, and reduces the affinity with mononuclear phagocytes, thereby escaping the recognition of RES and reducing the liposome’s affinity. Capture and prevent the interaction of liposomes with other molecules, such as various serum components, so they are also called stealth liposomes. A well-known example of the application of this technology is Doxil, which was developed by the American company Sequus. It is the first liposome drug approved by the US FDA and the first nano drug.

Although PEGylated liposomes have many advantages, with the deepening of research, PEGylated liposomes also bring corresponding problems. The steric hindrance of PEG chains inhibits the uptake of liposomes by target cells, and PEG interferes with the “nuclear escape” of pH-sensitive liposomes (PSLs) carried by gene and protein drugs, resulting in the accumulation of these drugs in lysosomes In addition, repeated injections of PEGylated liposomes in the same animal can cause the phenomenon of “accelerated blood clearance”. This series of negative effects is known as the “PEG dilemma.” The “PEG dilemma” brings severe challenges to the development of PEGylated liposomes.

5. Other applications

PEGylated Affinity Ligands and Cofactors for Purification and Analysis of Biomacromolecules and Cells in Aqueous Two Phase Distribution Systems. PEGylated saccharides can be used as materials and carriers for novel drugs. PEGylated oligonucleotides can improve solubility, resistance to nucleases, and permeability of cell membranes. PEGylated biomaterials can reduce thrombosis and reduce protein and cell adhesion.

III. Listed PEGylated drugs

Adagen, produced by Enzon Pharmaceuticals in the United States, was the first PEG-coupled protein and was approved by the FDA in March 1990 to enter the market. Since the advent of ADAGEN, dozens of PEGylated drugs have entered the clinic, and new PEGylated drugs continue to expand the clinical research pipeline and drug patent life. A large number of PEGylated protein and peptide drugs have maintained a good momentum of development, and many other drugs are also in clinical trials or development stage.

The list of PEGylated drugs approved by FDA Up to 2022
Entry Trade Name Company PEGylated entity Indications Molecular Weight Approved Year
Macromolecular Drugs
1 Fylnetra  Amneal Pharmaceuticals LLC G-CSF neutropenia 20 kDa 2022
2 Besremi PharmaEssentia Corp Interferon polycythemia vera 40 kDa 2021
3 Skytrofa Ascendis human growth hormone Growth hormone deficiency 4 x 10 kDa 2021
4 Empaveli Apellis Pentadecapeptide Paroxysmal nocturnal hemoglobinuria (PNH) 40 kDa 2021
5 Nyvepria Pfizer Inc. G-CSF Neutropenia Associated with Chemotherapy 20 kDa 2020
6 Esperoct Novo Nordisk recombinant antihemophilic factor hemophilia A 40 kDa 2019
7 Ziextenzo Sandoz G-CSF infection during chemotherapy 20 kDa 2019
8 Udenyca Coherus Biosciences G-CSF infection during chemotherapy 20 kDa 2018
9 Palynziq BioMarin Pharmaceutical recombinant phenylalanine ammonia lyase phenylketonuria ~9 X 20 kDa 2018
10 Revcovi Leadiant  Bioscience recombinant adenosine deaminase ADA-SCID 80 kDa 2018
11 Fulphila Mylan GmbH G-CSF infection during chemotherapy 20 kDa 2018
12 Asparlas Servier Pharma L-asparaginase leukemia 31~39 x 5 kDa 2018
13 Jivi Bayer Healthcare recombinant antihemophilic factor hemophilia  A 2 X 30 kDa 2017
14 Rebinyn Novo Nordisk recombinant coagulation factor lX hemophilia B 40 kDa 2017
15 Adynovate Baxalta recombinant antihemophilic factor hemophilia  A ≥1 X 20 kDa 2015
16 Plegridy Biogen peginterferon beta-1a multiple  sclerosis 20 kDa 2014
17 Omontys Takeda erythropoietin anemia 2 X 20 kDa 2012
18 Sylatron Merck peginterferon-alfa-2b melanoma 12 kDa 2011
19 Krystexxa Horizon Pharma recombinant  uricase  protein gout 9~11 X 10 kDa 2010
20 Cimzia UCB antitumor necrosis factor rheumatoid arthritis 40 kDa 2008
21 Mircera Roche erythropoietin anemia 30 kDa 2007
22 Macugen Pfizer aptamer macular degeneration 40 kDa 2004
23 Somavert Pfizer human growth hormone acromegaly 4~5 X 5 kDa 2003
24 Neulasta Amgen G-CSF infection during chemotherapy 20 kDa 2002
25 Pegasys Roche peginterferon-alfa-2a hepatitis B and C 40 kDa 2002
26 Pegintron Schering peginterferon-alfa-2b hepatitis C, melanoma 12 kDa 2001
27 Oncaspar Enzon asparaginase leukemia 5 kDa 1994
28 Adagen Enzon adenosine deaminase ADA-SCID 5 kDa 1990
Small Molecular Drugs
29 Movantik AstraZeneca naloxone constipation 339 Da 2014
30 Asclera Chemische Fabrik Kreussler dodecyl alcohol varicose veins 400 Da 2010
Liposomal/Nanoparticles
31 Doxil Schering liposomal ovarian cancer, multiple myeloma 2 kDa 1995

IV,  Advantages of PEGylated drugs

The effect of PEG on proteins is mainly reflected in two aspects: reducing renal clearance and enhancing protection against protein degradation, both of which reduce the total clearance of the drug. Therefore, the main advantage of PEGylated protein drugs is to prolong the half-life.

1. Improve pharmacodynamic properties and reduce known toxicity

PEG minimizes exposure of epitopes, reducing or preventing the production of neutralizing antibodies. Reduce antigenicity and immunogenicity and maximize biological activity.
For drugs whose toxicity is related to peak plasma, a flatter pharmacokinetic profile can be obtained by subcutaneous injection of PEGylated protein. Immune-related adverse reactions caused by certain protein drugs can also be reduced by PEGylation.

2. Improve drug stability

In aqueous solution, PEG forms a thick hydration film with water molecules through hydrogen bonds. This hydration film and the flexible chain of PEG are connected in series to resist the adsorption of proteins to the underlying surface and prevent protein aggregation and precipitation. Modification of the linkage between PEG and lipid derivatives (acyl, ether, disulfide bonds, etc.) can also increase the stability of liposomes. The flexible chain of PEG can produce a steric hindrance effect, protect the modification from protease attack, and increase the stability of the modification. PEGylation can also improve the thermal and mechanical stability of the molecule.

3. Improve the distribution of drugs in the body and improve the pharmacokinetic properties

After PEG modification, the molecular weight of the drug increases, which greatly reduces its glomerular filtration effect when it is administered systemically, and reduces the renal clearance rate, thereby reducing urinary excretion. At the same time, it escapes the clearance mechanism of RES, thereby significantly prolonging the plasma half-life in vivo and increasing the release of drugs in the body. In addition, PEGylated drugs improve the stability of the systemic circulation and prolong the residence time, which is beneficial to improve the distribution of drugs in the body, especially the accumulation of macromolecular drugs in tumors and inflammatory sites. PEGylation can improve bioavailability by reducing loss at the subcutaneous injection site. PEGylation modifies the in vivo circulation time of the drug and protects it from proteolytic or metabolic bioinactivation, thus also reducing the dose and improving patient compliance by reducing the number of injections.

4. Improve solubility

PEG has been found to be soluble in water and many organic solvents such as toluene, dichloromethane, ethanol and acetone. One application of this technology is the phase separation of target molecules or cells using PEG-modified antibodies.
Additionally, PEGylated antibody fragments can be concentrated to > 200 mg/mL, providing more options for formulation and administration, such as subcutaneous administration of high-dose proteins. This contrasts with the intravenous administration of many other therapeutic antibodies.