Release date:2020/2/28 10:11:01
In the past 30 years, polymer-drug conjugates have successively been approved by the regulatory authorities for listing, and they have attracted increasing attention from the pharmaceutical industry. The coupling of therapeutic drugs with polymer-carriers such as polyethylene glycol (PEG) has several pharmaceutical and clinical treatment advantages, such as improved solubility for drugs, prolonged circulation in the body, controlled release and enhanced safety. Today, the development of different types of polymer-drug conjugates (including polymer-macromolecule conjugates, polymer-small molecule drug conjugates, dendrimers, polymer nanoparticles) has made positive progress.
Image source: Nature

1. Polymer-macromolecule conjugates

The approved drugs are mainly polyethylene glycol-protein conjugates.

35 years have elapsed since the researchers first realized the polymer-drug combination in 1955 and the first polymer-drug conjugate was approved for clinical use in 1990. Since then, the floodgates for research and marketing of polymer-drug conjugates have opened. As of 2018, there were 16 polymer-drug conjugate products approved for marketing, the vast majority of which were polymer-protein conjugates (see related article: FDA Approved PEGylated Drugs).

The first polymer-protein conjugate Adagen (pegademasebovine, bovine deaminase) was approved for marketing in 1990. Adagen is a polyethylene glycol-adenosine deaminase conjugate used to treat severe combined immunodeficiency (ADA-SCID) caused by hereditary adenine deaminase deficiency.

Currently approved polymer-drug conjugate products, 15 of which are polyethylene glycol-protein conjugates for a variety of indications, including hepatitis C, acute lymphoblastic leukemia, and rheumatoid arthritis, etc.

PEGylation of protein therapeutic drugs can improve the pharmacokinetics and other characteristics of the drug, such as prolonging the plasma half-life of the original drug, thereby reducing the frequency of administration. The polyethylene glycol asparaginase Oncaspar, which was approved for the treatment of acute lymphocytic leukemia in 1994, can extend the half-life of asparaginase from 20 hours to 357 hours and reduce the frequency of dosing from 2-3 times per week to once every two weeks. The polyethylene glycol erythropoietin beta conjugate Mircera was approved in 2007 for the treatment of renal anemia in patients with chronic kidney disease (CKD), and the plasma half-life was extended from <25 hours to 134 hours, thereby extending the dosing interval and reducing patients with chronic kidney disease cost of anemia management.

The application of polyethylene glycol-protein conjugates in the fields of virus infection and chemotherapy-induced neutropenia has shown its clinical value. PEGylation of interferon and granulocyte colony-stimulating factor (G-CSF) can achieve sustained and potent antiviral and leukocyte production in patients with chemotherapy, respectively.

For example, pegylated interferon alpha-2b (PegIntron) and pegylated interferon alpha-2a (Pegasys) can enhance the efficacy and sustained virus response rate by administering a single dose per week. It is equivalent to the effect of unmodified interferon α-2b and interferon α-2a for three consecutive weeks. The efficacy of a single dose of pegylated G-CSF pefilgrastim (Neulasta) per chemotherapy cycle is equivalent to a single injection of unmodified G-CSF for 11 consecutive days.
In addition to therapeutic benefits, pegylation can improve the design of existing protein therapies. For example, Fragment antigen-binding (Fab ') of an antibody can be produced more easily and at a lower cost than an intact protein, but Fab' usually has the drawback of circulating in the body for a shorter time. PEGylation solves this limitation, and Cetzumab (Cimzia) is a PEGylated anti-tumor necrosis factor (TNF) Fab '.

PEGylation is not limited to proteins, but pegylation of nucleic acids can reduce renal clearance and thus prolong the half-life of drug circulation in the body. For example, the aptamer treatment drug pegathanib sodium (Macugen) has also been approved for marketing for the treatment of neovascular age-related macular degeneration.

New drugs for new indications

Polymer-macromolecule conjugates, especially polyethylene glycol-protein conjugates have been repeatedly approved for marketing, which has greatly stimulated the research of PEGylation of macromolecules (such as enzymes, cytokines, growth factors and antibodies). At present, multiple polymer-macromolecule conjugates have entered the evaluation of clinical trials. Compared with approved drugs, polymer-macromolecule conjugates being developed are continuously exploring new indications (see Table 1).

 Table 1: Polymer-macromolecule conjugates in clinical development
Product Polymer Carrier Drug Treatment Research Stage Company
Turoctocog alfa pegol PE6 Factor VIII Hemophilia A pre-registration  Novo Nordisk
Calaspargase pegol PEG Asparaginase Acute lymphocytic leukemia and lymphoblastic lymphoma pre-registration Servier
Elapegademase PEG ADA ADA- SCID pre-registration Leadiant
Pegvorhyaluronidase alfa PEG Hyaluronic acid Pancreatic cancer PhaseⅢ Halozyme 
TransCon Growth Hormone PEG Human growth hormone Growth hormone deficiency PhaseⅢ Ascendis 
Pegilodecakin PEG IL-10 Pancreatic cancer PhaseⅢ ARMO
Pegargiminase PEG Arginine dehypoenzyme Mesothelioma PhaseⅢ Polaris 
BCT-100 PEG m-oxidase 1 Acute myeloid leukemia Phase Ⅱ/Ⅲ Bio-Cancer
Pegsiticase PEG Uric acid Chronic gout PhaseⅡ Selecta
Sanguinate PEG Carboxyhemoglobin Sickle cell disease PhaseⅡ Prolong 
Pegzilarginase PEG mm acidase 1 Arginase 1 deficiency PhaseⅡ Aeglea
BMS-986036 PEG FGF21 Nonalcoholic steatohepatitis PhaseⅡ Bristol-Myers Squibb
Dapirolizumab pegol PEG Anti-CD40L Fab_ Systemic lupus erythematosus PhaseⅡ UCB
Zimura PEG Aptamer complement CS inhibitor Neovascular macular degeneration PhaseⅡ Ophthotech
NKTR-214 PEG L-2 Solid tumor PhaseⅡ Nektar
BIW001 XTEN Recombinant factor VI 丨 丨 Fc-von Willebrand factor Hemophilia A PhaseⅠ/Ⅱ Bioverativ 
olaptesed pegol PEG Anti-CXCL12 aptamer Mullion and pancreatic cancer PhaseⅠ/Ⅱ NOXXON
Fovista PEG Anti-PDGFB aptamer Ophthalmology VonHippel-Lindau syndrome PhaseⅠ/Ⅱ Ophthotech
BMS-986171 PEG FGF21 Nonalcoholic steatohepatitis PhaseⅠ Bristol-Myers Squibb
NKTR-358 PEG IL-2 Systemic lupus erythematosus PhaseⅠ Nektar
RH-FGF-21 PEG FGF21 diabetes / Wenzhou Medical University
Remarks: ADA, adenosine deaminase; CXCL12, CXC-chemokine ligand 12; Fab,  fragment antigen-binding; FGF21, fibroblast growth factor 21; PDGFB, platelet-derived growth factor subunit B; SCID, severe combined immunodeficiency

2. Polymer-small molecule drug conjugate

The combination of small-molecule biologically active substances with polymer-carriers also has several advantages, including improved drug water solubility, enhanced stability, extended plasma half-life, ability to deliver in active cells, altered biodistribution in the body, and the possibility of targeted delivery by adding the targeting moiety. In addition, the chemical characteristics of the connector facilitate the control of molecular release and activity. These advantages are most closely related to cytotoxic chemotherapy drugs, which are generally poorly soluble, easily cleared, and have limited tumor exposure. Importantly, the efficacy of anticancer drugs is severely limited by off-target toxicity, prompting the development of methods that can control biodistribution and activity are particularly urgent. Importantly, the efficacy of anticancer drugs is severely limited by off-target toxicity, so it is particularly urgent to develop methods that can control biodistribution and activity.

The first polymer-small molecule drug conjugate approved for marketing was polyethylene glycol naloxone (Movantik), which was approved in 2014 to treat constipation caused by opioids in patients with chronic pain. Movantik's penetration into the central nervous system is significantly reduced compared to small-molecule drugs. Therefore, the drug significantly improves opioid-related constipation while reducing the effect of naloxone on opioid-induced analgesia.
The class 1 innovative drug, polyethylene glycol losenatide injection (Fulaimei), developed by Jiangsu Hansoh received NDA approval from National Medical Products Administration on May, 2019 for Blood sugar control. Unlike the similar long-acting GLP-1 analogues (abirutin, doxatide, and somalutin) for the treatment of type 2 diabetes.

Although polymer-small molecule drug conjugates currently approved for marketing are non-tumor indications, tumor indications remain the focus of polymer-small molecule drug conjugate research. Since polymer-small molecule drug conjugates have been shown to improve their safety and efficacy in preclinical animal models, many drugs have now entered the clinical trial evaluation stage (see Table 2).

Clinical development-polymer-small molecule drug conjugates, dendrimers and polymer nanoparticles
Product Polymer Carrier Drug Treatment Research Stage Company
Onzeald PEG Irinotecan metastatic breast cancer and brain metastases pre-registration Nektar
NKTR-181 PEG μ-Opioid Receptor Agonist moderate to severe chronic pain pre-registration Nektar
PEX168 PEG Losenatide  type 2 diabetes NMPA examined Jiangsu Haosen 
NC-6004 PEG-b-poly (glutamic acid micelle acid) Cisplatin Pancreatic Cancer PhaseⅢ NanoCarrier
Opaxio Polyglutamic acid Paclitaxel Ovarian, peritoneal, and fallopian tube cancer PhaseⅢ CTI
APL-2 PEG Cyclic peptide complement C3 inhibitor Paroxysmal nocturnal hemoglobinuria PhaseⅢ Apellis
CRLX101 Cyclodextrin-PEG self-assembled nanoparticles Camptothecin Ovarian, peritoneal, and fallopian tube cancer PhaseⅡ BlueLink 
NK012 PEG-b-poly (glutamic acid) micelles SN-38 Breast cancer PhaseⅡ Nippon Kayaku
OsteoDex Dextran Alendronate Prostate cancer PhaseⅡ DexTech Medical
Somadex Dextran Somatostatin Neuroendocrine tumors and acromegaly PhaseⅡ DexTech Medical
BP-C1 Benzocarbonate polymer Platinum_ (Ⅱ) Breast cancer PhaseⅡ Meabco A/S
Pegcantratinib PEG TrkA inhibitor Pruritus PhaseⅡ Sienna
DEP docetaxel PEG • polylysine dendrimer Docetaxel Solid tumor PhaseⅡ Starpharma
NC-6300 PEG-b-poly (aspartic acid) micelles Epirubicin Solid tumors and soft tissue sarcomas PhaseⅠ/Ⅱ NanoCarrier
CRLX301 Cyclodextrin-PEG self-assembled nanoparticles Docetaxel solid tumors PhaseⅠ/Ⅱ BlueLink 
DEP cabazitaxel PEG-polylysine dendrimer Cabatha solid tumors PhaseⅠ/Ⅱ Starpharma
NKTR-262 PEG TLR7 / TLR8 agonist solid tumors PhaseⅠ/Ⅱ Nektar
CriPec Docetaxel Core-crosslinked PEG-polymer micelles Docetaxel Solid tumors and ovarian cancer Phase Ⅱ Cristal
NC-4016 PEG-b-poly (glutamic acid) micelles Oxaliplatin Solid tumors and lymphomas PhaseⅠ NanoCarrier
RadProtect PEG-b-poly (glutamic acid) chelate complex micelles Amifostine Acute radiation syndrome PhaseⅠ Origina
SER-214 Poly (2-ethyl-2-oxazoline) Rotigotine Parkinson syndrome PhaseⅠ Serina
DFP-13318 PEG SN-38 refractory or relapsed solid tumors PhaseⅠ Delta-Fly Pharma 
Remarks: PEG, polyethylene glycol; TLR, Toll-like receptor; TrkA, tropomyosin receptor kinase

In addition to chemical small molecule drug polymers, research into small molecule peptides and polymer conjugates has also entered clinical trials. APL2, a PEGylated cyclic peptide inhibitor of complement C3, is well tolerated in clinical evaluation and has a continuous inhibitory effect on hemolysis in patients with paroxysmal nocturnal hemoglobinuria. Polymer conjugates are also in the development of topical drugs. The PEGylated small molecule TrkA kinase inhibitor Pegcantratinib can significantly alleviate pruritus in patients with psoriasis and is currently in phase II clinical trials.

3. Evolving new technologies

In addition to conventional small and macromolecular polymers, polymer-drug conjugates are also exploring other new technical fields, and corresponding products have already entered clinical trials.

Dendrimers are three-dimensional spherical polymer nanostructured polymers with many pharmaceutical uses. The first dendrimer, SPL7013 (VivaGel), has been approved by Australia and the European Union for the treatment of bacterial vaginosis. VivaGel is a local fungicide based on poly (l-lysine) dendrimers, in which dendrimers themselves are active drugs. The poly (L-lysine) dendrimer-docetaxel conjugate DEPdocetaxel is also under development. Phase I clinical trial results show that it has higher safety than ordinary docetaxel, longer plasma half-life, lower peak blood concentration, and higher overall drug exposure.

In addition, polymer nanoparticles are colloidal carriers with nanometer scale and have been widely used as drug delivery carriers. Although multiple polymer nanoparticle conjugates have entered clinical development, no approval has been obtained to date. Despite repeated setbacks in this area of research, the recently cross-linked polyethylene glycol-polymer micelles CriPec docetaxel with covalently embedded docetaxel cores have also entered phase II clinical development.
Polymer-drug conjugate technology is becoming increasingly mature. As more and more new drugs in this field enter the advanced clinical stage, polymer-drug conjugates will enter the market's bumper period in the next few years.

Benefits of Monodisperse PEG Linkers in Drug Development
PEGylation of Therapeutic Proteins: Development and Challange
PEGylation of Small Molecule Drugs

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