One of the latest developments in drug discovery – Targeted antibody and chemotherapy conjugates
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Cancer has become a leading cause of death worldwide. Although standard treatments have achieved important effects in inhibiting cancer cell growth and eliminating tumors, most administered drugs show only limited selectivity for malignant cells, leaving their antitumor efficacy weak while carrying a potential for serious adverse effects. The desired goal is therefore to address tumor cells specifically without affecting healthy tissue. Certain cell surface receptors are overexpressed in cancer cells and may therefore be considered promising targets for selecting and treating the tumor.
Disadvantages of chemotherapy and radiotherapy
For the past 60 years, drugs used in cancer treatment have included chemotherapy. This approach uses highly cytotoxic (cell-killing) drugs that seek rapidly dividing cancer cells. They are administered systemically and may also damage healthy cells. Damage to healthy cells leads to hair loss, anemia and bruising, among other adverse effects.
Unlike systemic drug administration, radiation therapy (radiotherapy) is a treatment that acts locally. As it is more localized than chemotherapy, it causes damage in the area where it is applied or passes through. The main principle of this method is to use high-energy radiation to damage genetic material and prevent further cancer cell proliferation.
Radiation therapy is also frequently integrated with surgery and chemotherapy to increase its antitumor effect. However, a disadvantage of radiation therapy is that its damage to genetic material increases the risk of a second malignancy developing.
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Various approaches have been developed to increase tumor cell sensitivity to radiation, but all have required drugs that selectively seek out cancer cells. This can be achieved by exploiting biochemical characteristics that distinguish cancer cells from healthy tissues.
For example, altered epigenetic regulatory mechanisms, overproduction of enzymes or changes such as lower pH in the tumor microenvironment can be used for selective therapeutic drug delivery. Cancer cells also frequently overexpress cell surface proteins that bind structurally different ligands, and these overexpressed surface receptors allow tumor cells to be targeted by various classes of molecules.
The idea of targeted cancer treatment
Targeted therapy was first proposed by the German scientist Paul Ehrlich, who received the Nobel Prize in Medicine in 1908.
He initially proposed the concept of specifically killing disease-causing pathogens in the body without harming the body itself. His idea evolved over time, and the proposed concept was transferred to cancer treatment, where malignant cells need to be eliminated. The main rationale is to combine agents that trigger apoptosis with molecules able to select and bind tumor cells. Although this concept appears quite simple, it remains a problem that has not yet been solved.
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Various approaches to selectively delivering different molecules to cancer cells have been investigated and continue to be studied.
Selective drug conjugates
In principle, all conjugates used for drug delivery consist of three modules:
- The first module facilitates tumor targeting.
- The second module is the drug itself, which triggers various biological functions (most often a chemotherapy drug).
- The third module links the first two modules together.
All three components contribute to overall biological activity and selectivity.
The first module is the tumor-targeting molecule. Many classes of molecules, including small molecules, aptamers and polysaccharides, are being investigated for this purpose. Alongside these molecular classes, monoclonal antibodies (mAbs) have become the fastest-developing class of drugs to receive approval. However, producing mAbs is very expensive and time-consuming. Most are also too large to penetrate tumors, and although prepared for human use, they tend to accumulate in organs such as the liver and kidneys.
Note: A peptide is a short amino acid chain. Amino acids are linked together by bonds called peptide bonds. Typically, peptides are distinguished from proteins by their shorter length.
Many of these disadvantages can be eliminated by using smaller biomolecules such as peptides. Peptide–Drug Conjugates (PDCs) have many advantages as carrier molecules. Peptides can be rapidly degraded by proteolytic enzymes and quickly cleared from the bloodstream through the liver and kidneys. They have low immunogenicity and are considered safe because they produce nontoxic metabolites. As low-molecular-weight molecules, they can also penetrate solid tissues more effectively, leading to antitumor effects.
Peptides and peptide receptors as targets in cancer treatment
Peptides used in Peptide–Drug Conjugates can be divided into two categories:
- Cell-penetrating peptides (CPPs)
- Cell-targeting peptides (CTPs)
The mechanisms by which CPPs are taken up into cells across the cell membrane are not yet clearly understood. Their widespread application is also limited by low cell specificity.
In contrast, CTPs are ideal drug carrier molecules because they have the same capability as mAbs. CTPs bind with high affinity to receptors overexpressed on the tumor cell surface without exhibiting the disadvantages of mAbs. However, conjugating payloads to peptide molecules is more critical because receptor binding and selectivity may be affected by the steric requirements of the payload, interfering with receptor recognition. Comprehensive knowledge of the interaction between the peptide and receptor is therefore needed to introduce drug packages rationally.
The greatest challenge in developing new and highly effective anticancer drugs is the inability to protect healthy tissues while selectively delivering drugs to the tumor environment. Cell surface receptors attract great interest in targeted cancer treatment because they provide the desired properties for selective tumor targeting. To date, two “Peptide–Drug Conjugates” have received FDA approval for cancer diagnosis and treatment, but challenges remain in developing new Peptide–Drug Conjugates targeting overexpressed receptors (see the latest FDA approval in this area, loncastuximab tesirine).
Table: Receptors being studied in targeted cancer treatment.
|
Receptor |
Tumor expression |
|
Integrin (αvβ3) |
|
|
EGFR |
Ovarian cancer |
|
GPCRs |
Breast cancer Lung cancer Breast cancer Ovarian cancer Intestinal carcinoids Bronchial carcinoids |
|
GnHR-R |
Ovarian cancer Breast cancer Prostate cancer Lung cancer |
|
VIP receptors |
Colon cancer Breast cancer |
|
MC1R |
|
|
Neurotensin receptors (NTSR1) |
Breast cancer Colon cancer Pancreatic cancer Lung cancer Prostate cancer |
Integrins
Integrins connect the extracellular matrix to the intracellular cytoskeleton to mediate cell adhesion, migration and proliferation. All these processes are highly relevant to carcinogenesis. Integrin avp3 has been developed as an important anticancer target primarily because it is associated with tumor angiogenesis and metastasis. Integrins are also overexpressed in activated endothelial cells, newly formed vessels (angiogenesis) and various other tumor cells, but are absent from most adult epithelial cells.
Epidermal growth factor receptor (EGFR)
EGFR has been found to be expressed at very high levels in various cancer types and to be associated with a strongly increased rate of cancer cell proliferation. Many monoclonal antibodies and small-molecule inhibitors therefore target EGFR in the clinical setting, inhibiting EGFR and slowing tumor growth. EGFR is also regarded as a system for intracellular uptake in targeted drug delivery because of its internalization behavior following ligand binding and receptor dimerization.
G protein-coupled receptors (GPCRs)
This receptor group contains more than 800 receptors and constitutes the largest class of transmembrane proteins. Of FDA-approved targeted drugs, 35% are associated with this receptor class.
The physiological response depends largely on the activated G protein. Because the induced signaling cascades control fundamental processes within the cell, problems in this system are often associated with carcinogenesis. GPCRs have been found to be overexpressed in these situations, allowing tumor cells to be specifically targeted with Peptide–Drug Conjugates.
Other receptors
In addition to the receptor targets already included, several other peptide receptors are being investigated as potential targets for anticancer drug delivery.
The gonadotropin-releasing hormone receptor (GnRH-R), expressed mainly in pituitary gonadotroph cells but also found in lymphocytes, breast, ovary and prostate, is another example of a receptor being studied in this field. Activation of GnRH-R causes release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), known as gonadotropins. In recent years, GnRH-R has emerged as a potentially promising drug-delivery system because of its overexpression in various human tumors, including prostate, endometrial, epithelial ovarian, bladder, breast, lymphomas and lung cancers.
Another example is vasoactive intestinal peptide (VIP) receptors 1 and 2, found to be overexpressed in colon, breast and endocrine tumors. The natural ligand VIP and its analogues are considered suitable targets for tumor molecular imaging and therapeutic interventions.
Melanocortin Receptor 1 (MC1R), highly expressed in most melanomas, is also considered a receptor that could be targeted for peptide drugs because conventional chemotherapy for metastatic melanoma is not very effective.
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Finally, Neurotensin Receptor 1 (NTSR1) has been found to be overexpressed in breast, prostate, colorectal, lung, liver and pancreatic cancers. However, the natural ligand neurotensin is conjugated with various toxic agents because its metabolic stability is insufficient for use as a Peptide–Drug Conjugate.
Smart linker technology
Another crucial consideration in designing Peptide–Drug Conjugates is the selected linker technology connecting the carrier molecules and payload. Different linker strategies have been reported for PDCs that exploit various changes in the biological environment of cancer cells to facilitate controlled release.
For example, because tumor cells grow and metabolize rapidly, tumor blood vessels often cannot provide sufficient nutrients and oxygen. Anaerobic glycolysis within tumor cells therefore produces lactic acid, causing tumor tissue acidification. For this reason, payload release can be achieved using pH-sensitive linkers. The most commonly used pH-sensitive linker is the hydrazone bond.
Another example is the use of redox-sensitive linkers. In cancer cells, glutathione (GSH) concentrations have been found to be higher because of hypoxia caused by abnormal blood flow in tumor tissue. Disulfide bonds have therefore been widely used in targeted drug delivery.
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Enzymes are also used for this purpose. Short amino acid sequences are used as linkers specifically recognized by proteases overexpressed in tumor tissues.
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Payloads in targeted cancer treatment
At the heart of every Peptide–Drug Conjugate is the drug. While the peptide and linker structure provide PDC selectivity, the drug is the actual purpose of the conjugates.
Chemotherapeutic agents
Today, more than 250 FDA-approved drugs are used to treat malignant cancers. Most of these classic chemotherapeutic drugs have potent pharmacological activity because of their high cytotoxicity. However, a disadvantage of these small molecules is their uncontrolled toxicity, which causes serious adverse effects.
Drugs must meet certain design principles for a PDC to be created and used appropriately. Moreover, because cancer cells often have drug resistance mechanisms, the drug must be selected to exhibit sufficient and potent cytotoxicity against malignant cells.
Chemotherapeutic agents used in PDCs can be classified according to their general mode of action:
- The first group of molecules binds to and interacts with cellular DNA or DNA-protein complexes. As a result, transcription and DNA replication are disrupted and apoptosis is induced.
- The second group of molecules exerts its cytotoxicity by inhibiting DNA biosynthesis. Antimetabolites, such as the deoxycytidine nucleoside analogue gemcitabine or the folate derivative methotrexate (MTX), which inhibits the enzyme dihydrofolate reductase, have shown a major effect on cancer cells.
- The third group of chemotherapeutics consists of antimitotic substances acting on microtubules. Drugs such as paclitaxel (PTX), which inhibits microtubule depolymerization, and vinca alkaloid analogues that inhibit tubulin polymerization belong to this group.
- Another promising group of molecules consists of kinesin spindle protein inhibitors (KSPi), which affect spindle formation during mitosis. When this process is disrupted, cell cycle arrest is induced, subsequently leading to apoptosis. These KSPs have been found to be highly potent in various cancer types. More work on their specificity is needed before they can be translated into the clinical setting.
Radionuclides
Among chemotherapeutic drugs, radionuclides form the second major payload group in PDCs. They can be used for two purposes in cancer: diagnosis and treatment.
PDCs can be labeled with positron-emitting radioisotopes such as fluorine, copper and gallium to create PET imaging agents, or with gamma-emitting radioisotopes containing technetium and iodine that can be used in single-photon emission computed tomography.
In addition to the diagnostic approach, radionuclide-labeled PDCs may also be viewed therapeutically when β-emitting, Auger electron-emitting or α-emitting nuclides are used.
Boron neutron capture therapies
To date, different approaches to targeted cancer treatment have been developed and reached the clinic. Despite excellent antitumor efficacy, these treatment approaches have only partly achieved the expected reduction in serious adverse effects. In particular, Antibody–Drug Conjugates targeting specific cell surface receptors show adverse effects such as fever, nausea and vomiting, infection and skin rashes. The causes of these unwanted and nonspecific effects are often carrier molecules that deliver their payloads not only to the targeted tumor site but also to healthy tissues expressing the targeted markers. One way to overcome this problem is to use nontoxic payloads that must be converted into their active forms inside tumor cells. If the second step is tumor-selective, the toxic payload is produced only in tumor cells, while all healthy cells remain unharmed because they contain only the inactive payload. This principle is used in a binary radiotherapy approach called boron neutron capture therapy (BNCT).
Figure: Schematic representation of the neutron capture reaction in boron neutron capture therapy.
Boron delivery agents must meet several criteria:
- Uptake by tumor tissue must be highly specific
- Boron delivery agents must remain within tumor tissue throughout neutron irradiation
- At the same time, the drug must be rapidly cleared from the blood and healthy tissue
- Loaded agents must be chemically and metabolically stable
- They must not have any cytotoxicity
- They must have suitable water solubility
Each of these demanding requirements, especially combinations of them, makes developing suitable boron delivery agents difficult and has so far limited the use of BNCT as a clinically applicable cancer treatment method.
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Conclusion
Today, targeted administration of anticancer agents remains one of the most attractive methods for cancer treatment. Peptide receptors are considered promising targets because of their very high overexpression in various tumor types. Synthetic analogues of natural peptide ligands are of great interest for PDCs because they have high affinity and specificity, rapid intracellular uptake rates and low immunogenicity.
More conjugates containing classic chemotherapeutic agents appear to be progressing toward clinical trials. This demonstrates the applicability of Peptide–Drug Conjugates in future cancer treatments.
PDCs with smart linkers or nonradioactive payloads such as boron may not only provide better tumor selectivity but also show greater efficacy. The peptide-based and receptor-mediated drug delivery approach will therefore bring innovations to future cancer treatments.
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