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Peptide Drug Conjugates (PDCs): New
Generation of Targeted Cancer Treatment
Antibody-drug conjugates (ADCs) are a class of biopharmaceutical drugs designed as
a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target
and kill tumor cells while sparing healthy cells. We have already witnessed the success of
antibody-conjugated drugs (ADC). To date, there are 12 ADCs drugs approved by the
FDA. Although the ADC therapies continues to make progress, there are still some
problems with these therapies. As a cytotoxic drug, ADC may have serious toxicity and
hinder its further treatment, the complex structure of ADC leads to high production costs,
and the large molecular weight limits the ability to penetrate solid tumors, thereby limiting
its efficacy. Peptides can provide some unparalleled advantages to some extent,
including enhanced tumor penetration, reduced immunogenicity, and lower production
costs.
Schematic structure of receptor targeting drug conjugates.
The drug conjugates are comprised of three modules: payload, linker, and carrier.
What is PDCs (Peptide Drug Conjugates)?
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PDCs (Peptide Drug Conjugates) is a new type of conjugated drug. Compared with ADC,
it relies on a peptide chain of about 10 amino acids to target tumor cells, so it will not
cause an immune response. The conjugated hydrophobicity and ionization are altered by
controlling the amino acid sequence of the peptide chain, both of which affect the
bioavailability in vitro and in vivo. Low molecular weight PDC can be easily purified by
HPLC technology. These properties of PDC are essential for optimizing pharmacokinetics.
PDC consists of three important components: peptides, linkers, and cytotoxic payloads.
They work synergistically to deliver cytotoxins by targeting specific receptors on tumor
cells. As a new generation of targeted cancer treatment, the well-designed PDC not
only retains the advantages of traditional drug delivery, but also increases the
penetration of tumor drugs and reduces the toxicity to liver and kidney.
Three elements of PDC
In January 2018, the FDA approved the first PDC drug Lu 177 dotatate, a radiolabeled
somatostatin analog for the treatment of somatostatin receptor-positive
gastroenteropancreatic neuroendocrine tumors (GEP-NETs), proving the applicability of
PDC drugs in future cancer treatments . At present, a variety of PDC drugs have entered
the clinic, which shows the huge market prospect of PDC drugs in the future.
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The advantages of PDCs
PDC integrates the advantages of polypeptides, it has a small molecular weight, it is
biodegradable and won’t cause immunogenic reactions. PDC can change the conjugated
hydrophobicity and ionization properties by modifying the amino acid sequence of the
peptide chain to solve the problems of poor water solubility and delayed metabolism, while
promoting cell permeability, avoiding the difficulty of high wear rate of small molecule
drugs in clinical development due to poor physical and chemical properties. In addition,
low molecular weight PDC is easier to be purified by HPLC technology, which is also
crucial in pharmacokinetics. PDC largely provides a more flexible pharmacokinetic
optimization platform. Compared with Antibody Drug Conjugate (ADC), it has a smaller
molecular weight and is less likely to cause autoimmune reactions. Compared with the
complex process of antibody production, PDC is easier to synthesize and purify,
effectively reducing the cost of large-scale production.
Clinical application of PDCs in cancer
Currently, only two PDC drugs are approved by the FDA for clinical cancer treatment.
They are Melflufen and Lu 177 dotatate.
Melflufen in combination with dexamethasone is approved for the treatment of patients
with severe relapsed or refractory multiple myeloma (R/R MM). The FDA’s accelerated
approval of Melflufen is based on the results of the Phase II HORIZON study, which is
aimed at patients with heavily treatment, drug resistance, and high-risk RRMM. Melflufen
has an overall response rate (ORR) of 29% in the overall population and an ORR of 26%
in patients with grade 3 refractory MM. Melfulfen is effective in refractory MM patients who
are resistant to multiple drugs, high-risk cytogenetics and/or extramedullary diseases. In
addition, the results of the Phase III OCEAN study (NCT03151811) showed that in RRMM
patients, the progression-free survival (PFS) of Melflufen plus dexamethasone was longer
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compared with the standard treatment of pomalidomide plus dexamethasone. However,
melflufen was withdrawn for safety reasons.
The approval of Lu 177 dotatate is based on the results of the third phase of the
NETTER-1 study, which showed that compared with LAR alone, Lu 177 dotatate
combined with octreotide (LAR ) was given once every 8 weeks in patients with metastatic
midgut neuroendocrine tumors (four doses in total) has significant advantages in PFS,
ORR and OS.
Two PDCs currently under clinical development target Sortilin1 (SORT1) receptors:
TH1902 and TH1904. The SORT1 receptor is overexpressed in several malignant tumors,
including breast cancer and ovarian cancer. TH1902 is a PDC with a payload of docetaxel.
It has obtained fast track designation from the FDA for the treatment of sortilin-positive
patients with recurrent advanced solid tumors that do not respond to standard treatments.
TH1902 is currently being studied in phase I clinical trials. TH1904 contains doxorubicin
payload and is currently undergoing preclinical research.
Other PDCs in clinical development include synthetic analogs of natural peptide ligands
linked to cytotoxic chemotherapeutics (doxorubicin and paclitaxel). So far, the results of
these PDCs have been mixed, which shows that there are still some challenges in
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transforming the good pharmacodynamic properties of PDC into improving the clinical
outcome of patients.
Future directions of PDCs
With the application of new technologies that support the development of new PDC
models, peptide-drug conjugates will continue to develop as a new field of cancer therapy.
Affibodies (consisting of 58 amino acids) and albumin binding domain derived affinity
proteins (ADAPTs; consisting of 46 amino acids) are two types of peptides, which can be
folded into a stable triple-helix bundle structure and can be designed to bind selectively
with high affinity to a variety of target structures, including cell surface receptors on tumor
cells. These peptides are very promising as targeting units in future PDCs, especially
because of their typical high affinity, easy production, and control of drug molecular
loading and spatial arrangement.
Bicycle-toxin conjugates (BTC) is another new form. The homing part of the tumor is a
synthetic bicycle peptide (9-20 amino acids) that includes three cysteine residues. Like
other PDCs, the advantages of BTC over ADC include enhanced tumor penetration, rapid
extravasation, and slower renal clearance. Many BTCs are in the early stage of clinical
development. BT5528 contains a bicyclic peptide that is linked to MMAE via a cleavable
linker to target the tumor antigen EphA2. A phase I/II study (NCT04180371) for patients
with recurrent advanced solid tumors expressing EphA2 is ongoing.
Dendritic peptide complexes are another promising drug delivery method. Dendrimers
are nanoparticles that can encapsulate cytotoxic drugs. They are composed of spherical
molecules composed of branched layers. Using functional groups or peptide sequences to
modify the surface of dendrimers, targeting receptors or other cell surface antigens, can
be used to make "smart nanoparticles" that target cancer cells.
Biochempeg https://www.biochempeg.com
Self-assembled PDC is an emerging subset of PDC, in which conjugated compounds
can form nanostructures with unique physical and chemical properties. Therefore, the
drug delivery vehicle formed by self-assembled PDC has the ability to decompose over
time or due to specific stimuli in order to release the active drug. Self-assembled PDC
helps to avoid premature degradation and rapid clearance of active drugs. For example,
self-assembled PDC based on camptothecin and paclitaxel has high drug loading and
excellent stability. Self-assembled PDC can enhance the accumulation of active drugs in
tumor sites by enhancing permeability and retention effects.
Conclusion
As a novel cancer therapy, PDC has the potential to overcome some of the limitations of
ADC. However, the withdrawal of melflufen indicates that there are still many challenges
in clinical application of PDC. With the research of more innovative methods, it is
expected that safer and more effective tumor-targeted PDC will appear, which will bring
hope to patients with refractory cancer.
As a worldwide leader of PEG linker, Biopharma PEG offers a wide array of
different ADC Linkers to empower our customer's advanced research. We are committed
to promoting the progress of your PDC discovery and development projects.
References:
[1]. Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy.
Molecules. 2021 Oct;26(19): 6042.
[2]. Peptide-drug conjugates and their targets in advanced cancer therapies
Related article:
[1]. Anti-Cancer Peptide Drug Conjugates (PDCs): An Overview
[2]. Advances In Long-Acting Technology For Protein And Peptide Drugs
[3]. Global Antibody-drug Conjugates (ADCs): Approvals & Clinical Trails Review
[4]. History and Development of Antibody Drug Conjugates (ADCs)

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Peptide drug conjugates (pd cs) new generation of targeted cancer treatment

  • 1. Biochempeg https://www.biochempeg.com Peptide Drug Conjugates (PDCs): New Generation of Targeted Cancer Treatment Antibody-drug conjugates (ADCs) are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. We have already witnessed the success of antibody-conjugated drugs (ADC). To date, there are 12 ADCs drugs approved by the FDA. Although the ADC therapies continues to make progress, there are still some problems with these therapies. As a cytotoxic drug, ADC may have serious toxicity and hinder its further treatment, the complex structure of ADC leads to high production costs, and the large molecular weight limits the ability to penetrate solid tumors, thereby limiting its efficacy. Peptides can provide some unparalleled advantages to some extent, including enhanced tumor penetration, reduced immunogenicity, and lower production costs. Schematic structure of receptor targeting drug conjugates. The drug conjugates are comprised of three modules: payload, linker, and carrier. What is PDCs (Peptide Drug Conjugates)?
  • 2. Biochempeg https://www.biochempeg.com PDCs (Peptide Drug Conjugates) is a new type of conjugated drug. Compared with ADC, it relies on a peptide chain of about 10 amino acids to target tumor cells, so it will not cause an immune response. The conjugated hydrophobicity and ionization are altered by controlling the amino acid sequence of the peptide chain, both of which affect the bioavailability in vitro and in vivo. Low molecular weight PDC can be easily purified by HPLC technology. These properties of PDC are essential for optimizing pharmacokinetics. PDC consists of three important components: peptides, linkers, and cytotoxic payloads. They work synergistically to deliver cytotoxins by targeting specific receptors on tumor cells. As a new generation of targeted cancer treatment, the well-designed PDC not only retains the advantages of traditional drug delivery, but also increases the penetration of tumor drugs and reduces the toxicity to liver and kidney. Three elements of PDC In January 2018, the FDA approved the first PDC drug Lu 177 dotatate, a radiolabeled somatostatin analog for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), proving the applicability of PDC drugs in future cancer treatments . At present, a variety of PDC drugs have entered the clinic, which shows the huge market prospect of PDC drugs in the future.
  • 3. Biochempeg https://www.biochempeg.com The advantages of PDCs PDC integrates the advantages of polypeptides, it has a small molecular weight, it is biodegradable and won’t cause immunogenic reactions. PDC can change the conjugated hydrophobicity and ionization properties by modifying the amino acid sequence of the peptide chain to solve the problems of poor water solubility and delayed metabolism, while promoting cell permeability, avoiding the difficulty of high wear rate of small molecule drugs in clinical development due to poor physical and chemical properties. In addition, low molecular weight PDC is easier to be purified by HPLC technology, which is also crucial in pharmacokinetics. PDC largely provides a more flexible pharmacokinetic optimization platform. Compared with Antibody Drug Conjugate (ADC), it has a smaller molecular weight and is less likely to cause autoimmune reactions. Compared with the complex process of antibody production, PDC is easier to synthesize and purify, effectively reducing the cost of large-scale production. Clinical application of PDCs in cancer Currently, only two PDC drugs are approved by the FDA for clinical cancer treatment. They are Melflufen and Lu 177 dotatate. Melflufen in combination with dexamethasone is approved for the treatment of patients with severe relapsed or refractory multiple myeloma (R/R MM). The FDA’s accelerated approval of Melflufen is based on the results of the Phase II HORIZON study, which is aimed at patients with heavily treatment, drug resistance, and high-risk RRMM. Melflufen has an overall response rate (ORR) of 29% in the overall population and an ORR of 26% in patients with grade 3 refractory MM. Melfulfen is effective in refractory MM patients who are resistant to multiple drugs, high-risk cytogenetics and/or extramedullary diseases. In addition, the results of the Phase III OCEAN study (NCT03151811) showed that in RRMM patients, the progression-free survival (PFS) of Melflufen plus dexamethasone was longer
  • 4. Biochempeg https://www.biochempeg.com compared with the standard treatment of pomalidomide plus dexamethasone. However, melflufen was withdrawn for safety reasons. The approval of Lu 177 dotatate is based on the results of the third phase of the NETTER-1 study, which showed that compared with LAR alone, Lu 177 dotatate combined with octreotide (LAR ) was given once every 8 weeks in patients with metastatic midgut neuroendocrine tumors (four doses in total) has significant advantages in PFS, ORR and OS. Two PDCs currently under clinical development target Sortilin1 (SORT1) receptors: TH1902 and TH1904. The SORT1 receptor is overexpressed in several malignant tumors, including breast cancer and ovarian cancer. TH1902 is a PDC with a payload of docetaxel. It has obtained fast track designation from the FDA for the treatment of sortilin-positive patients with recurrent advanced solid tumors that do not respond to standard treatments. TH1902 is currently being studied in phase I clinical trials. TH1904 contains doxorubicin payload and is currently undergoing preclinical research. Other PDCs in clinical development include synthetic analogs of natural peptide ligands linked to cytotoxic chemotherapeutics (doxorubicin and paclitaxel). So far, the results of these PDCs have been mixed, which shows that there are still some challenges in
  • 5. Biochempeg https://www.biochempeg.com transforming the good pharmacodynamic properties of PDC into improving the clinical outcome of patients. Future directions of PDCs With the application of new technologies that support the development of new PDC models, peptide-drug conjugates will continue to develop as a new field of cancer therapy. Affibodies (consisting of 58 amino acids) and albumin binding domain derived affinity proteins (ADAPTs; consisting of 46 amino acids) are two types of peptides, which can be folded into a stable triple-helix bundle structure and can be designed to bind selectively with high affinity to a variety of target structures, including cell surface receptors on tumor cells. These peptides are very promising as targeting units in future PDCs, especially because of their typical high affinity, easy production, and control of drug molecular loading and spatial arrangement. Bicycle-toxin conjugates (BTC) is another new form. The homing part of the tumor is a synthetic bicycle peptide (9-20 amino acids) that includes three cysteine residues. Like other PDCs, the advantages of BTC over ADC include enhanced tumor penetration, rapid extravasation, and slower renal clearance. Many BTCs are in the early stage of clinical development. BT5528 contains a bicyclic peptide that is linked to MMAE via a cleavable linker to target the tumor antigen EphA2. A phase I/II study (NCT04180371) for patients with recurrent advanced solid tumors expressing EphA2 is ongoing. Dendritic peptide complexes are another promising drug delivery method. Dendrimers are nanoparticles that can encapsulate cytotoxic drugs. They are composed of spherical molecules composed of branched layers. Using functional groups or peptide sequences to modify the surface of dendrimers, targeting receptors or other cell surface antigens, can be used to make "smart nanoparticles" that target cancer cells.
  • 6. Biochempeg https://www.biochempeg.com Self-assembled PDC is an emerging subset of PDC, in which conjugated compounds can form nanostructures with unique physical and chemical properties. Therefore, the drug delivery vehicle formed by self-assembled PDC has the ability to decompose over time or due to specific stimuli in order to release the active drug. Self-assembled PDC helps to avoid premature degradation and rapid clearance of active drugs. For example, self-assembled PDC based on camptothecin and paclitaxel has high drug loading and excellent stability. Self-assembled PDC can enhance the accumulation of active drugs in tumor sites by enhancing permeability and retention effects. Conclusion As a novel cancer therapy, PDC has the potential to overcome some of the limitations of ADC. However, the withdrawal of melflufen indicates that there are still many challenges in clinical application of PDC. With the research of more innovative methods, it is expected that safer and more effective tumor-targeted PDC will appear, which will bring hope to patients with refractory cancer. As a worldwide leader of PEG linker, Biopharma PEG offers a wide array of different ADC Linkers to empower our customer's advanced research. We are committed to promoting the progress of your PDC discovery and development projects. References: [1]. Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy. Molecules. 2021 Oct;26(19): 6042. [2]. Peptide-drug conjugates and their targets in advanced cancer therapies Related article: [1]. Anti-Cancer Peptide Drug Conjugates (PDCs): An Overview [2]. Advances In Long-Acting Technology For Protein And Peptide Drugs [3]. Global Antibody-drug Conjugates (ADCs): Approvals & Clinical Trails Review [4]. History and Development of Antibody Drug Conjugates (ADCs)