From ADC (Antibody-Drug Conjugate) to PDC (Peptide-Drug Conjugate)

Huateng Pharma https://us.huatengsci.com

From ADC (Antibody-Drug Conjugate) to

PDC (Peptide-Drug Conjugate)

ADC drugs are favored by innovative pharmaceutical companies because of
their combined therapeutic effects. PDC (Peptide-Drug Conjugate), as a new
type of conjugated drug, has also begun to attract attention in the
research and development field due to its unique advantages.

There are currently 14 ADC drugs approved in the world, which have
undergone three generations of technological changes. However, only two
PDC products were approved, namely Lutathera and Pluvicto (both
polypeptide-nuclide conjugates), which were approved by Novartis in 2018 and
2022.

Compared with ADC, PDC has lower molecular weight, strong tumor
penetration and low immunogenicity. In addition, compared with the complex
process of antibody production, PDC is easier to synthesize and purify, with
good uniformity and lower production cost. PDC is expected to become a new
generation of targeted anticancer drugs following small molecule drugs,
monoclonal antibodies and ADC drugs.

The concept of PDC

PDC is a new type of conjugated drug. It is composed of three parts:
peptides, cytotoxic payloads and linkers. The targeted peptides is used as a
targeted drug delivery carrier to covalently couple with toxic drug molecules to
enhance the targeting of drugs. The choice of linker has an important influence
on whether PDC drugs can stably reach the target site. The goal of PDC is to
improve the efficacy of chemotherapy drugs and overcome the challenges of
short circulating half-life and off-target side effects of chemotherapy drugs.

PDC Market Outlook

Huateng Pharma https://us.huatengsci.com

If the use of peptides as active targeting to couple other substances is all
attributed to PDC, there are currently only two approved in the world. The use
of polypeptide-conjugated cytotoxic substances or chemotherapeutic drugs
has not yet been approved in the world. From this perspective, the use of PDC
to deliver cytotoxic substances is still being explored around the world. At
present, the fastest conjugated cytotoxic substances in the world have entered
clinical phase III, and other PDCs are in preclinical or clinical phase I.
Therefore, from PDC's global perspective, there are opportunities for domestic
enterprises, and they are synchronous.

Regarding the use of PDC, it covers four aspects of tumor:
1. In tumor metabolism and immunotherapy, the metabolism of tumors can be
affected by coupling cytotoxic substances, and immune agonists can also be
coupled.
2. In terms of gene therapy, some enterprises are exploring the therapeutic
method of coupling small nucleic acid.
3. In terms of tumor microenvironment, conjugated chemotherapeutic agents
can act through non-endocytic extracellular release mechanism, that is,
using the tumor microenvironment.
4. From the perspective of everything coupling, PDC research (including
preliminary clinical experiments) has been conducted abroad, and PDC can be
applied to many aspects of clinical practice.

Regarding the application of PDC, the hottest ones are the following two:
1. Polypeptide-cytotoxin conjugate: It will improve the clinical effect of first-line
chemotherapeutic drugs while improving side effects.
The functional targeting role as a polypeptide is also fully demonstrated at this
point. In the future, chemotherapy needs to further expand its use, increase its
safety, and will have a good application. From the perspective of the market,
chemotherapy drugs are always the first-line drugs for most tumors and the
most widely used drugs in the tumor treatment guidelines of any country in the
world.
2. Polypeptide-oligonucleotide/small nucleic acid conjugates: Polypeptides
can have new and wider uses.

Key points of PDC structure design

Like ADC, PDC binds to target antigens on the surface of tumor cells, and then
enters endosomes through endocytosis and then lysosomes. Under the action
of lysosomal cathepsin B, the toxin is degraded and can play its anti-tumor
effect in cells.

However, compared with ADC, PDC has a small relative molecular weight,
and a part of it can penetrate into tumor cells in tumor tissues.

Huateng Pharma https://us.huatengsci.com

Targeting is the core. Targeting peptides face three problems:
The first is affinity. The molecular weight of the targeting peptide is only 1/50 or
1/100 of that of the antibody. Relatively speaking, its affinity for the target
antigen is slightly weaker than that of the antibody. However, in the
current ADC research, clinical practice has shown that the affinity needs to be
of an appropriate size.

The second is stability. Targeting peptide as a peptide substance, to solve its
stability problem in plasma. There are many enzymes in plasma that degrade
amino acid chains. Appropriate chemical modification of targeting peptides is
therefore required to enable drug delivery to target tissues.

The third is the half-life. Almost natural peptides enter the blood, and their
half-life is less than half an hour, making it impossible to complete drug
delivery. Therefore, prolonging the half-life of the targeted peptide can also
make PDC play a real role in the human body.

How to solve the above three core problems through technology?

First of all, the main technology used for targeting peptides is to cyclize linear
peptides or chemically modify the main and side chains to improve their
stability and affinity with the target protein.
Second, among chemical modifications, the natural amino acids of the main
peptide chain are replaced with non-natural amino acids to improve stability
and prolong half-life.

Finally, the modification of the side chain of the peptide chain, especially the
modification of the aliphatic chain, can achieve the balance of

Huateng Pharma https://us.huatengsci.com

hydrophilicity/hydrophobicity to make it into a drug. In addition, because the
stability and half-life issues are solved, the safety of PDC is also improved.

Conclusion

Traditional treatment can effectively prevent or slow down the growth of
malignant tumors, but it does not have the ability to target the recognition of
tumor cells. It is usually accompanied by systemic toxicity and large adverse
reactions. So how do you improve efficacy while reducing side
effects? Conjugated drug technology can effectively solve the above
problems.

Although there are not many PDC drugs approved at present, with the
development of technology, PDCs will become a research and development
hotspot of pharmaceutical enterprises like ADCs in the future.

The cytotoxic drugs used in current PDC drugs, such as doxorubicin, paclitaxel,
gemcitabine, and camptothecin, are highly effective drugs that exhibit
cytotoxicity through different mechanisms.

The global representative PDC drug R&D has a wide range of indications,
mainly including esophageal tumors, brain tumors, metastatic non-small cell
lung cancer, gastric tumors, ovarian tumors, multiple myeloma, pancreatic
tumors, advanced solid tumors, etc. The indications of PDC drugs under
research in China mainly include recurrent tumors, digestive tract cancer,
prostate cancer, lung cancer, digestive system cancer, breast cancer, etc. It
can be seen that PDC has a wide variety of drug indications, a large market
scale in the future, and a good prospect for industry development.

As a novel anti-cancer therapy, PDC has the potential to overcome some of
the limitations of ADC. Huateng Pharma is a worldwide leading PEG supplier
that 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.

Related articles:
[1] A Look into Antibody–drug conjugates (ADCs) Targets
[2] ADC Linker - Development and Challenges
[3] Antibody-Drug Conjugates for Cancer Therapy - Prospects and Challenges