Antibody-Drug Conjugates (ADCs) are known as a “biological missile”. In 2019, four ADC drugs (Policy, the Padcev, Enhertu, and Trodelvy) received FDA approval, sparking a new R&D boom.
More than 100 years ago, Professor Paul Ehrlich first proposed the “Magic Bullet” theory. The theory suggests a “magic bullet” or ideal therapeutic agent can specifically recognize and kill cancer cells without harming normal cells [1]. In 1989, Nobel Laureate Andrew V. Schally from Tulane University’s School of Medicine invented the use of peptides as carriers for cancer chemotherapy, which allows the delivery of drug molecules to the receptor-specific target sites [2]. Various advantages and specificities of peptides as targeting carriers are attracting more and more attention worldwide.
Peptide Drug Conjugate (PDC) is also becoming an important R&D component of the pharmaceutical industry. PDC drugs are a conjugation between targeted peptides and drug molecules, which can enhance the target accuracy. They focus the drug on the target tissues while reducing their relative concentrations in other tissues, increasing potency, and reducing adverse effects. As an ideal drug delivery system, it must be capable of transporting the drug to a specific site in the body and releasing the drug within it at that site. At the same time, the carrier itself must be non-toxic or degraded to a non-toxic product and eliminated from the body. Peptides as carriers have high transport efficiency, low toxicity, no significant limitation on the size of all substances, and no association with inflammatory reactions. It can also effectively control the amount of material entering the cell, and is therefore widely used in the field of drug transportation.
Currently, researches of PDC drugs are mainly focused on antitumor and tumor vascular expression specific markers. Conventional chemotherapeutic drugs are usually not selective for cancer cells and therefore often cause serious side effects. Improving the target specificity of these drugs is one of the industry trends in developing anticancer drugs. Some small-molecule peptides can target specific receptors, and thus can be used as carriers for cancer chemotherapy drugs. Chemotherapeutic drugs conjugated with peptide carriers to form brand new antitumor drugs. The advantages of these drugs include high specificity, high affinity, high tumor permeability, and can be delivered through specific receptors on the cell surface into cancer cells. This ability effectively improves the anti-cancer effect, reducing side effects and drug resistance. PDC drugs are considered one of the latest generations of target-specific anticancer drugs. Compared with ADC drugs, PDC drugs have the following advantages: a lower molecular weight (generally less than 3 kD), a higher loading capacity, lower immunogenicity, and lower production costs.
Figure 1. General Formula for PDC Drug Structure [3]
Figure 2. PDC Drug Mechanism [3]
PDC drugs consist of three parts: a targeting peptide that specifically recognizes the receptor associated with the tumor cell, drug molecules that kill the tumor cell, and a linker that connects the drug molecule to the targeting peptide.
The drug molecules in PDC drugs are divided into chemical and non-chemical. Cytotoxic drugs such as paclitaxel, camptothecin, doxorubicin, and phenyl butyric acid nitrogen mustard are commonly used for tumor-targeting peptide conjugation. The cytotoxic loads of non-chemical drugs are commonly TNF, interfering small RNAs (siRNAs) and antisense oligonucleotides (AONs), etc.
According to Globe Newswire, the global therapeutic peptide drug market was worth $25.35 billion in 2018, which is expected to reach $50.6 billion by 2026, at a compound annual growth rate of 9.0%. Peptide drugs will be used as targeted drugs for the treatment of cancer, metabolic disorders, and cardiovascular diseases [4]. Biotech companies represented by Oncopeptides, Angiochem, PeptiDream. Mainline Bioscience and Theratechnologies have achieved significant technological breakthroughs after years of dedicated research, coupled with capital driving and accelerated audit speed. As a result, more and more PDC drugs with different indications exist in the clinical I/II phase, especially, those antitumor PDC drugs will open up the CDMO market at a rapid pace.
| Drug Name | Company | Therapeutic Area | Highest Clinical Phase |
| Melflufen | Oncopeptides | Cancer | Phase 3 |
| ANG1005 | Angiochem | Cancer | Phase 3 |
| MLB1707 | Mainline Bioscience | Cancer | Phase 2 |
| BT1718 | Bicycle Therapeutics | Cancer | Phase 1 |
| TH1902 | Theratechnologies | Cancer | Pre-Clinical |
| TH1904 | Theratechnologies | Cancer | Pre-Clinical |
Figure 3. Main Players of PDC Drugs
Asymchem (stock code: 002821.SZ) is a global leading CDMO promoting chemical macromolecule business like peptides, ADC/Drug-Linker, oligonucleotides, and polysaccharides based on the consolidated capabilities for small molecules. In recent years, Asymchem’s chemical macromolecular team has made full use of its technical advantages in peptide synthesis/quality control and experience in ADC/Drug-Linker, advancing in process development and GMP production of PDC APIs.
SPPS Reactor DAC Prep-HPLC Nanofiltration Lyophilizer
Many years of efforts in the R&D and production of peptide synthesis and purification provide the technical basis for the development of PDC peptide fragments, offering advantages to Asymchem in such a field. We can achieve both short peptide synthesis with <10AA and long peptide synthesis with >40AA, as well as the cyclic peptide synthesis. The peptide team has also developed a non-natural amino acid synthesis technology and established a non-natural amino acid library, which can easily introduce non-natural amino acid to peptide chain synthesis. We have 800 m2 kg-level lab, 800 m2 cGMP workshop and 3 independent peptide production lines, 5 independent Class D areas, which can meet GMP production requirements of 1~100Kg, and have equipped complete analytical and quality control support.
Asymchem’s long-standing and valuable expertise in the field of highly potent compounds provides safety assurance for exposure control of cytotoxic small-molecule fragments in PDC drugs. TJ1 site has compliance R&D and production area for highly potent compounds, with a mature exposure risk assessment system to adapt different requirements of customers. The production scales range from milligrams to kilograms and we have successfully delivered multiple PDC-related projects to many customers at home and abroad.
Asymchem always insists on the customer-centered service philosophy and develops the peptide Plus business based on the peptide technology platform. Relying on existing strong R&D capability, advanced management system, mature supply chain, and advanced equipment and facilities, we can quickly address clients’ orders in each stage from quotation to project delivery. Also, we can produce cGMP-compliant high-quality PDC products for customers quickly. The professional service level and win-win philosophy of Asymchem have become a key factor in accelerating clients’ drug discovery and development process, to meet unmet clinical needs around the world.
Reference:
[1] Schwartz RS. Paul Ehrlich’s magic bullets. N. Engl. J. Med., 2004, 350, 1079-1080.
[2] Bajusz S, Janaky T, Csernus VJ, et al. Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone. Proc. Natl. Acad. Sci. USA, 1989, 86, 6313-6317.
[3] Liang Ma, Chao Wang, Zihao He, et al. Peptide-drug conjugates: A novel drug design approach. Curr. Med. Chem., 2017, 24, 3373-3396.
[4] http://www.globenewswire.com/news-release/2020/03/23/2005016/0/en/
Peptide-Therapeutics-Market-To-Reach-USD-50-60-Billion-By-2026-Reports-and-Data.html