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- In 1913, German Nobel Prize winner Paul Ehrlich proposed the concept of magic bullet. The toxin (bullet) is installed on a carrier that can accurately target cancer cells, thereby accurately killing cancer cells without harming normal cells. This idea was considered a fantasy at that time.In 1989, Professor Andrew v. Schally, a professor at Tulane University School of Medicine and Nobel Prize winner, for the first time connected the small molecule anti-tumor drugs sarcolysin (melphalan) and chlorambucil to multiple luteinizing hormone-releasing hormones (LHRH), forming a new LHRH receptor-targeting antitumor complexes.In 2000, the FDA approved the ADC (antibody drug conjugates) drug Mylotarg® developed by Pfizer, turning the "magic bullet" into a reality.
- PDC（peptide-drug conjugate),Another "Golden Track" after ADCCurrently, 16 ADC drugs have been approved for marketing around the world, and 7 ADCs have been approved for marketing in China. Although ADC has made great progress, as a cytotoxic drug, ADC may produce severe toxicity that hinders its further treatment; the complex structure of ADC leads to high production costs; the large molecular weight of ADC limits its ability to penetrate solid tumors, thereby limiting its efficacy.In view of this, peptide-drug conjugate (PDC), which integrates the advantages of peptides, has emerged. Compared with ADC, PDC 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. It is expected to become a new generation of targeted anti-cancer drugs after small molecule drugs, monoclonal antibodies, and ADC drugs.
PDC Mechanism of Action
Medicilon Peptide Drug Conjugate (PDC) R&D Service Platform- Research and Development of Innovative Peptide DrugsEstablishing a computer prediction model for the antibacterial activity of peptide drug moleculesEstablish molecular simulation technology for targeted binding of peptide drugs and assist in rapid activity-based optimization of moleculesComplete professional team for innovative drug development, which can assist in the research and development of new peptide drug conjugates (PDC).
- Research and Development of New Peptide FormulationsPossess R&D technology for new long-acting formulations of peptide drugs, including sustained-release microspheres, sustained-release gels, nano-preparations, etc.
- Research and Development of Peptide Generic DrugsComplete peptide generic drug research and development system, systematically mastering the key core technologies of every professional sectorLay out the featured product pipeline of peptide generic drugs
Advantages of Medicilon PDC R&D Service Platform- Rich Experience in Peptide SynthesisThe choice of peptide will affect the efficiency of drug endocytosis in PDC, and once the target is selected, it is also important to select the appropriate peptide. An ideal PDC peptide should have strong target binding affinity, high stability, low immunogenicity, efficient internalization and long plasma half-life.The Medicilon peptide synthesis research team has now established a complete system from upstream synthesis of unnatural amino acid structural units, peptide drug modification and large-scale synthesis, to downstream peptide drug signal transduction pathways and mechanism of action research. Through multi-disciplinary collaboration in chemistry, biology, medicine and pharmacy, we can respond to client needs faster and provide technical support for the synthesis and selection of PDC peptides.
- Successful ADC Drug Development ExperienceMedicilon's antibody drug conjugate (ADC) R&D service platform can provide clients with services such as ADC Payloads synthesis, ADC drug conjugation, ADC pharmacodynamics evaluation, ADC pharmacokinetics evaluation, and ADC safety evaluation. As of the end of 2022, Medicilon has successfully helped 12 ADC drugs obtain clinical approval, and has more than 10 ADC projects under development. These experiences provide solid support for the selection of PDC connectors.
- Efficient One-Stop R&D ServicesMedicilon has successfully created a comprehensive and integrated service model, which can not only seamlessly connect traditional R&D links (peptides, conjugates, APIs, preparations, etc.) in series, but also integrate them into a parallel R&D model. This shows the service advantages of rigorous planning, efficient collaboration, and orderly advancement, which can empower the research and development of new drugs faster, better, and cost-effective.
PDC R&D Key Technologies- PDC is a targeted therapy drug whose structure and function are similar to ADC and consists of three important components: targeting peptide (homing peptide), connecting chain and cytotoxin. The three work synergistically to deliver cytotoxins by targeting specific receptors on tumor cells. The selection of these three elements is the key to technology.
PDC Drug Structure Diagram - Targeting Peptides
Optimization Methods for Targeting PeptidesTargeting peptides used in PDC can generally be divided into two categories: cell-penetrating peptides (CPPs) and cell-tropic peptides (CTPs). CPPs are short peptides (less than 30 residues) with the ability to transport across membranes and can be divided into three categories: protein-derived CPPs, modified CPPs and designed CPPs. CTPs can interact with overexpressed receptors in specific cells. Once CTPs are combined with therapeutic drugs, they can transport the therapeutic compounds and concentrate them at the target location, thus reducing the side effects of therapeutic drugs. - Linker
Type of linker Non-lytic PH-sensitive REDOX sensitive Enzyme sensitive Carbon chain Hydrazone bond Disulfide bond Gly-Phe-Leu-Gly Amido bond Alken-ether bond Val-Cit(Cit-Citrulline) Ether bond Acetal/ketal bonds Phe-Lys Common Linker Types in PDCThe choice of linker needs to take into account the microenvironment in which the PDC is located to avoid interfering with the binding affinity of the peptide to its receptor and drug efficacy. There are many different types of Linkers used in PDC based on their length, stability, release mechanism, functional groups, affinity/hydrophobicity and other characteristics. - CytotoxicCytotoxins are used as "toxic warheads" in PDC. If the unmodified original cytotoxin is not combined with the targeting peptide, its ability to distinguish cancer cells from normal cells is poor, and the shortcomings of uncontrolled toxicity are exposed. In addition, cytotoxins also require suitable carriers for efficient delivery to tumor tissues to counteract their high hydrophobicity, thereby enhancing the pharmacokinetics and therapeutic window of the cytotoxic agent.
Pic: Dau Daunorubicin; DOX doxorubicin; CPT camptothecin; PTX paclitaxel; Gem gemcitabine (the red circle is the most common coupling site)Currently, the representative cytotoxins include gemcitabine, doxorubicin, daunorubicin, paclitaxel and camptothecin, etc.
