$860 million market size, PDC drug development and market analysis

Polypeptide-drugconjugate drugs (PDC) are conjugate drug molecules. PDC (Peptide-DrugConjugate) can be used to conjugate peptides with other therapeutic molecules in a covalent manner to produce new compounds.

By combining a peptide with another molecule, such as a chemotherapy drug or a diagnostic imaging agent, the resulting molecule can specifically target cells that express the receptor, making PDC a new modality for tumor therapy and diagnosis.

01
Characteristics and antitumor efficacy of PDC

The targeting mechanism of PDC is related to many factors, and the function of receptor determines the mechanism of action. Similar to ADCs (antibody-drug conjugates), homing peptides target the surface of cell membranes, triggering receptor-mediated drug endocytosis and internalization. PDC and ADC are conceptually similar, but have distinct structures and attributes. Antibodies have higher specificity and longer half-life, while homing peptides have better drug loading and tissue penetration.

Peptides used in PDC can be divided into two classes: cell penetratingpeptides (CPP, Cell-Penetratingpeptides) and cell targetingpeptides (CTP, cell-targetingPeptides).

The mechanism of CPPs uptake across the membrane is not fully understood. Some CPPS have been reported to cross cell membranes through energy-dependent cellular processes such as endocytosis or receptor-mediated uptake, while others use energy-independent non-endocytotic translocation pathways. However, wide application of CPPs is limited due to their low cell specificity. In contrast, CTPS are ideal carrier molecules because they have similar capabilities to mAb. They bind with high affinity to overexpressed receptors on the surface of tumor cells.

Although two polypeptide-drug couplings have been approved by the FDA for the treatment and diagnosis of cancer, the development of novel peptide-drug couplings targeting overexpressed receptors remains very challenging.

02
PDC targeting receptors and connectors

The receptors most frequently targeted by PDC include:

Integrins

The epidermal growth factor receptor (EGFR, EpidermalGrowthFactorReceptors)

G protein-coupled receptors (GPCR)

Neuropeptide Y receptors (NPYR neuropeptideYReceptors)

BombesinReceptor

SomatostatinReceptors (SSTR)

Common joint types and cracking modes in PDC structure include:

Hydrazone; Hydrazone; Cleavage method: acid hydrolysis

Disulfide; Disulfide; Cracking mode: reduction

Azo compounds (Azo); Cracking mode: reduction

ester; Cracking method: acid - base catalytic hydrolysis or enzymatic hydrolysis

carbamate; Cleavage mode: enzymatic hydrolysis

Amide; Cleavage mode: enzymatic hydrolysis

03
PDC main load

At the heart of each PDC is the cytotoxic therapeutic agent payload. Polypeptide carriers and joint structures provide selectivity for PDC, but drugs are the only hope for achieving PDC efficacy.

In many cases, the term "drug" in PDC refers to a cytotoxic (chemotherapy) anticancer agent, but may also refer to a broad spectrum of active therapeutic ingredients. The combination of radionuclide and peptide, can produce a cancer diagnosis or PRRT (peptide receptor radionuclide therapy, peptidereceptorradionuclidetherapy) molecules. In addition, non-radioactive molecules such as boron can be used as loads to generate PDC for boron neutron capture therapy (BNCT). Payloads commonly used in PDC include:

3.1 Chemotherapy drugs

There are currently more than 250 FDA-approved drugs for the treatment of malignant tumors (see Cancer.gov), and many of these classic chemotherapeutic agents have strong pharmacological activity due to their powerful cytotoxicity.

Chemotherapeutic drugs that bind DNA

Chemotherapy agents used in PDC can be classified according to their general mode of action. The first group of molecules bind to and interact with cellular DNA or DNA-protein complexes, thus interfering with transcription and DNA replication and inducing apoptosis.

These drugs include metal complexes,Camptothecin (CPT,Camptothecin), anthracyclines, such as daunorubicin (DAU) and doxorubicin (DOX, doxorubicin) (Figure 1). These highly effective molecules are widely used in PDC. For example, octreotide targeting SSTR2 (somatostatin receptor 2) binds to DOX or 2-pyrrolin-Dox via ester ligand and shows selective toxicity to targeted tumor cells in vivo.

Inhibit DNA synthesis of chemotherapy drugs

The second class of frequently used cytotoxic compounds achieve cytotoxicity by inhibiting DNA biosynthesis. These antimetabolites, such as gemcitabine, a nucleoside analogue of deoxycytidine, or MTX,methotrexate, a folate derivative that inhibits dihydrofolate reductase (FIG. 2), which are structural-like to natural metabolites, It is potent in the process of anticancer cells.

Antimitotic agent

A third group of chemotherapeutic agents consists of anti-mitoticagents that act on microtubules. Examples include paclitaxel (PTX, paclitaxel, FIG. 3), which inhibits microtubulin depolymerization, and vinca alkaloid analogues, which inhibit tubulin polymerization.

3.2 Radionuclides

Among chemotherapy agents, radionuclides are the second largest payload group in PDC and can be used in two major modes of diagnosis and treatment related to cancer. PDCS labeled with positron emission radioisotopes, such as Fluorine 18(18F), Copper 64(64Cu) and gallium 68(68Ga), can be used as PET (positron emission tomography) imaging agents, and PDCS labeled with gamma ray radioisotopes, such as technetium 99m(99mTc) and iodine 123(123I), It can be used for single photon emission computed tomography (SPECT). By binding to targeted receptors on tumor cells, malignant tissue can be precisely located.

In addition to diagnostic methods, tumors can also be treated using radionuclide labeled PDC in a therapeutic setting if beta emitting nuclides, Augerelectron-emitting nuclides or alpha emitting nuclides are used.

The choice of radionuclides depends largely on the size of the target tumor or metastasis. The most commonly used radionuclides are indium 111(111In), yttrium 90(90Y), and lutetium 177(177Lu). The most successful therapeutic peptide radiopharmaceutical to date is 177Lu-DOTA-TATE. In patients with advanced mid-gut neuroendocrine tumors, 177Lu-DOTA-TATE was associated with a longer progression-free survival and significantly improved response rate compared with high-dose octreotide long-acting repeatable therapy.

The European Commission approved 177Lu-DOTA-TATE(Lutathera®) in October 2017 and the FDA approved it in January 2018. This advance demonstrates the great potential of receptor-mediated drug delivery methods in cancer treatment and is considered an important milestone on the road to peptide-based medicine and personalized medicine in this field.

04
PDC market analysis

4.1 Driving factors of PDC global market

Increased prevalence of chronic diseases

Chronic diseases such as cancer, diabetes and autoimmune diseases are often difficult to treat with traditional drugs due to their complex nature and the difficulty of targeting specific cells or tissues.

Peptide-drug couplings offer a more targeted approach to therapy that can deliver drug payloads more precisely and reduce the likelihood of side effects. The growing prevalence of chronic diseases is driving the development and use of peptide-drug couplings in a number of ways.

According to the World Health Organization, chronic diseases account for about 71 percent of all deaths worldwide, with cardiovascular disease alone responsible for 17.9 million deaths each year. Similarly, the American Hospital Association reports that about 133 million Americans -- nearly 50 percent of the population -- have at least one chronic medical condition, such as heart disease, high blood pressure or arthritis. That number has increased by 15 million over the past decade and is expected to rise to 170 million by 2030.

Increase in R&D activities

The pharmaceutical industry is investing heavily in peptide drug research and development, leading the development of new and innovative drugs. Major pharmaceutical companies are investing large amounts of money in the research and development of polypeptide drug conjugates.

4.2 Main Trends of PDC

Demand for targeted therapies is on the rise

The growing demand for targeted therapies is one of the key trends in the global peptide-drug conjugate market.

The development of more precisely targeted therapies could lead to more effective and safer treatment for a range of diseases, such as breast cancer, where conventional chemotherapy for breast cancer often causes adverse side effects due to its non-selective nature. Peptide-drug conjugations have been shown to be an emerging target therapy of choice for breast cancer.

4.3PDC development collaboration and partnership

Collaboration and partnerships between pharmaceutical companies are becoming more common in PDC development. These partnerships enable companies to leverage their respective expertise and resources to accelerate the development of new therapies. For example, BicycleTherapeutics and Genentech have collaborated to develop new peptide-based cancer therapies, combining Bicycle's expertise in peptide drug conjugations with Genentech's expertise in oncology research and development.

AstraZeneca and BicycleTherapeutics have also entered into a partnership to develop PDC for respiratory and cardiovascular disease, combining AstraZeneca's expertise in drug development and commercialization, And Bicycle's specialty in PDC.

Ipsen and EpiVaxOncology collaborate to develop new peptide-based cancer therapies; Pfizer and GlycoMimetics have also teamed up to develop peptide-based treatments for blood disorders.

4.4PDC Modes

The global PDC market can be divided into therapeutic and diagnostic. The therapeutics segment currently dominates the market due to the increasing demand for targeted therapies for a variety of diseases.

Oncology: The oncology PDC therapy space dominates the market due to the high demand for peptide-based therapies in oncology.

Metabolic disorders: PDC is used to treat metabolic disorders such as diabetes and obesity.

Cardiovascular diseases: PDC was developed to treat cardiovascular diseases, such as hypertension and heart failure.

Infectious diseases: PDC is also used in the treatment of infectious diseases such as HIV/AIDS and tuberculosis.

4.5 Characteristics of PDC market region

From a geographic perspective, North America has been the dominant region in the global PDC market due to the following factors:

Established pharmaceutical companies: North America is home to some of the world's largest pharmaceutical companies, which have invested heavily in the development of peptide drug conjugates. These companies have the resources and expertise to bring new treatments to market within the best turnaround time.

High incidence of chronic diseases: North America has a high incidence of chronic diseases such as cancer, diabetes and cardiovascular disease, which require long-term treatment. Peptide drug couplings provide targeted and personalized treatment options, making them the first choice for patients and healthcare providers.

Favorable regulatory environment: Regulators have established clear guidelines and processes for PDC approval, making it easier for pharmaceutical companies to bring new products to market.

The Asia-Pacific region is the fastest growing segment of the global peptide drug conjugate market due to the following factors:

Growing demand for targeted therapies: The demand for targeted therapies is increasing in the Asia-Pacific region due to the rising prevalence of chronic diseases and the need for more effective and safer treatments.

Increase investment in health care: Governments and private organizations in the Asia-Pacific region are investing heavily in health care infrastructure and research and development. This investment has led to the development of innovative therapies for a range of diseases, including peptide-drug couplings.

Favorable Regulatory environment: The regulatory environment in the Asia-Pacific region is increasingly conducive to the development and commercialization of polypeptide drug conjugations. Regulators are developing clearer guidelines and processes for approving these therapies, making it easier for drug companies to bring new products to market.

The global polypeptide drug conjugate market is expected to be $860 million in 2023, and the global PDC market is expected to grow at a compound annual growth rate (CAGR) of 13.7% from 2022 to 2030.

4.6 Major PDC Participants

Key players in the PDC market include:

NovartisAG,AstraZeneca,BicycleTherapeutics,CybrexaTherapeutics,EsperancePharmaceuticals,OncopeptidesAB,PepgenCorporation ,SoricimedBiopharma,Theratechnologies,PfizerInc,ValidusPharmaceuticalsLLC,AntisenseTherapeutics,MidatechPharmaPLC,IpsenP harma,ChiasmaInc.,PeptronInc.,CrineticsPharmaceuticals,DauntlessPharmaceuticals,CamurusAB,TevaPharmaceuticalsInc.,Pharma Spur, AspireoPharmaceuticals IonisPharmaceuticalsInc, MidatechPharmaPlc, etc.