PDC: A Complement to ADC or a New Frontier?

Exploring new types of drugs is a continuous endeavor in the pharmaceutical industry. After small molecules consistently produced ‘blockbuster drugs’ and ‘multi-billion-dollar’ successes, biologics (especially monoclonal antibodies) have changed the market landscape, such as PD-1 monoclonal antibodies. In recent years, peptide-based drugs like GLP-1 agonists have also started to shine. Consequently, more novel and creative types of drugs are being actively explored, with PDCs (Peptide-Drug Conjugates) being one of them.

Characteristics of PDC Drugs

Peptide-Drug Conjugates (PDCs) are an emerging class of targeted drugs that have garnered significant attention following ADCs. Structurally, they typically consist of three parts: a targeting receptor peptide, a cleavable or non-cleavable linker, and a cytotoxic molecule.

Figure 1. Structure of PDCs (Image Source: doi.org/10.1016/j.apsb.2022.07.020)

Taking the oncology field as an example, compared to large antibody molecules, the advantages of combining targeting peptides with toxin molecules are mainly reflected in the following aspects: 1）Smaller molecular size (2-20 kDa), making it easier to penetrate the tumor stroma and enter tumor cells. 2) Can be chemically synthesized, making the production process simple and easy to scale up. 3) Can be conjugated with various clinically validated cytotoxic molecules like doxorubicin and paclitaxel to prepare targeted formulations, without being limited to a few highly toxic structures like MMAE and DM-1 in the ADC field, significantly reducing off-target toxicity and greatly enhancing the feasibility of the PDC formulation platform. 4) Some targeting peptides can overcome tumor cell resistance by altering the mechanism of cell entry, effectively killing resistant tumors and breaking the common dilemma of resistance leading to ineffective treatment in traditional chemotherapy.

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Table 1. Comparison Between ADCs and PDCs

(Image Source: doi.org/10.1016/j.apsb.2022.07.020)

Compared to ADCs, the most significant difference in PDCs is the ‘P’—peptide. Based on the long-term development and significant success of peptide drugs, the entire industry has accumulated extensive research on peptides. Taking the oncology field as an example, the peptides used in PDC structures mainly include tumor cell-targeting peptides, tumor vasculature-targeting peptides, organelle-targeting peptides, cell-penetrating peptides, tumor microenvironment-sensitive peptides, and therapeutic peptides. The components and design of Peptide–Drug conjugates are shown in the figure below.

Figure 2. Components and Design of Peptide–Drug Conjugates

Characteristics of Approved PDCs

According to literature reports, several PDC drugs have been approved for market, with the most representative and frequently mentioned being Lutathera ([177Lu] Lu-DOTATATE), approved by the FDA in January 2018, and Pepaxto (Melflufen), granted accelerated approval by the FDA in February 2021. However, Pepaxto (Melflufen) has had a tumultuous fate, being withdrawn from the U.S. market and later having its accelerated approval revoked by the FDA.

Lutathera ([177Lu] Lu-DOTATATE)

Lutathera ([177Lu] Lu-DOTATATE), developed by Novartis subsidiary Advanced Accelerator Applications SA (which Novartis acquired for $3.9 billion in 2017), was approved by the FDA for market release in January 2018. The approved indication is for SSTR-positive gastroenteropancreatic neuroendocrine tumors. In China, the highest development stage is Phase III clinical trials.

This PDC (Peptide Drug Conjugate) is formed by chelating the radiotherapeutic drug 177Lu with octreotide through a high-affinity binder, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). After binding to cells expressing somatostatin receptors (including somatostatin receptor-positive malignant tumors), it is internalized. The β-rays from 177Lu induce cell damage by forming free radicals in the cells and neighboring cells, and it is used to treat somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. This is the first time a radiotherapeutic drug has been approved for the treatment of neuroendocrine tumors, and it is one of the earlier therapeutic drugs in the PDC field to be marketed. According to the annual report, Lutathera achieved $605 million in revenue in 2023.

Figure 4. Product Information of Lutathera ([177Lu] Lu-DOTATATE)

Figure 3. Product Information of Lutathera ([177Lu] Lu-DOTATATE)

(Image Source: Strait Pharmaceutical Journal (2023) & https://www.adacap.com)

Pepaxto (Melflufen)

Pepaxto (Melflufen) was developed by Oncopeptides and was granted accelerated approval by the FDA in February 2021 for use in combination with dexamethasone to treat adult patients with relapsed/refractory multiple myeloma who have received at least four prior therapies and are resistant to at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 monoclonal antibody. In October 2021, Oncopeptides announced the withdrawal of Pepaxto from the U.S. market due to its failure to reduce the risk of death in the ITT population in the confirmatory Phase III OCEAN study. In February 2024, the FDA issued a final decision to withdraw the accelerated approval of Pepaxto (melphalan flufenamide) by Oncopeptides.

Pepaxto is a first-in-class, targeted PDC developed using the company’s proprietary peptide-drug conjugate platform, designed to rapidly deliver the DNA alkylating agent melphalan to tumor cells. Due to its high lipophilicity, melflufen is rapidly absorbed by myeloma cells. Once inside the cells, the conjugated peptide of melflufen is immediately cleaved by aminopeptidases, releasing the hydrophilic alkylating agent melphalan, which is then trapped inside the cells. In vitro studies have shown that melflufen is 50 times more potent than melphalan in myeloma cells due to the increased concentration of the intracellularly retained alkylating agent melphalan, rapidly inducing irreversible DNA damage and leading to cell apoptosis.

Figure 2-2. Product Information of Pepaxto (Melflufen)

Figure 4. Product Information of Pepaxto (Melflufen)

(Image Source: Strait Pharmaceutical Journal (2023) & https://www.fda.gov/drugs)

Characteristics of PDCs in Development Globally

The literature “Research advances in peptide-drug conjugates” (2023) provides a representative overview of PDC drugs in development. Below are examples of some products mentioned in the literature and other domestic products in development.

ANG1005, developed by AngioChem, is a PDC drug that has entered Phase III clinical trials and is being co-developed with the domestic company Sinobiopharm. According to the official website, this product is a conjugate formed by combining paclitaxel ( Paclitaxel | CAS:33069-62-4 ) molecules with chemically synthesized amino acid peptides and is the first new drug in China that can specifically deliver paclitaxel to the brain. Completed Phase II clinical trials for breast cancer brain metastases have shown that this product has clear clinical efficacy for both brain metastases and extracranial tumors in breast cancer, with safety similar to that of regular paclitaxel and no severe allergic reactions.

Zoptarelin doxorubicin (AEZS-108), developed by Aeterna Zentaris, is a PDC designed using D-Lys6-GnRH as a target-specific ligand, glutaric acid as a linker, and ADM as a cytotoxic molecule. It has high affinity for GnRH receptor-positive tumor cells. In breast cancer cell lines MCF-7 and MDA-MB-231, the EC50 values for AEZS-108 binding to GnRH receptors are approximately 2-13 nM. Studies have shown that AEZS-108 has good therapeutic effects on ovarian cancer, breast cancer, endometrial cancer, and other tumors overexpressing GnRH receptors, with stronger activity than ADM and fewer side effects. However, due to its inability to improve the median survival of patients with advanced endometrial cancer, the Phase III clinical trial of AEZS-108 has been terminated.

Figure 5. Structural Characteristics of ANG1005 and Zoptarelin Doxorubicin

(Image Source: Strait Pharmaceutical Journal (2023))

CBP-1008, developed by Tongyi Pharmaceutical based on the first-generation bi-XDC technology platform, is a dual-ligand conjugate drug. It consists of an optimized dual-ligand linker system targeting FOLR1/TRPV6, a cleavable trifunctional linker, and the cytotoxin MMAE as the payload. CBP-1008 has shown significant dual-ligand synergistic effects in preclinical experiments, overcoming competition from endogenous ligands. This has been demonstrated in preclinical CDX and PDX model efficacy tests, showing a strong correlation between receptor expression and efficacy. Phase I has basically completed the exploration of safety and tolerability without reaching the MTD. A Phase II single-arm study for patients with FRα-positive, platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer who have received 1-3 lines of systemic anti-tumor therapy was officially launched in February 2023. An open-label, international multicenter Phase II single-arm study on the efficacy and safety in patients with recurrent or persistent platinum-resistant ovarian cancer, primary peritoneal cancer, and fallopian tube cancer clear cell subtype is also ongoing.

PDC: A Complement to ADC or a New Frontier?

Characteristics of PDC Drugs

Characteristics of Approved PDCs

Lutathera ([177Lu] Lu-DOTATATE)

Pepaxto (Melflufen)

Characteristics of PDCs in Development Globally

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