Peptide-drug conjugates (PDCs) are an emerging targeted therapeutic that present increased tumor penetration and selectivity. PDC consists of three important components: homing peptides, linkers, and cytotoxicity payloads.

Figure 1. Structure of PDC

Compared to non-targeted anticancer drugs, PDCs can significantly prolong circulation time, increase maximum tolerated dose, enhance drug accumulation in tumor cells, and improve anticancer biological activity. Because normal cells lack the targeted receptors necessary for binding with tumor-targeting peptides, compounds accumulate in receptor-positive tumor cells, allowing for lower dosages and reduced side effects. Additionally, PDCs can rely on the properties of peptides to enhance drug solubility, permeability, and selectivity.

Compared with antibody drug conjugates (ADCs), PDCs possess several advantages, including smaller molecular weights, easy industrial synthesis, low cost, high tissue penetration and fast clearance. Due to their strong penetration into tumor tissues, PDCs can accumulate at high concentrations at the target site, allowing for the use of relatively low-toxicity chemotherapy drugs such as doxorubicin and paclitaxel, which are widely used clinically. Therefore, PDCs are expected to become a new generation of anti-tumor drugs following small molecule drugs, monoclonal antibodies, and ADC drugs. Currently, there are two PDC drugs on the market globally.

FDA Approved PDCs

Currently, there are only two PDCs approved for therapeutic use globally.

177Lu-DOTA-TATE (Lutathera®) is the world's first PDC drug on the market. In 2018, the FDA approved its use for treating gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Lutathera generated revenue of $605 million in 2023, representing a 28% year-over-year growth. In January 2024, the Phase III NETTER-2 study for Lutathera also achieved great success. Lutathera®  plus long-acting release (LAR) octreotide reduced the risk of disease progression or death by 72% as first-line therapy in patients with somatostatin receptor-positive (SSTR+) well-differentiated grade 2/3 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) versus high-dose octreotide LAR alone.

In 2022, Novartis gained approval for ILu-PSMA-617 (Pluvicto), another PDC drug targeting PSMA, for prostate cancer treatment. Novartis' 2023 financial report highlighted Pluvicto's rapid growth, soaring to $980 million, marking a remarkable 261% increase. Furthermore, in January 2024, the FDA greenlit Novartis to begin commercial production of Pluvicto at its Indianapolis manufacturing site.

On February 26 2021, the U.S. FDA approved Pepaxto® (melphalan flufenamide, known as melflufen) in combination with dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy. But, in 2024,  the FDA has issued a final decision to withdraw approval status for Pepaxto®. 

Figure 2. Structure of approved PDCs, A. Lutathera. B. Pepaxto. C. Pluvicto3

PDCs in Clinical Trials

According to incomplete statistics, there are currently over 40 PDC drug pipelines in global development, with nearly 20 pipelines in Phase I or later stages. From the standpoint of indications under investigation, PDCs have shown efficacy across various cancer treatment domains, particularly in treating certain malignant tumors and challenging-to-target tumors like triple-negative breast cancer and brain metastases.

Table 1. PDCs in clinical trials [2]

Conclusion

While PDCs offer a promising novel therapeutic approach with the potential to address some of the limitations of ADCs, the withdrawal of Pepaxto® highlights ongoing challenges in their clinical application, particularly in terms of targeting capabilities and safety concerns that require attention. However, once these challenges are fully addressed, PDC drugs have the potential to emerge as valuable assets in the field of cancer treatment.

Huateng Pharma is a worldwide leading PEG supplier that offers a wide array of different ADC & PDC Linkers to empower our customer's advanced research. We are committed to promoting the progress of your PDC discovery and development projects.

References:
[1] Peptide-Drug Conjugate: A Novel Drug Design Approach. Curr Med Chem. 2017;24(31):3373-3396.
[2] Heh E, Allen J, Ramirez F, Lovasz D, Fernandez L, Hogg T, Riva H, Holland N, Chacon J. Peptide Drug Conjugates and Their Role in Cancer Therapy. Int J Mol Sci. 2023 Jan 3;24(1):829. doi: 10.3390/ijms24010829. PMID: 36614268; PMCID: PMC9820985.