Peptide-Drug Conjugates (PDCs): A New Hope in Targeted Cancer Therapy

Cancer remains one of the leading causes of death worldwide, projected to claim 10 million lives by 2030. Current standard therapies, predominantly chemotherapy, lack tumor specificity and often cause severe off-target toxicities, limiting clinical efficacy and imposing heavy physiological, economic, and psychological burdens on patients. As a next-generation targeted therapeutic platform following Antibody-Drug Conjugates (ADCs), Peptide-Drug Conjugates (PDCs) integrate three core modules: Tumor-Targeting Peptides (TTPs), cytotoxic payloads, and linkers. Leveraging the advantages of peptides—high specificity, strong tumor penetration, and low immunogenicity—PDCs aim to achieve precise drug delivery, maximizing therapeutic efficacy while minimizing systemic toxicity, thereby offering a new breakthrough direction in cancer treatment. Based on relevant research, Amy Armstrong and colleagues systematically summarize the core design principles, targeting mechanisms, key components, current status of clinical translation, existing challenges, and future trends of PDCs, providing a clear reference for R&D and application in this field.

 1. PDC Design and Advantages: An Optimized Evolution from ADCs

The design concept of PDCs originates from ADCs, but it replaces antibodies with peptides as the targeting vector, thereby avoiding some inherent limitations of ADCs and forming unique technical advantages. A typical PDC structure consists of a targeting peptide, a cleavable linker, and a cytotoxic payload. Each module can be independently optimized and flexibly assembled to suit the therapeutic needs of different tumor types and to support theranostic applications—exemplified by Lutathera, an FDA-approved PDC that integrates tumor targeting with radiotherapy.

Compared to ADCs, PDCs offer several advantages: their smaller molecular weight (typically 2–20 kDa) facilitates better penetration into tumor tissue; their manufacturing process is relatively simpler and less costly, with lower immunogenicity and more controllable pharmacokinetic profiles; furthermore, peptide structures are easily optimized through chemical modifications to further enhance their targeting specificity, stability, and responsiveness to the tumor microenvironment, making them more suitable for developing multi-target or smart stimulus-responsive drug delivery systems.

The mechanism of action of PDCs primarily relies on the recognition of tumor cell surface-specific markers or tumor microenvironment (TME) signals by the targeting peptide, leading to cellular internalization via endocytosis. Under specific intracellular or TME conditions, the linker undergoes cleavage, releasing the cytotoxic payload, which then induces tumor cell apoptosis by mechanisms such as disrupting DNA replication or inhibiting topoisomerase, thereby achieving precise killing of cancer cells.

 2. Targeting Mechanisms of PDCs: Receptor-Dependent and Independent Pathways

2.1 Receptor-Dependent Targeting

This mainstream approach utilizes tumor cell surface-overexpressed specific receptors (e.g., somatostatin receptors, GnRH receptors) for precise delivery via high-affinity binding of the targeting peptide. Representative examples include:

•   Somatostatin Receptor (SSTR) Targeting: SSTRs are overexpressed in various tumors like neuroendocrine tumors (NETs) and breast cancer. Lutathera (¹⁷⁰Lu-DOTA-TATE), using the TATE peptide as the targeting vector, is the representative PDC in this class. It delivers the radioactive payload ¹⁷⁰Lu via the DOTA chelator. Following receptor-mediated endocytosis, it releases β-radiation, inducing DNA damage in cancer cells. It is currently the only FDA-approved PDC.
•   GnRH Receptor Targeting: GnRH receptors are overexpressed in reproductive system cancers like endometrial and prostate cancer. The representative agent AEZS-108 uses a modified GnRH analog as the targeting peptide linked to a doxorubicin payload. It achieved partial or complete remission in some patients in Phase II trials, but its Phase III study was terminated due to a lack of significant progression-free survival improvement, highlighting the clinical translation challenges for receptor-targeting PDCs.
•   Other Key Receptor Targeting: This includes targeting EGFR/HER2 receptors (suitable for breast, gastric cancer) and integrin αvβ6 (suitable for pancreatic cancer). For instance, SG3299, targeting integrin αvβ6 via an RGD motif, demonstrated selective cytotoxicity in pancreatic cancer models, validating the potential of this targeting pathway.

2.2 Receptor-Independent Targeting

This strategy bypasses the need for tumor surface receptor expression by responding to unique physicochemical features of the tumor microenvironment (e.g., acidic pH), offering a new solution for tumors with heterogeneous or low receptor expression.

•   The representative agent CBX-12 employs a pH-sensitive insertion peptide (pHLIP) as the targeting module. Under the acidic conditions of the TME (pH 6.5-7.4), it forms an α-helical structure that directly inserts into the cancer cell membrane, releasing the topoisomerase I inhibitor exatecan via a glutathione-sensitive linker. Its receptor-independent nature has shown promising activity in refractory tumors like platinum-resistant ovarian cancer, advancing rapidly to Phase II trials.
•   Another example, Pepaxto (melphalan flufenamide), releases its payload via aminopeptidase-mediated cleavage, entering tumor cells without requiring receptor binding. Although approved by EMA and MHRA for multiple myeloma, it was withdrawn from the US market after subsequent FDA trials failed to confirm clinical benefit and identified mortality risks, reflecting the safety management challenges for this class of PDCs.

3.Key Components of PDCs: Linkers, Payloads, and Synthesis Technology

3.1 Linkers: Balancing Stability and Selective Release

Linkers must satisfy the dual requirements of "stability in circulation to prevent premature release" and "efficient cleavage and drug release within the tumor." They are mainly categorized into two types:

•   Cleavable Linkers: Predominate current PDC R&D. Types include enzyme-sensitive linkers (e.g., amide bonds, valine-citrulline dipeptide linkers cleaved by tumor-overexpressed cathepsins or aminopeptidases), redox-sensitive linkers (e.g., disulfide bonds responding to high intracellular glutathione), and pH-sensitive linkers (e.g., hydrazone bonds suited for the acidic TME). For example, the glutathione-sensitive linker in CBX-12 enables specific payload release within tumor cells.
•   Non-Cleavable Linkers: Such as thioether bonds, offer greater circulatory stability. The payload is released only after the PDC is internalized and degraded in the lysosome. While this can reduce off-target toxicity, the lack of a "bystander effect" may limit efficacy against heterogeneous tumors, making their current application relatively less common.

3.2 Payloads: Balancing High Potency and Manageable Toxicity

PDC payloads are mainly divided into three categories, with the core requirement being high cytotoxicity and pharmacokinetic properties suitable for targeted delivery:

•   Ultra-Potent Toxins (e.g., Auristatins): Derived from natural products with sub-nanomolar potency, requiring targeted delivery to mitigate systemic toxicity.
•   Classic Chemotherapeutic Agents (e.g., Doxorubicin, Gemcitabine): Targeted delivery aims to reduce off-target effects, potentially overcoming the dose limitations of traditional chemotherapy.
•   Agents with Novel Mechanisms (e.g., Topoisomerase I Inhibitor Exatecan): The PDC platform can improve their pharmacokinetic shortcomings and expand their application scope.

3.3 Synthesis Technology: Ensuring Efficiency and Precision

PDC synthesis primarily relies on Solid-Phase Peptide Synthesis (SPPS) to produce the targeting peptide. Precise conjugation of the peptide, linker, and payload is achieved via click chemistry, thiol-maleimide reactions, etc. Chelation chemistry is crucial for synthesizing radioactive PDCs (e.g., Lutathera) to ensure stable linkage between the payload and the peptide.

 4. Current Status of Clinical Translation for PDCs

The clinical translation of PDCs is characterized by a "rich pipeline but scarce approvals," reflecting both their technological maturity and clinical challenges.

•   Approved Products: Only one product, Lutathera, is FDA-approved (2018) for inoperable or metastatic NETs. Pepaxto, embroiled in efficacy and safety controversies among regulators, is approved only by EMA and MHRA and is not widely used globally.

•   Clinical Pipeline: Approximately 96 PDCs are in clinical development, with 6 in Phase III trials, covering both solid and hematological malignancies. Key candidates include ANG1005 (targeting LRP1 receptor for breast cancer brain metastases) and BT8009 (bicyclic peptide targeting Nectin-4 for urothelial carcinoma), all focusing on unmet clinical needs.

 5. Challenges in PDC R&D and Translation

5.1 Druggability Deficiencies

Peptide carriers are susceptible to proteolytic degradation. Their small size also leads to rapid renal clearance, resulting in short in vivo half-lives. Insufficient circulatory stability of linkers can cause premature payload release, increasing off-target toxicity. For instance, some cleavable linkers are prone to hydrolysis by esterases in the blood, impacting efficacy and safety.

5.2 Clinical Translation Bottlenecks

Some PDCs show promising activity in preclinical models but fail to replicate efficacy in clinical trials due to the complexity of the TME (e.g., fibrotic stroma in pancreatic cancer hindering drug penetration) and patient heterogeneity, as seen in the Phase III failure of AEZS-108. Furthermore, the lack of unified clinical evaluation standards for PDCs, with significant variations in dosing regimens and efficacy endpoints across studies, hampers the comparability of results.

5.3 Manufacturing and Cost Issues

PDC synthesis involves multiple chemical modification and precise conjugation steps, making batch-to-batch consistency control difficult during scale-up. The complexity of SPPS and purification processes leads to high production costs, limiting accessibility.

6. Future Directions for PDC Development

To overcome current technological bottlenecks, the future development of PDCs will rely on technological innovation and interdisciplinary convergence. Key R&D directions include: In structural design, enhancing metabolic stability through peptide backbone modifications (e.g., cyclization, D-amino acid substitution), and developing smart linkers responsive to the TME and multi-targeting peptides to improve tumor specificity and address heterogeneity. Regarding payload types, expansion from traditional cytotoxic drugs to novel agents like immunomodulators and gene therapy drugs is underway, aiming to develop combination strategies like "PDCs + Immunotherapy" to enhance anti-tumor immunity and overcome resistance. Concurrently, artificial intelligence and computational tools (e.g., molecular docking, deep learning) are being widely applied for the rational design of targeting peptides and linkers, accelerating the discovery of highly active and specific candidates, and utilizing ADMET prediction platforms to optimize their pharmacokinetics and safety. Additionally, the introduction of innovative delivery technologies (e.g., nanocarriers, liposomes) aims to further improve tumor-targeting accumulation and stability of PDCs, while the development of oral or topical formulations offers new possibilities for enhancing patient adherence.

7.Summary

Peptide-Drug Conjugates (PDCs), with their advantages of precise targeting, strong tumor penetration, and controllable safety, have emerged as an important new direction in targeted cancer therapy. Their design concept, derived from ADCs, offers greater flexibility and cost advantages. Currently, PDCs have established dual targeting pathways—receptor-dependent and independent—covering various refractory tumors. Although approved products are limited, the rich clinical pipeline and technological innovations lay a solid foundation for their future development.

However, challenges such as insufficient druggability, low clinical translation efficiency, and complex manufacturing processes need to be overcome. In the future, through structural optimization, payload innovation, AI-assisted R&D, and multi-technology integration, PDCs are expected to further enhance efficacy and accessibility, filling the treatment gap between traditional chemotherapy and ADCs, providing superior therapeutic options for cancer patients, and driving continuous innovation in the field of targeted therapy.

Original article：

Armstrong, Amy, et al. "Peptide‐Drug Conjugates: A New Hope for Cancer." Journal of Peptide Science 31.8 (2025): e70040.