In the era of precision medicine, targeted drug delivery systems have become the core driving force for innovation in cancer therapy. Among these, antibody-drug conjugates (ADCs) stand out as a pioneering breakthrough technology, with multiple drugs successfully launched to validate their immense clinical value. However, as research deepens, peptide-drug conjugates (PDCs) are gaining increasing attention as an emerging, more flexible alternative. For specific R&D projects, choosing between PDC and ADC technology pathways represents a strategic decision impacting development efficiency, costs, and ultimate clinical outcomes. Both technologies share a similar "targeting head-linker-payload" tripartite design philosophy aimed at delivering cytotoxic drugs precisely to diseased cells. Yet they exhibit fundamental differences in molecular size, pharmacokinetics, manufacturing processes, and applicable scenarios. This article systematically compares the technical characteristics, advantages, and limitations of PDCs and ADCs, providing scientific decision-making support for researchers in formulating early-stage project strategies.
Antibody-drug conjugates (ADCs) can be viewed as "precision-guided missiles" that harness the body's own immune system. Their core component is a highly specific, high-affinity monoclonal antibody capable of precisely recognizing and binding to antigens unique to tumor cell surfaces. Through a chemical linker, this antibody is covalently attached to one or more highly cytotoxic small-molecule drugs (the payload). The design philosophy of ADCs is to leverage the antibody's targeting capability to safely deliver chemotherapy drugs—which traditionally cannot be administered at high doses due to systemic toxicity—directly to tumor sites, thereby expanding the therapeutic window. After over two decades of development, ADC technology has matured and is successfully applied in treating both hematologic malignancies and solid tumors.
In contrast, peptide-drug conjugates (PDCs) can be likened to "precise and agile special forces." They utilize short peptide chains (typically composed of 5-30 amino acids) instead of antibodies as the targeting vehicle. These peptide sequences, often identified through technologies like phage display, can specifically bind to receptors highly expressed on tumor cells or tumor blood vessels. PDCs inherit the targeted delivery concept of ADCs, yet their smaller molecular size and simpler chemical structure confer unique properties. Although PDCs entered clinical development later than ADCs, their potential advantages in tumor penetration, manufacturing processes, and cost control position them as a rising force in targeted therapy that cannot be overlooked.
Structurally, PDC and ADC share core design principles yet differ significantly in detail, with these distinctions directly determining their biological behavior. The molecular weight of ADCs typically reaches approximately 150 kDa, representing a complete immunoglobulin G (IgG) structure. While this substantial size ensures excellent serum stability (with a half-life extending to several days or even weeks), it also limits penetration and diffusion into the depths of solid tumors—a phenomenon known as the "tumor barrier."
PDCs, by contrast, possess significantly smaller molecular weights, generally ranging from 1 to 10 kDa—an order of magnitude smaller than ADCs. This size reduction introduces fundamental changes. Antibodies exhibit complex tertiary or even quaternary structures with large, relatively flat binding epitopes, whereas peptides typically form simpler linear or cyclic structures with smaller, deeper binding interfaces. Regarding coupling chemistry, the antibody backbone of ADCs contains numerous lysine and cysteine residues. This results in products with heterogeneous drug loading using traditional coupling techniques, though site-specific coupling technologies are improving this situation. In contrast, PDC peptides feature shorter chains with defined amino acid sequences, facilitating precise control over drug-loading sites through solid-phase synthesis and yielding more uniform conjugates. These structural differences form the foundation for understanding all subsequent pharmacological distinctions between the two.
The mechanisms of action for PDC and ADC begin with the specific binding of their carriers to target sites, but subsequent internalization processes and efficiencies may differ significantly. ADCs rely on the high-affinity binding of their antibody moiety to cell surface antigens, which typically triggers efficient receptor-mediated internalization, engulfing the entire ADC molecule into the cell and directing it toward the endosomal-lysosomal pathway. Within the acidic environment of lysosomes and under the action of abundant hydrolases, the linker cleaves, releasing the cytotoxic payload to induce apoptosis.
PDC mechanisms share similarities, though interactions between their peptide carriers and receptors may exhibit distinct kinetic properties. Peptide-receptor affinity may sometimes be lower than that of antibodies, but this is not necessarily a disadvantage. Excessively high affinity may cause antibodies to become "bound" at tumor peripheries, impeding penetration into core regions (binding site barrier effect). Peptides with moderate affinity may exhibit faster binding/dissociation rates, facilitating more uniform distribution within tumor tissues. Furthermore, peptides may target different receptor types than ADCs. For instance, certain peptides effectively target integrins highly expressed in tumor neovasculature, indirectly inhibiting tumor growth by disrupting blood supply. Some cell-penetrating peptides (CPPs) can even enter cells directly without relying on receptor-mediated internalization pathways, offering additional flexibility in delivery strategies.
The widespread interest in PDC technology stems from its several potential advantages over ADCs, which are particularly well-suited for certain specific drug development scenarios.
The most significant advantage of PDC lies in its exceptional tissue penetration capability due to its small size. The internal tissue structure of solid tumors is exceptionally complex, featuring high-pressure interstitial fluid, dense extracellular matrix, and dysfunctional vascular systems. These factors collectively form a physical barrier that impedes the effective distribution of macromolecular drugs such as ADCs. With a molecular weight significantly smaller than ADCs, PDCs can more readily extravasate from blood vessels and effectively diffuse within the tumor interstitium. This enables more uniform penetration to the tumor core, targeting and eliminating deeply embedded cancer cells. This enhanced penetration capability is particularly significant for treating solid tumors characterized by hypoxia, necrosis, and resistance to conventional therapies.
From a production standpoint, the preparation process for PDC is far simpler, more economical, and more controllable than that for ADC. ADC production relies on complex mammalian cell culture systems (such as CHO cells), involving large-scale cell fermentation, cumbersome downstream purification processes (like protein A chromatography), and a biologically coupled process that is difficult to achieve complete uniformity. The entire cycle is lengthy and costly. In contrast, the peptide backbone of PDCs can be chemically synthesized using mature, efficient solid-phase peptide synthesis methods. This approach facilitates automation, shortens production cycles, and enables precise control over conjugation sites, yielding highly pure, uniform products. This synthetic convenience not only significantly reduces production costs but also better meets the scalability requirements for future commercial manufacturing.
The plasticity of peptide molecules offers tremendous flexibility for drug design. By introducing non-natural amino acids, performing cyclization modifications, or incorporating stabilizing groups (such as polyethylene glycolation), the stability, pharmacokinetic properties, and affinity of PDCs can be systematically optimized. This "engineerable" characteristic enables researchers to conduct detailed structure-activity relationship studies and iterative optimization on PDCs, much like designing small-molecule drugs. In contrast, substantially modifying antibody frameworks presents significantly greater difficulty and risk.
Despite the promising prospects of PDC, ADC remains unshakable at this stage due to its inherent advantages as a platform with extensive clinical validation.
The antibody carrier of ADCs confers a long half-life in the bloodstream (typically measured in weeks), owing to its FcRn-mediated recycling mechanism. This extended half-life allows for longer dosing intervals, improving patient compliance. Simultaneously, monoclonal antibodies typically exhibit high affinity for their target antigens at the picomolar to nanomolar level, ensuring efficient ADC accumulation at the target site. In contrast, small-molecule peptides are rapidly cleared by the kidneys and have shorter half-lives (measured in hours). While modifications can improve this, they generally struggle to match antibody levels. Furthermore, the high affinity of antibodies allows them to remain at the target site for extended periods.
The ADC field has accumulated over two decades of R&D experience and extensive clinical data. To date, more than ten ADC drugs have been approved globally for treating various malignancies including leukemia, lymphoma, breast cancer, and gastric cancer, with their efficacy and safety validated in real-world settings. This substantial portfolio of successful cases provides invaluable reference for subsequent ADC projects, encompassing lessons learned in target selection, linker technology, and payload pairing. In contrast, PDC clinical progress remains in its early stages with fewer approved drugs, and its long-term safety and efficacy require further data support. The technical maturity of ADC platforms and the clarity of regulatory review pathways represent significant advantages for mitigating R&D risks and accelerating project advancement.
Each IgG antibody possesses multiple conjugation sites (typically capable of carrying 4-8 small-molecule drugs), meaning ADCs exhibit high drug-loading capacity and can achieve a higher drug-to-target ratio. Furthermore, the antibody backbone in ADCs (particularly the IgG1 subtype) retains effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). These inherent immune-activating effects synergize with the released cytotoxic drugs to kill tumor cells, forming a complex anti-tumor mechanism. In contrast, PDCs typically carry only 1-2 payloads and lack the ability to activate the immune system.
Both technologies present distinct challenges. Key risks associated with ADCs include:
Limitations of PDCs manifest as:
Choosing between PDC and ADC is not a simple matter of superiority or inferiority, but rather requires comprehensive consideration based on the specific objectives of the project. The following decision matrix can serve as a reference for selection:
Looking ahead, the relationship between PDC and ADC is not one of simple competition or substitution, but rather one of complementarity and synergy. On one hand, PDC technology will continue to be optimized, expanding its application boundaries through novel stabilizing peptides, dual-targeting strategies, and integration with prodrug technologies. On the other hand, ADC technology is also evolving toward "miniaturization," such as ADCs based on single-domain antibodies or scFv fragments, aiming to balance antibody stability with the penetrating power of smaller sizes.
Ultimately, we may witness a convergent paradigm: PDCs, ADCs, and other conjugation formats (such as small molecule-radionuclide conjugates, antibody-oligonucleotide conjugates, etc.) will collectively form a diversified precision drug delivery toolkit tailored to distinct disease types, target characteristics, and clinical requirements. Astute developers will no longer be confined to a single technological approach. Instead, guided by clinical needs as the ultimate objective, they will select or design the most suitable "biological missiles" to deliver the right drug to the right cell at the right time.
1. What are the key differences between PDCs and ADCs?
PDCs use peptides for targeting, while ADCs use antibodies. This affects size, tumor penetration, and drug load.
2. Which has better tumor penetration: PDCs or ADCs?
PDCs are smaller and penetrate tumors more effectively, while ADCs often struggle in dense tumor tissue.
3. What are the advantages of ADCs?
ADCs can carry more payload molecules per conjugate and are already validated in several approved therapies.
Choosing between PDCs and ADCs can be complex. Our team evaluates your project goals and develops tailored PDC strategies that maximize selectivity, scalability, and cost-effectiveness. We help partners adopt the right conjugate technology for their pipeline.
