Targeted therapy has shown significant potential in cancer treatment by directly targeting specific molecular markers on tumor cells, significantly improving treatment selectivity and efficacy. Targeted therapies work by specifically targeting certain features of tumor cells, such as cell pH, GSH content, cell morphology, and enzyme activity, thereby enhancing therapeutic effects and reducing side effects. There are three main approaches to targeted therapy: first, by inhibiting the expression of specific proteins, such as protein kinases; second, by linking cytotoxic payloads (such as ADCs (Antibody-Drug Conjugates), toxin small molecules, or CAR-T) to overexpressed proteins on tumor cells; third, by using PDCs (Peptide-Drug Conjugates), which guide toxic drugs directly to tumor cells via peptides. Despite their different structures and mechanisms, both ADCs and PDCs aim to increase the precision and effectiveness of cancer treatment while minimizing harm to healthy cells.

Figure 1. Different targeted approaches in cancer therapy are illustrated. These include ADC (antibody-drug conjugate), CAR T (chimeric antigen receptor T cell), and PDC (peptide-drug conjugate). It is important to note that the aminopeptidase is located intracellularly. ( Lindberg J, et al., 2021)

Creative Biogene provides comprehensive tools and services to support innovative research in targeted therapies. Our products are specifically designed to meet the diverse needs of scientists developing ADCs and PDCs, ensuring that your research remains at the forefront of scientific advancement.

Differences between PDCs and ADCs

ADCs consist of three parts: monoclonal antibodies (mAbs), cytotoxic payloads, and linkers. mAbs specifically bind to antigens on the surface of tumor cells, delivering the drug precisely to the affected area. The linker plays a crucial role in connecting the antibody with the drug, while the cytotoxic payload is responsible for killing cancer cells. PDCs replace the antibody with a peptide, with the remaining structure being similar to ADCs. Due to the smaller molecular size of PDC targeting peptides, they generally have better tissue penetration compared to ADCs. However, PDCs may face issues with structural changes and stability due to their relatively complex structure, which needs to be addressed during design and development. Specific differences are illustrated below:

Limitations of PDCs and ADCs

Despite significant successes in some indications, PDCs and ADCs still face several challenges and limitations in clinical development. Firstly, toxicity is a major concern, with potential adverse effects including liver, eye, and lung toxicity, which can significantly impact patient quality of life and limit the feasibility of treatment. Tumor heterogeneity may also restrict efficacy, as different cells within a tumor might not express the same target antigen, leading to suboptimal drug effectiveness in some tumor cells.

Drug delivery efficiency is another issue, as the distribution of PDCs and ADCs in tumor tissue may be uneven, affecting the overall therapeutic efficacy. The stability of the linker is crucial for ensuring drug stability in circulation and effective release within tumor cells. The choice of payload is also critical, but not all types of cytotoxins are suitable as payloads. The complexity of production and manufacturing processes, such as precise control of the drug-to-antibody ratio (DAR) and maintaining the biological activity of the antibody, also adds to the development difficulty. Additionally, the high costs of development and production may limit accessibility to certain patient populations. Finally, due to their complex structure, regulatory review typically requires more data to ensure safety and efficacy, potentially extending the approval process.

Considerations for Targeting Design in PDCs and ADCs

1. Target Specificity

High expression of target antigens is often considered a key indicator of drug efficacy but is not an absolute requirement. The example of T-DXd demonstrates that certain antibody-drug conjugates (ADCs) can show efficacy even in tumors with low or no target expression. This may be because the payload can generate a baseline anti-tumor effect. For instance, the single-cell copy number of HER2 shows that its expression in tumors is significantly higher than in normal tissues, suggesting that low-level expression can still support ADC efficacy in some cases. However, "low-level" expression must be balanced with enhanced efficacy and toxicity issues. Therefore, specific design considerations should include:

Target Specificity: Ideally, targets should be expressed specifically on tumor cell surfaces and absent in normal tissues. In reality, successful targets like HER2 and TROP2 also have some degree of expression in non-tumor tissues, potentially leading to both target-dependent and off-target toxicity, impacting clinical trial progress. To improve specificity, research is exploring antibodies that recognize tumor-specific antigen variants, such as variant III of EGFR, gap TROP2, and glycosylated PD-L1.

Impact on Pharmacokinetics (PK): Expression of targets in non-tumor tissues can affect the pharmacokinetics of the drug. Some antibody drugs have significant clearance mediated by target-mediated drug disposition (TMDD), which is more pronounced at low doses. Higher target expression in non-tumor tissues may reduce drug efficacy. Therefore, target selection should consider reducing TMDD effects by using another more specific target in bispecific ADCs to enhance efficacy.

2. Internalization and Turnover Rate

The internalization rate and turnover rate of ADCs impact treatment efficacy. The rate at which antibodies are internalized from the cell surface can range from minutes to hours. Faster internalization facilitates payload entry into the tumor but may limit ADCs' penetration into the tumor interior, requiring dose optimization for ideal effects. Moderate internalization rates are generally preferable, but experimental validation is needed for existing successful targets' internalization rates and new targets to ensure drug effectiveness.

3. Affinity

High-affinity antibodies may restrict drug distribution and diffusion within tumors, while low-affinity antibodies facilitate more uniform distribution and deeper penetration but may lead to ineffective toxin release. For ADCs, low-affinity antibodies can diffuse further into tissues but may not deliver toxins effectively. Therefore, choosing antibodies should balance affinity, internalization rate, and toxin potency to ensure optimal efficacy.

4. IgG Subtype Selection and Related Factors

The molecular weight of antibodies significantly affects their penetration ability and accumulation in tumor tissues. Although smaller antibodies may offer better penetration, they may also increase toxicity to normal cells. Most successful ADCs use full IgG antibodies, which are larger but do not significantly affect efficacy. Thus, when selecting molecular weight, the balance between drug distribution in tumor tissues and toxicity to normal tissues should be considered.

Innovative Strategies for ADCs and PDCs

Currently, approved and clinically researched ADCs and PDCs have different applications and developmental statuses. Lutathera and Meflufen are two approved PDCs showing good results in treating specific types of cancer. Additionally, many new PDCs are undergoing clinical trials, with researchers continually exploring their potential in treating other diseases. Future innovative strategies include:

1. Bispecific Antibodies or Peptides

Bispecific antibodies (BsAbs) and bispecific peptides (BsPs) are important strategies in innovative drug design. Bispecific antibodies can simultaneously recognize and bind two different antigens, allowing them to target complex biomarkers or multiple targets within the tumor microenvironment. Specifically:

Enhanced Targeting: Bispecific antibodies can simultaneously target specific antigens on tumor cell surfaces and specific cells in the immune system (e.g., T cells), enhancing efficacy through dual mechanisms. For example, CD3 × HER2 bispecific antibodies can bind both HER2 on tumor cells and CD3 on T cells, leading to T cell-mediated tumor cell killing.

Overcoming Drug Resistance: This strategy can avoid the problem of resistance to single target antigens, improving the durability of treatment.

Targeting Complex Biological Environments: In the tumor microenvironment, some bispecific antibodies can modulate multiple cell populations, improving the overall efficacy of the drug.

2. Humanized Antibodies and Site-Specific Conjugation Technology

Humanized Antibodies: By replacing parts of non-human antibodies with human sequences, immunogenicity can be reduced, enhancing drug safety and tolerability. For example, anti-mouse antibodies often trigger immune responses, while humanized antibodies effectively minimize this reaction.

Site-Specific Conjugation Technology: This technology allows precise conjugation of drug payloads to specific sites on antibodies, ensuring drug stability and activity. Compared to traditional non-specific conjugation methods, site-specific conjugation technology improves the accuracy of the drug-to-antibody ratio (DAR), optimizing drug efficacy and safety. For instance, using site-specific techniques to conjugate drugs can ensure payloads are concentrated in the Fc region of the antibody, minimizing the impact on non-target cells.

3. Combination Therapies and Multifunctional Linkers

Combination Therapies: Combining ADCs with other therapeutic methods (e.g., immune checkpoint inhibitors, chemotherapeutic agents, or targeted drugs) can enhance efficacy and overcome the limitations of single therapies. For example, combining ADCs with immune checkpoint inhibitors may enhance anti-tumor effects by activating the immune system.

Multifunctional Linkers: Multifunctional linkers can not only connect drug payloads but also introduce additional functions, such as modulating the immune system or promoting drug distribution within tumors. This design can improve the overall efficacy of ADCs. For instance, linkers with targeting ligands can specifically bind to tumor cells, increasing drug accumulation.

4. Integration with Nanodrug Delivery Systems

Nano-drug Delivery Systems: Nanotechnology plays a significant role in drug delivery by enhancing drug stability, targeting, and penetration within the body. For example, combining ADCs with nanoparticles can increase drug concentration at tumor sites and improve drug biodistribution. Nanocarriers can also enable precise drug release through mechanisms such as pH sensitivity or enzymatic degradation.

Enhanced Drug Penetration: Nano-drug delivery systems can help drugs penetrate biological barriers in tumor tissues, improving efficacy and reducing side effects.

5. Artificial Intelligence (AI) in Drug Design

Drug Design and Screening: AI can analyze large volumes of biological data through data mining and machine learning algorithms to predict potential drug targets and drug molecules. This can accelerate drug discovery and optimization. For example, AI can help predict antibody affinity, stability, and potential side effects, leading to the design of more promising ADCs and PDCs.

Clinical Data Analysis: AI can also analyze clinical trial data to identify biomarkers of treatment response and predict patient responses. This can aid in personalized treatment strategies and improve clinical trial success rates.

Optimizing Drug Formulations: By simulating and optimizing drug formulations, AI can assist in designing more efficient drug-antibody conjugates, improving drug stability and biological activity.

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