In order to more effectively deliver chemotherapy drugs, Small Molecule Drug Conjugates (SMDC), Antibody Drug Conjugates (ADC), and Degradation Antibody Conjugates (DAC) have been successively explored and developed, enhancing the therapeutic index while providing selective delivery. What are their similarities and differences? What are their respective advantages? What is the current status of research and development? What are the prospects? This article analyzes each aspect.
Definitions
SMDC consists of a small molecule drug (usually a highly active chemotherapy drug) and a targeting ligand (usually a small molecule), connected through conjugation technology. This conjugate can selectively deliver the drug to disease-related cells, such as cancer cells, thereby increasing efficacy and reducing toxicity to normal tissues.
ADC is a complex composed of an antibody and a drug (usually a cytotoxic drug). The antibody component specifically targets surface antigens on specific cancer cells, while the drug component is responsible for killing these bound cancer cells. The design goal of ADC is to deliver the drug directly to cancer cells, thereby minimizing the impact on normal cells.
DAC is an emerging drug design that combines the targeting ability of antibodies with small molecules used to induce protein degradation. The antibody portion targets specific proteins, while the degradation agent prompts the cell’s degradation system to recognize and eliminate these proteins. The purpose of DAC is to treat diseases by targeting and degrading pathological proteins, such as degrading key proteins on the surface of tumor cells in cancer treatment.
Common Features of SMDC, ADC, and DAC
SMDC, ADC, and DAC all utilize advanced structure optimization techniques, combining the active ingredients of drugs with targeted strategies that enhance drug specificity, providing more precise and effective methods for disease treatment.
Targeting: SMDC, ADC, and DAC all possess targeting capabilities, using specific molecules (antibodies or small molecules) to precisely target disease-related cells or proteins. This targeting reduces the impact on normal cells, enhancing the specificity and effectiveness of treatment.
Composition of Conjugates: They are all composite drugs formed by the combination of two or more different components. Whether SMDC, ADC, or DAC, they include active ingredients for treatment (such as chemotherapy drugs or degradation agents) and guiding molecules (such as antibodies or small molecules) to direct the drug to specific targets.
Mainly Used for Cancer Treatment: SMDC, ADC, and DAC are primarily used for cancer treatment. They reduce tumor growth or promote the death of tumor cells by targeting cancer cells or specific proteins associated with cancer progression.
Innovative Biotechnological Products: SMDC, ADC, and DAC are products of recent biotechnological developments, representing advanced technologies and innovative approaches in drug discovery and cancer treatment.
Part of Personalized Medicine: The development and use of these drugs align with the trend of personalized medicine, selecting the most suitable treatment method based on the specific pathological characteristics and gene expression of individual patients.
Unique Advantages of SMDC, ADC, and DAC
The three types of drug conjugates share common advantages in improving drug targeting, reducing side effects, and treating refractory diseases. However, each conjugate has its unique advantages, allowing them to play crucial roles in different treatment scenarios.
Featured Services at BOC Sciences
| Name | Description |
| Lys Conjugation | Currently, lysine has been extensively studied in many bioconjugation applications, including the synthesis of antibody-drug conjugates (ADCs), drug delivery, and antimicrobial vaccines. |
| Cys Conjugation | The cysteine conjugation strategy is based on the reaction between cysteine residues of antibodies and specific thio groups anchored on linkers. |
| Unnatural Amino Acid Conjugation | Unnatural amino acid (uAA) conjugation refers to the process of chemically linking or conjugating unnatural amino acids to antibody, protein or peptide sequences. |
| Site-Specific Conjugation | Site-specific conjugation of antibody-drug conjugates (ADCs) refers to the process of attaching drug molecules to specific sites on antibody molecules. |
| Disulfide Conjugation | Disulfide conjugation is a chemical process that involves the formation of a covalent bond between two molecules through a disulfide bridge. |
| Enzymatic Conjugation | Enzymatic conjugation involves modification of an antibody or linker molecule to introduce site-specific attachment points for enzymes. |
| Small Molecule-Drug Conjugates | As a leading supplier of small molecule drug development and bioconjugation, BOC Sciences has launched a new SMDC one-stop platform. |
| XDC Bioconjugation | As a drug discovery service provider, BOC Sciences offers a complete category of X-Drug conjugates (XDCs). |
Common Advantages
Targeted Therapy: All three conjugates can provide more precise targeted treatment, effectively locating lesion cells compared to traditional therapies, and minimizing damage to normal cells.
Reduced Side Effects: Due to their targeting capabilities, these conjugates can enhance drug efficacy while reducing toxicity and side effects.
Treatment of Refractory Diseases: They offer new approaches to treating some refractory diseases, such as certain types of cancer.
Special Advantages of SMDC
Small Molecule Characteristics: The small molecule nature of SMDC allows for easier penetration into the interior of cells to target intracellular points.
Cost Advantage: Compared to ADC and DAC, SMDC typically has lower production costs, making it more suitable for large-scale production.
Special Advantages of ADC
High Specificity: The highly specific antibody component enables ADC to precisely target specific cell surface antigens.
High Drug Payload: ADC can carry higher doses of drugs, enhancing therapeutic effectiveness.
Wide Applicability: ADC has widespread applications in cancer treatment, with several ADC drugs already on the market or in development.
Special Advantages of DAC
Novel Mechanism: DAC works by degrading target proteins, presenting a new therapeutic strategy distinct from traditional drug mechanisms.
Resistance Avoidance: Treating diseases by degrading target proteins may help avoid resistance issues associated with certain drugs.
Broad Applicability: In theory, DAC can target a variety of different protein targets, offering a wide range of potential applications.
Design and Mechanism Comparison of SMDC, ADC, and DAC
These three drugs exhibit significant differences in carrier type, mechanism of action, drug release, and clinical applications.
Carrier Type
SMDC: Utilizes small molecule compounds as carriers, which can more easily penetrate cell membranes and tissue barriers.
ADC: Employs antibodies as carriers, which are large molecular biological agents capable of specifically recognizing and binding to particular antigens.
DAC: Also uses antibodies as carriers, but its purpose is to deliver attached degradation agents to specific proteins, triggering their degradation.
Mechanism of Action
SMDC: Delivers drugs into cells through the high permeability of small molecules, typically targeting intracellular sites.
ADC: Directly delivers chemotherapy drugs to cancer cells through the targeting specificity of antibodies. The antibody identifies and binds to specific antigens on the cancer cell surface, leading to internalization, drug release, and subsequent killing of cancer cells.
DAC: Recognizes and binds to specific cell surface proteins through antibodies, then triggers the protein degradation mechanism inside cells using the attached degradation agent, resulting in the degradation of the target protein.
Drug Release and Mechanism of Activity
SMDC: Drug release relies on the intracellular penetration of small molecule carriers, which enhances drug distribution and permeability in the body, allowing the drug to reach the target more effectively.
ADC: Drug release depends on the binding and internalization of antibodies with cancer cells. The antibody delivers the drug directly to targeted cancer cells, and the drug is released inside the cells, commonly used to kill cancer cells.
DAC: The mechanism of activity is based on the degradation agent-induced degradation of the target protein.
Clinical Applications and Treatment Targets
SMDC: Suitable for situations requiring drug penetration into cells or tissues, such as certain types of cancers.
ADC: Primarily used in cancer treatment, especially in scenarios requiring precise targeting of tumor cells.
DAC: Mainly employed in treating cancer or other diseases by degrading key proteins.
Facing Different Research and Development Challenges
Challenges in SMDC Development
Targeting Specificity: One of the challenges in SMDC development is ensuring that the drug accurately targets and acts on specific pathological cells rather than normal cells.
Drug Release Mechanism: Developing an effective drug release mechanism to release the drug within target cells at an appropriate rate and quantity is also a significant challenge.
Toxicity and Side Effects: Balancing the efficacy of the drug with the toxicity risk to normal tissues is essential to minimize side effects.
Synthesis and Production: SMDC synthesis is complex and costly, requiring optimization of the production process to enhance efficiency and reduce costs.
Challenges in ADC Development
Structural Optimization: The key to reducing “on-target, off-tumor” toxicity lies in the differentiation of tumor-associated antigens (TAAs) between tumor cells and normal tissues. Finding more ideal targets is a common direction for scientists in future development. The “bystander effect” is a characteristic that successful ADCs generally possess, and it is an important factor in personalized ADC design. Balancing target efficacy and bystander effects remains a challenge. Current approved ADC payloads are mainly concentrated in two categories, and the development of more effective payloads is ongoing. Additionally, the optimal Drug-Antibody Ratio (DAR) has not been established. There is currently a mismatch between administration time and half-life, and optimizing the exposure-response relationship of the drug further awaits clarification.
Clinical Applications: Unacceptable toxicity remains a major obstacle in developing new drugs. Improving the prediction of severe adverse events is another approach to reduce premature drug discontinuation. Managing the toxicity of novel drugs requires long-term efforts. As the use of ADCs in clinical settings increases, cost-effectiveness will become an increasingly important consideration. The competitive landscape of ADCs compared to other antigen-specific immunotherapy approaches is still unknown. Additionally, finding new biomarkers to guide the clinical application of ADCs is a key and challenging focus. Similar to other anti-tumor drugs, most patients experiencing initial relief with ADC treatment in the late stages will eventually undergo tumor progression. However, the mechanisms of ADC resistance, which may be more complex compared to other anti-tumor drugs, are still unclear, presenting an unavoidable challenge.
Development Challenges of DAC
Selection of Target Proteins: Choosing the right target protein is crucial, ensuring that it plays a significant role in the disease.
Design and Stability of Linkers: Designing effective and stable linkers is essential to enable precise targeting and promote the degradation of target proteins. Due to the relatively weaker nature of hybrid degraders compared to cytotoxic ADC payloads, higher payload may be needed to achieve similar efficacy (i.e., DAR value greater than 4). Due to their hybrid nature, DAC PROTAC payloads are typically larger or more lipophilic than the cytotoxic molecules of ADCs, especially cell-penetrating molecules. When PROTAC is attached to an antibody, these differences may amplify aggregation and pharmacokinetic issues, possibly requiring new linker designs and coupling methods different from those used in the ADC field.
Intracellular Degradation Mechanisms: Understanding and utilizing intracellular degradation mechanisms are necessary to ensure the drug’s effectiveness.
Safety and Side Effects: Considering that DAC may affect the balance of multiple proteins within cells, safety and potential side effects are important considerations.
Other challenges that may need to be addressed in DAC design include: (1) the good stability of DAC payloads in the lysosomal environment, (2) the ability of payloads to effectively escape the lysosomal compartment, and (3) the tendency of payloads to produce bystander effects. The last two characteristics may be influenced by the cell permeability of the degrader itself.
Overall, all three drug conjugates need to consider various factors such as targeting, drug release, stability, safety, and production efficiency in the development process. With the progress of technology and deeper research, these challenges are expected to be gradually overcome.
SMDCs, ADCs, and DACs form a network of drug conjugates with a promising future in the field of medicine. They exhibit tremendous potential in treating various diseases, especially cancer, each with its unique advantages. With continuous advancements in synthetic technology, coupling techniques, targeting technology, and structural optimization, efficacy and safety are expected to improve further. ADCs have already established a significant position in cancer treatment, and their market size is expected to continue growing. The unique and novel treatment mechanism of DACs makes them potentially effective in treating various diseases related to target proteins, including those traditionally challenging to treat. DACs have broad potential applicability and may provide new treatment options for refractory diseases, addressing certain drug resistance issues and offering new therapeutic choices for challenging conditions.