Scientific Corner

Antibody-drug conjugates (ADCs), as a significant breakthrough in tumor-targeted therapy, have therapeutic efficacy that depends not only on the selection of antibodies and toxins but is also directly influenced by the design and performance of the linker. An excellent linker design can ensure the stability of the ADC in vivo and enable precise release at tumor cells, thereby improving therapeutic efficiency and reducing off-target toxicity. This article will systematically explore the critical role of ADC linkers, challenges in development, application scenarios of different types of linkers, optimization strategies, and comprehensive support provided by BOC Sciences in ADC linker development.

Antibody-drug conjugates (ADCs) have become an effective solution for cancer therapy and targeted drug delivery systems. The creation of ADCs requires a sophisticated approach because the carrier antibody determines both therapeutic effectiveness and specificity, which affects the entire treatment outcome. The paper analyzes carrier antibodies' essential roles in ADC development alongside the challenges faced during antibody selection and optimization strategies.

Antibody-drug conjugates (ADCs) represent an innovative cancer treatment approach that merges monoclonal antibodies targeting precision with highly toxic therapeutic drugs. ADC conjugation efficiency measures how effectively antibodies attach to cytotoxic drugs throughout the ADC drug development stage. The procedure demands exact chemical reactions while also guaranteeing a uniform and stable linkage between the antibody and the drug. The conjugation efficiency level determines both the yield and ADC quality, which in turn influences their clinical application effectiveness.

Antibody-Drug Conjugates (ADCs) are complexes that conjugate cytotoxic drugs to monoclonal antibodies. ADC drugs can not only specifically recognize tumor surface antigens through monoclonal antibodies, but also use their own highly efficient small molecule drug toxins to kill tumor target cells. They combine the advantages of targeted drugs and chemotherapy drugs. In the past 20 years, the research and development of ADC drugs has become a hot topic of competition among major pharmaceutical companies. More than 10 ADC drugs have been approved by the FDA, and there are more than 100 ADC drugs in clinical trials or pharmaceutical research and development stages.

The absorption, distribution, metabolism and elimination (ADME) of Antibody-Drug Conjugates (ADCs) drugs are crucial to the understanding of their pharmacokinetic (PK) and PK/PD relationships, which will influence the selection of candidate molecules during drug development. Since the structural composition of ADC drugs includes both macromolecular antibodies and small molecule toxins, a mixed approach may be required to characterize their ADME properties.

Antibody-Drug Conjugates (ADCs) consists of antibodies, linkers and small molecule toxins. While having the advantages of high targeting and high cytotoxicity, the diversity and complexity of ADC structure and the low content of small molecule toxins released in the circulatory system have brought many challenges to its pharmacokinetic research. In ADC molecules, the selection of targets and antibodies is the starting point of ADC drug design and the decisive factor of drug indications. The selected target antigens should usually be expressed at a high level associated with tumors or diseases. The linker should be stable enough during the circulation of ADC in vivo, and ADC drugs should be able to rapidly release small molecule toxins in an efficient and active form after entering the target cells. Small molecule toxins should have an effective killing effect on tumor cells. Targets, antibodies, linkers and other factors will affect the efficacy and safety of ADC drugs, which will be discussed below.

Antibody-Drug Conjugates (ADCs) are a new class of biotherapeutics that typically consist of a cytotoxic payload covalently bound to an antibody via a linker. ADC undergoes continuous decoupling and biotransformation processes in the body, resulting in the formation of complex and structurally heterogeneous mixtures. In addition to decoupled free antibodies and free payloads, there are also ADC molecules conjugated to small molecule drugs to varying degrees. Therefore, it poses great challenges to the development of bioanalytical methods. In order to understand the pharmacokinetic and pharmacodynamic characteristics of ADC drugs in non-clinical and clinical research and development stages, as well as the immunogenicity and safety, different molecular forms of entities such as drug-coupled antibodies, naked antibodies and total antibodies in the body after administration need to be analyzed using different methods. Among them, the biological analysis of total antibodies, conjugated antibodies, free loads and related metabolites runs through the entire process of early discovery/screening, preclinical and clinical of conjugated drugs.

ADC is a complex that conjugates cytotoxic small molecule drugs to monoclonal antibodies through a rationally constructed linker, which can selectively deliver effective cytotoxic drugs into tumors. Currently, the FDA has approved 14 ADC drugs for marketing, and hundreds more are in clinical trials (Table 1).

In the past ten years, the number of Antibody-Drug Conjugates (ADCs) entering clinical trials has steadily increased. Currently, 9 ADCs have been approved, of which 5 are used for hematoma and 4 for solid tumor treatment. After more than 20 years of development, ADC biopharmaceuticals are becoming the main force in the treatment of cancer.

ADC drugs are currently mainly used in the field of tumors. Therefore, antigen targets are required to be highly expressed in tumor cells, but low or not expressed in normal tissues, or only expressed in specific tissue types. When selecting a target, it is necessary to integrate other factors, including the type of cell expressing the antigen, the cycle state of the cell (such as the division or quiescent phase), the expression level of the target, and the accessibility of the target. The target antigen should be present on the cell surface so that circulating mAb can bind to the target cell. At the same time, the antigen target should have a certain endocytosis ability to trigger the transport of the ADC-antigen complex into the cell. However, the number of surface antigens on tumor cells is usually limited, and the internalization process of antigen-antibody complexes is usually inefficient. Therefore, the selection of targets is challenging.

The number of cytotoxic drugs connected to each antibody is the drug-to-antibody ratio (DAR). When the DAR increases, the drug metabolism rate of ADC drugs increases, the half-life decreases, and the systemic toxicity increases. Ideally, when the DAR is 4, the drug has the highest efficacy. Therefore, in actual production, the drugs with DAR less than 2 or DAR greater than 4 are removed through quality control and purification processes to ensure the uniformity of the drugs.

Antibodies are the precise guidance components of ADCs. In theory, molecules that bring effector molecules to the surface of tumor cells can play the role of antibody guidance.

Antibody-Drug Conjugates (ADCs) is a humanized or human monoclonal antibody conjugated to highly cytotoxic small molecules (payloads) through a chemical linker. It is a novel form of treatment with great potential to make a paradigm shift in cancer chemotherapy. Compared with traditional chemotherapy, this new antibody-based molecular platform can selectively deliver effective cytotoxic payloads to target cancer cells, thereby improving efficacy, reducing systemic toxicity, and having better pharmacokinetics (PK)/Pharmacodynamics (PD) and biodistribution. So far, 8 ADC drugs have been approved by the FDA, and about 164 ADCs are in clinical trials.

Antibody-Drug Conjugates (ADCs) combines the high specificity of antibodies with the strong cytotoxicity of small molecule drugs. This combination combines the unique and very sensitive target capabilities of antibodies, which can distinguish healthy tissues from cancerous tissues. It also has the cell-killing ability of cytotoxic drugs, potentially minimizing dose-limiting toxicity, while maximizing the desired therapeutic effect.