On April 27, ENHERTU, an innovative ADC drug jointly developed by Daiichi Sankyo Co., Ltd. and AstraZeneca for the treatment of HER2-low breast cancer, was granted Breakthrough Therapy Designation (BTD) by the FDA. Enhertu has now received five Breakthrough Therapy Designations, three for breast cancer, one for lung cancer and one for gastric cancer. At the same time, on April 24, ENHERTU was also included in the priority review by CDE, and its market potential is huge.
Under the tide of ADC drugs, various enterprises are enthusiastic and cooperate continuously to overcome the problems of ADC drug research and development. In April 2022 alone, ADC drugs from several pharmaceutical companies, such as Yilian Biologics, Connoia, Xinma Biologics, were approved, and which indications are mainly for solid tumors.
As a professional biopharmaceutical preclinical comprehensive R&D service CRO, Medicilon is also continuously improving the research capabilities of
ADC drugs. As of May 2022, Medicilon has successfully helped
10 ADC drugs to be approved for clinical use, half of which target HER2.
Medicilon helps ADC drug results:
| Target | HER2 | ERBB2 | TROP2 | Muc1 | FRα | Undisclosed |
| Quantity | 5 | 1 | 1 | 1 | 1 | 1 |
Four breakthroughs in ADC drug R&D
ADC is composed of a monoclonal antibody (Antibody) targeting a specific antigen or tumor-associated antigen, a cytotoxin (Payload), and a linker (Linker) connecting the antibody and the cytotoxin. This structure allows ADC drugs to combine the powerful killing effect of traditional small molecule chemotherapy with the tumor targeting of antibody drugs. Among them, the antibody is responsible for finding tumor cells, the linker allows the antibody to be entrained, and the toxic small molecules are brought into the tumor cells,and the cytotoxin is a sharp sword to kill the tumor cells.
At the same time, due to its unique mechanism of action, the research and development of ADC drugs has high technical barriers, so it is necessary to focus on the following four breakthroughs:
01 Target
ADC drugs target tumor cells to avoid damage to normal tissues of the human body on the basis of the high specificity of antibody drugs. Compared with traditional tumor treatment methods (radiotherapy and chemotherapy), ADC drugs have fewer side effects and have stronger effects on tumor cells. Limited by the high specificity of the ADC drug antigen and the comprehensive factors that satisfy the effect of the ADC drug, the target must not only exist on the surface of tumor cells, but also ensure that it can trigger endocytosis after binding to the antibody to facilitate the transport of cytotoxins into tumor cells. Therefore, the selection of targets is challenging.
Medicilon has rich experience in developing and validating analysis methods for different targets, and can effectively analyze the expression level and accessibility of targets according to needs, and provide constructive suggestions for target selection.
02 Antibody
Antibodies of ADC drugs have high specificity, which is the key to the efficacy of ADC. The selection of highly specific antibodies can greatly reduce the off-target effects of ADC drugs, avoid the binding of antibodies to free antigens in the circulation, and lead to systemic toxicity, thereby improving the efficacy and safety of drugs.
When screening ADC drug antibodies, a phenomenon that has to be faced - bystander effect. Bystander effect refers to the fact that some ADCs also have antitumor activity on other tumor cells surrounding the target antigen tumor cells, regardless of the target antigen expression status of these cells. The causes of this are mainly divided into two types: the release of cytotoxins before ADC internalization and the extracellular diffusion of cytotoxins through the cell membrane. The bystander effect is a double-edged sword for ADC drug development, which is beneficial to the ADC efficacy against tumors with heterogeneous expression of target antigens (such as Her2), but may also cause non-tumor tissue death due to toxicity.
For the bystander effect, the Medicilon antibody screening platform has more than 200 cancer cells with positive and negative expression of selected ADC target proteins, which can analyze the release and release of ADC drugs through powerful fluorescent cell labeling and further analysis of cell viability based on flow cytometry. Diffusion situation, evaluate the degree of bystander effect of ADC drugs, and help screen out the optimal antibody according to the actual situation.
At the same time, with the continuous development of ADC drugs, in order to reduce the rejection of foreign proteins such as ADC antibodies by the human immune system, humanized antibodies are widely used, but this does not mean that the development of ADC drugs can skip the determination of immunogenicity . The immunogenicity test is an important measurement index for biological drugs, and it needs to be controlled at all stages of the research. The immunogenicity of biopharmaceuticals may lead to rapid clearance of ADCs in vivo, affecting their PK profiles and related assays. Immunogenicity may also affect the efficacy and safety of ADC drugs, which is a mountain that has to be climbed in the development of ADC drugs.
In order to ensure the accuracy and effectiveness of ADC drug antibody screening results, the four major platforms of Medicilon immunogenicity research provide a variety of technical solutions for antibody immunogenicity testing to meet the different needs of customers to the greatest extent.
03 Linker
The linker is the part of the ADC drug that connects the antibody and the cytotoxin. It seems insignificant, but it is a key factor in determining the safety and clinical efficacy of the ADC drug. When the ADC drug enters the human body, the failed linker will be cleaved and decomposed in the blood, resulting in the early release of cytotoxins before entering the tumor cells, resulting in serious systemic toxic side effects. Therefore, the stability of the linker is critical. The types of linkers are divided into cleavable linkers and non-cleavable linkers, each of which has advantages and disadvantages.
In order to solve this problem, the Medicilon team combined the action sites and indications of the ADC drugs developed, and gave reasonable and effective suggestions based on the existing linker system, and verified the effectiveness with experimental results.
| Linker | Type | Mechanism | Advantage | Disadvantage |
| Cleavable Linker | Hydrazone Bond | Acid Dependence | Hydrophilic Payload Traceless Release | Unstable |
| Disulfide bond | Redox | Intracellular efficient release |
| Peptide bond | hydrolase cleavage |
| Non-cleavable linker | Thioether bond | Lysosomal cleavage | More stable and safe in blood | Non-cleavable linker will remain on cytotoxin and affect drug efficacy |
04 Cytotoxic Payload
Cytotoxin is a key factor determining the effect of ADC drugs. The amount and type of cytotoxins carried by antibodies will have a huge impact on the effect of ADC drugs.
In this regard, Medicilon's ADC payloads molecular library can effectively solve the problem of cytotoxin selection. In the molecular library of ADC payloads, the Medicilon drug discovery team has accumulated a variety of different mechanisms of action and different types of cytotoxins for customers to choose from. At the same time, one or several ADC cytotoxins can be customized and synthesized to meet the needs of customers. on demand.
√Tubulin inhibitors/stability disruptors
√DNA synthesis inhibitor
√ Topoisomerase inhibitors and RNA polymerase II inhibitors
MEDICILON
Medicilon's ADC preclinical solution can help you break through the above-mentioned research and development problems, and at the same time provide preclinical research and application services that comply with GLP specifications, and complete the preclinical research and application of antibodies and ADC drugs in one-stop.
01
ADC Pharmacodynamic Evaluation
In vivo efficacy test in animals is an important pharmacological parameter in ADC research, which directly reflects the efficacy of ADC and affects clinical trial design.
Medicilon is committed to providing customers with mature tumor models for evaluating ADC in vivo efficacy, completing the modeling and feeding of various model animals in an AAALAC-certified environment, and completing relevant pharmacodynamic evaluations with high GLP-like standards test. At present, Medicilon has established nearly 300 tumor evaluation models in six categories, which can cover most conventional tumor diseases.
02
ADC Pharmacokinetic Evaluation
Due to the complex composition of ADC drugs, their PK properties must be evaluated with multiple analytes, thus increasing the difficulty of analysis.
Medicilon provides a variety of high-quality test methods for various ADC component analytes in the in vivo analysis of ADC drugs, and provides customers with reliable and high-quality PK data by analyzing plasma/serum samples collected in animals. Thanks to advanced experimental equipment and high-quality and stable analytical methods, not only can we benchmark against international experimental standards and obtain results that are highly consistent with the conclusions of American laboratories, but also ultimately obtain test results that are well correlated with ADC and total antibodies.
03
ADC toxicokinetics and safety evaluation
The toxicokinetics of ADC drugs is directly related to cytotoxicity. The known side effects of ADC drugs include peripheral neuropathy, skin and ocular toxicity, and symptoms such as hyperglycemia. To minimize the toxicity risk of ADC drugs, toxicity testing and safety evaluation are particularly important.
Medicilon follows ICH guidelines S6 and S9, customizes a personalized safety evaluation plan based on the specific circumstances of each project, and provides safety evaluation services that comply with international GLP standards such as NMPA, FDA, OECD, TGA, etc., including single and Repeated dose toxicity test (accompanied by toxicokinetic study), safety pharmacology (including tissue cross-reaction), immunogenicity test.
Medicilon has in-depth exchanges with customers in the formulation of the preclinical integrated research plan of ADC. The backbone of scientific research combines the characteristics of each case with years of practical experience and technical accumulation, and carefully submits high-quality experimental plans and results to customers. .
In the future, Medicilon looks forward to overcoming more scientific research problems, assisting more customers in the research and development of ADC drugs, riding the wind and waves in the ADC drug market boom, and opening the door of hope for cancer patients around the world!
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