Antibody-drug conjugates (ADCs) are a family of targeted therapeutic agents for the treatment of cancer. Compared to traditional small-molecule approaches, ADCs offer enhanced targeting of cancer cells along with reduced toxic side effects, making them an attractive prospect for the field of oncology.
An antibody-drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker. As all these components affect the ADC performance in equal measure, their optimisation is essential for the development of successful conjugates.
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It has taken a while for this field to take off, but to date, over 100 ADCs are under clinical development. Since December 2021, after several decades of efforts to optimise their key components, a total of 14 ADC drugs have received the marketing approval in different countries worldwide. Coincidently, half of the approved ADCs are mainly used against haematological malignancies, the rest being prescribed by and large for solid tumours.
Medicilon is an integrated contract research organisation (CRO) providing comprehensive one-step new drug R&D for pharmaceutical companies and scientific research institutions around the world. Since May 2022, Medicilon has successfully assisted no less than ten ADC drugs on their path to approval for clinical use, and it’s committed to continuously improving the research capabilities of ADC drugs. As a matter of fact, half of these drugs target the protein HER2 (human epidermal growth factor receptor 2), member of the HER family of membrane tyrosine kinases, developed for many years as an important target in breast cancer treatment.
The design idea of the ADC drugs is to couple antibodies with cytotoxic drugs, to simultaneously exert the high specificity of antibodies and the high toxicity of cytotoxic small molecules. The emergence of ADC drugs fills the gap between antibody drugs and traditional chemotherapeutic drugs, increasing the specificity of drugs and improving the therapeutic window.
Medicilon ADC R&D Service Platform
Each ADC R&D project is its own challenge due to the varieties in the assembly of ADC molecules. With this concept in mind, Medicilon promises careful planning, meticulous execution and accurate results through years of practical experience and effective communication with our clients.
Mechanism of Action of ADCs
When designing an ideal ADC, it’s essential to understand the mechanism of action, for the purpose of identifying the desired features of each of its three components: monoclonal antibody, linker, and cytotoxic small molecule drug (small molecule drugs are linked to monoclonal antibodies through coupling chains).
An ideal ADC is one that retains the selectivity and killing capacity of a mAb while still being able to release the cytotoxic drug in quantities large enough to kill tumour cells. However, each of the steps involved in the mechanism of action is associated with unique challenges that complicate the design of ADCs. The mAb binds to cell-surface antigens expressed on target cells, is internalised via endocytosis, and then transported to the lysosome, where proteases degrade the ADC. Subsequently, the payload is released and diffuses into the cytoplasm, resulting in cell death.
Compared with traditional tumour treatment methods (radiotherapy and chemotherapy), ADC drugs have fewer side effects and stronger effects on tumour 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 tumour cells, but also ensure that it can trigger endocytosis after binding to the antibody to facilitate the transport of cytotoxins into tumour cells. Therefore, the selection of targets is challenging and extremely important.
With more than 18 years of experience in new drug R&D, Medicilon specialises in the development and validation of analysis methods for different targets and can effectively analyse the expression level and accessibility of targets according to specific needs, providing constructive suggestions for target selection.
Essential to the efficacy of ADCs, the selection of highly specific antibodies can greatly reduce the off-target effects of ADC drugs, avoiding the binding of antibodies to the free antigens in the circulation, leading to systemic toxicity, and as a result improving the efficacy and safety of drugs.
When screening for ADC drug antibodies, there is a phenomenon that must be addressed, the so-called “bystander effect”. The bystander effect refers to the fact that some ADCs also exert an antitumor activity on other tumour cells surrounding the target antigen tumour cells, regardless of the target antigen expression status of these cells. The bystander killing occurs either because of the release of cytotoxins before the ADC internalisation or the extracellular diffusion of cytotoxins through the cell membrane. In both cases, the drug is then taken up by and kills surrounding or bystander cells, which themselves may or may not express the ADC target antigen.
In fact, the bystander effect acts like a double-edged sword in the ADC drug development: whilst is beneficial to the ADC efficacy against tumours with heterogeneous expression of target antigens (such as Her2), it may also cause non-tumour tissue death due to toxicity.
Only to contend with the bystander effect, in Medicilon”weaponry” there are more than 200 cancer cell lines which can be selected for the cells with positive and negative expression of ADC target. And the company has a strong capability for cell labelling and further FACS-based cell viability analysis.
With the continuous development of ADC drugs, in an effort to reduce the rejection of foreign proteins such as ADC antibodies by the human immune system, humanised antibodies are widely used, but this does not mean that the development of ADC drugs can skip the determination of immunogenicity.
The immunogenicity test represents 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 can also affect the efficacy and safety of ADC drugs and it’s considered a major hurdle to overcome in the development of ADC drugs.
All current ADC antibodies are IgG molecules due to their high affinity for the target antigen and long half-life in the blood. Compared with other IgG molecules, IgG1 has proved to have better binding activity and easier production, representing the first choice in the ADC drug development at the moment.
The screening of antibodies needs to consider the following factors: specific binding, the endocytosis efficiency of the ADC drug mediated by the antigen-antibody complex, and the accurate localisation in cells after endocytosis (such as lysosomes). In addition, the modification of antibodies, such as glycosylation, modification of antibody constant regions or modification of attachment sites, can help to improve the properties and efficacy of drugs.
The four major platforms of Medicilon immunogenicity research provide a variety of technical solutions for antibody immunogenicity testing, to meet the different needs of the
customers first and foremost, but also as a means to ensure the accuracy and effectiveness of ADC drug antibody screening results.
The linker, the part of the ADC drug that connects the antibody and the cytotoxin, may seem insignificant, but it’s another 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 tumour cells and 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, and each of them comes with advantages and disadvantages. In this regard, the Medicilon team is combining the action sites and indications of the ADC drugs developed, giving reasonable and effective suggestions based on the existing linker system, and verifying the effectiveness with experimental results.
The amount and type of cytotoxins carried by antibodies will also have a huge impact on the effect of ADC drugs, but Medicilon can effectively solve the issue of cytotoxin selection.
In the molecular library of ADC payloads, Medicilon’s 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 customised and synthesized, on demand.
Medicilon’s ADC preclinical solution can help customers sail through all the research and development challenges and complexities, and at the same time providing preclinical research and application services that comply with GLP specifications, thus completing the preclinical research and application of antibodies and ADC drugs all in one-stop.
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 the clinical trial design.
Medicilon is committed to providing customers with mature tumour models for evaluating ADC in vivo efficacy, completing the modelling, and feeding of various model animals in an AAALAC-certified environment, and completing relevant pharmacodynamic evaluations with high GLP-like standards test. To date, Medicilon has established nearly 300 tumour evaluation models in six categories, which can cover most conventional tumour diseases.
ADC Pharmacokinetics Evaluation
Due to the complex composition of ADC drugs, their PK properties must be evaluated with multiple analytes, hence 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, delivering reliable and high-quality PK data by analysing plasma/serum samples collected in animals. Thanks to advanced experimental equipment and high-quality and stable analytical methods, Medicilon can not only 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.
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 hyperglycaemia. To minimise the toxicity risk of ADC drugs, toxicity testing and safety evaluation are particularly important.
Medicilon follows ICH guidelines S6 and S9, customises a personalised 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, including single and repeated dose toxicity test (accompanied by a toxicokinetic study), safety, pharmacology (including tissue cross-reaction) and immunogenicity testing.
Medicilon has in-depth exchanges with customers in the formulation of the preclinical integrated research plan of ADC. The backbone of scientific research, it combines the characteristics of each case with years of practical experience and technical accumulation, carefully submitting high-quality experimental plans and results to customers.
To date, ADC drugs have undergone three generations of technological changes. The application of the third-generation fixed-point coupling technology has made ADC drugs more uniform, stable, and effective, and increasingly better results in treatment have been achieved.
That’s why, currently, an efficient ADC drug needs to comprehensively consider antibodies (target and antibody screening optimisation), small molecule drugs, linkers and linking technologies, along with their most effective combinations.
Medicilon UK office is based in Cambridge, which is close to serve UK and European clients.
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