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Antibody Drug Conjugate, or ADC, is a complex that connects cytotoxic drugs to monoclonal antibodies that target
The ADC drug, known as the "magic bullet", is mainly composed of three parts (Figure 1): the "anti-personnel munition" small molecule cytotoxic drug (payload), the "guidance system" monoclonal antibody that targets the specific antigen on the surface of the tumor cell, and the linker that connects the two.
Figure 1 Composition of ADC drugsFigure 1 Composition of ADC drugs
On the one hand, ADC drugs continue the characteristics of monoclonal antibody drugs that can be specifically targeted, and at the same time, they avoid the shortcomings of conventional cytotoxic substances that cannot be systematically administered due to excessive toxicity, and can achieve precision treatment, which is one of the
fastest developing drug categories in oncology in recent years.
Since the approval of the first ADC drug, Mylotarg®, as of June 2022, 14 ADC drugs have been approved
for the market worldwide.
In addition, there are currently many ADC drugs in the clinical stage
As a new anti-cancer drug, ADC is leading a new era
of targeted cancer therapy.
Figure 2 Milestones of ADC drugsFigure 2 Milestones of ADC drugs
ADC drug conjugation processADC drug conjugation process
Since ADC is composed of three parts: antibody, cytotoxic drug and linker, the complexity of this structure determines that the preparation process of ADC drug will be more complex
than that of monoclonal antibody and other drugs.
In the preparation process of ADC drugs, it is necessary to comprehensively consider a variety of factors, such as antibodies, linkers, conjugation methods, and the selection of cytotoxic drugs, as well as the drug-antibody ratio, drug load distribution, free drug clearance, etc
These factors are intertwined, and problems in any one link may prevent ADC drugs from achieving good results
Therefore, overly complex preparation processes are one of
the challenges in ADC drug development.
One of the most important quality attributes of ADCs is the average number of conjugate drugs (DAR) , as this determines the "payload" that can be delivered to the tumor, which can directly affect safety and efficacy
Therefore, building an ADC with stable and uniform DAR values is the focus
of process optimization in the ADC coupling step.
In the early coupling optimization process, the DAR value may be affected by factors such as temperature, pH, stirring speed, antibody concentration, dosing amount and dosing rate, which is often challenged
in the process of traditional equipment optimization.
Figure 3 ADC drug conjugation processFigure 3 ADC drug conjugation process
- inaccurate control of parameters;
- parallelism of the DoE optimization process;
- batch-to-batch variation;
- the risk of toxicity from manual dosing;
- The difference
in the amplification process.
in the amplification process.
The fully automated reactor EasyMax optimizes ADC drug conjugation processesThe fully automated reactor EasyMax optimizes ADC drug conjugation processes
METTLER TOLEDO offers an automated platform for ADC coupling process optimization: precise temperature control, automatic programmed dosing and other features ensure high repeatability and stability of the experimental system, and the kettle design is closer to production for linear amplification
The synthesis platform has excellent scalability and can be equipped with online pH sensors to deepen the monitoring and control
of the process development process.
At the same time, the automatic program design greatly avoids the errors caused by manual operation and ensures the consistency
between synthetic batches.
Figure 4 METTLER TOLEDO Automated Chemistry One-Stop Automated Reaction PlatformFigure 4 METTLER TOLEDO Automated Chemistry One-Stop Automated Reaction Platform
The fully automatic reactor EasyMax provides precise temperature and pH control for batch-to-batch stability
The tolerance of the process to temperature changes caused by the addition of solvent DMSO without affecting the DAR value of ADC drugs can be investigated.
iControl software and automatic feeding pump SP-50 can automatically run the small molecule toxin dropping process, and record all process parameters online in real time, which can effectively reduce the error caused by manual operation and the toxicity risk caused by small molecule toxin;
High-quality data ensures reliable DoE results, greatly reduces the amount of experiments, shortens the project cycle, and improves development efficiency.
The reactor design fits the scale-up production scale reactor to provide data support for process scale-up; It can also investigate the influence of different stirring types (magnetic stirring and mechanical stirring) and stirring paddle types on the process under equal volume conditions, and convert the shock or magnetic stirring in the small-scale test process into mechanical stirring, which is convenient for establishing a stirring and mixing model in the later stage.
It has good scalability and can be used with in-line electrodes or in-line spectroscopic probes for online process monitoring
Ensure consistency between scale-up process related data and test data
Software programming automatesSoftware programming automates
Flexible configuration to suit a wide range of reactionsFlexible configuration to suit a wide range of reactions
Multiple types of stirring optionsMultiple types of stirring options
pH control modulepH control module
 Fu Z, Li S, Han S, Shi C, Zhang Y.
Antibody drug conjugate: the "biological missile" for targeted cancer therapy.
Signal Transduct Target Ther.
2022 Mar 22; 7(1):93.
PMID: 35318309; PMCID: PMC8941077.
 Hu X, Lerch TF, Xu A.
Efficient and Selective Bioconjugation Using Surfactants.
2018 Nov 21; 29(11):3667-3676.
Epub 2018 Oct 23.
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