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What is the subtleties of Antibody-drug conjugates

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Antibody-drug conjugates (ADCs) have been the focus of tumor therapy research in recent years. The mechanism of action of ADC is complex and usually requires drug internalization followed by intracellular processing and payload release. Unlike many standard therapies used in oncology, ADC must act on tumor cells for optimal results. The pharmacodynamic properties of ADC make it particularly suitable for the treatment of refractory cancer. Therefore, ADC has naturally become one of the fastest-growing drug categories in oncology.

Medicilon has a high level of expertise and rich experience in ADC projects and can provide pre-clinical efficacy, pharmacokinetics, and safety evaluation services and integrated IND registration services that meet the requirements of new drug declaration in China and the United States for domestic and foreign customers.

> > Read more: Medicilon’s ADC preclinical research solutions

Introduction to ADC drugs

Currently, many ADC drugs have shown activity in the treatment of refractory cancers, thus obtaining approval for many different indications. However, their wider application is limited by various challenges, including toxicity, predictive biomarkers, and more. The efficacy of ADC depends on antibody specificity, linker specificity, and effective load specificity, and each factor affects the complex interaction between ADC, tumor components, and tumor microenvironment (TME).
In recent years, ADC drugs have made continuous breakthroughs. The research and development of ADC drugs have also entered a golden age. In the next 5-10 years, the global market sales of ADC drugs will reach nearly 20 billion US dollars.

ADC structure and mechanism of action

Antibody-drug conjugate (ADC) consists of three main components: antibody, linker, and payload.

ADC structure.png

ADC structure [1]

The typical model hypothesis of ADC action is as follows: the binding of mAb with the target antigen, subsequent internalization, and transport into lysosomes through endosomes. In lysosomes, the linker or antibody of ADC is partially degraded and the payload is released. The payload further plays a role to generate cytotoxicity and kill tumor cells. But the reality is more complex, and there are clear differences between ADCs.

ADC Mechanism of Action.png

ADC Mechanism of Action [1].


The emergence of antibody-based drugs has made substantial progress in the treatment of cancer, autoimmune diseases, cardiovascular diseases, benign blood diseases, and bone diseases Antibody fragments and bispecific antibodies offer promising therapeutic prospects for innovative therapies. Antibodies need to meet the requirements of high specificity, strong target binding ability, low immunogenicity, and low cross-reaction activity to achieve more efficient uptake of ADC drugs by tumor cells and longer half-life of ADC drugs in serum. Immunoglobulin G (IgG) is the main antibody backbone used in ADC. Therefore, IgG is usually selected as the antibody targeting the target antigen for ADC drugs in clinical and preclinical studies.
IgGs can be divided into four subtypes: IgG1, IgG2, IgG3, and IgG4. Among them, IgG1 is the most studied and used ADC antibody because it can better balance the relationship between long blood half-life and strong immune activation, and has a high natural abundance. IgG4 is often used in the design of ADC drugs that require a high immunogenic response due to its low immune activation effect.

Comparison of different IgGs.png

Comparison of different IgGs [2]


Early ADC drug designs were designed to carry traditional chemotherapy drugs with known anticancer activity, such as methotrexate, doxorubicin, or vinca alkaloids. However, these ADCs are not more effective than their small molecule cytotoxic drugs and sometimes require extremely high active doses, which in turn increases toxicity. The data indicated that only a small fraction of the administered dose of tumor-targeted mAbs reached tumor tissue (approximately 0.1%), implying that a more cytotoxic payload was required to achieve a therapeutic effect. Experiment with ADCs carrying highly potent chemotherapeutics such as auristatin, calicheamicins, maytansinoids, and camptothecin analogs, which may be cytotoxic at sub-nanomolar concentrations.

The payload of ADC drugs.png

The payload of ADC drugs[2]

Selection of small molecule drugs

Auristatin includes monomethyl auristatin e (MMAE) and monomethyl auristatin f (MMAF), which are microtubule destabilizers. Calcinomycins, such as ozogamicin, are DNA-binding compounds that cause double-stranded DNA breaks. Maytansinoids, such as DM1, is derived from maytansine and bind to tubulin, thus destroying the dynamic instability of microtubules. Camptothecin analogs, including the exetecan derivative DXD and the irinotecan metabolite SN-38, inhibit topoisomerase I (topo1), leading to DNA fragmentation.
Now when selecting small molecule drugs, the IC50 value of small molecule drugs should be as low as nanomolar level or even picomolar level. In addition to the lower IC50 value, small molecule drugs are usually required, including the following points:

1. It is not easy to cause aggregation of ADC drugs after coupling with antibodies to ensure long circulation time in vivo;

2. The ADC drug itself and after formation should have low immunogenicity;

3. It is stable enough in an aqueous solution (blood) and has a suitable reaction site to be coupled with an antibody through a linker, and its biological activity can still be ensured after coupling;

4. It can be synthesized through a relatively economic process.


Linker technology has made great progress since the early development of ADC. The linker is designed with a dual purpose:

1. Ensuring that the cytotoxic payload is still firmly attached to the antibody portion when the drug is circulated in the plasma. Unstable linkers in the plasma may release the payload prematurely, leading to excessive systemic toxicity and reduced delivery of the payload upon antigen binding at the tumor site. This issue is particularly important considering that many ADCs carry highly efficient cytotoxic payloads with toxic characteristics, which makes them unsuitable for systemic administration.

2. To ensure the effective release of the payload in the tumor, especially in the cancer cells. ADCs that fail to deliver their payloads correctly lose their unique advantages over naked antibodies and traditional cytotoxic drugs.

The ideal linker should be very stable in the blood circulation to avoid the early release of small molecule toxins and damage to normal tissues or cells. At the same time, the payload needs to be released quickly and effectively into the tumor cells.
There are two main types of linkers: cleavable and non-cleavable.

(1)Cleavable linkers can be divided into acid cleavable, reducible, and protease cleavable.

(2)Examples of non-cleavable linkers include thioether linkers (as used in t-dm1) and maleimide-based linkers (as used in belantamab mafodotin). In practical use, the cleavable linker shows different degrees of stability in circulation and will degrade in plasma over time. In contrast, non-cleavable linkers tend to be more stable in plasma but rely on lysosomal degradation of the entire antibody linker construct to release its payload, often resulting in the retention of charged amino acids on the payload, which may affect its function or cell permeability.

The linker of ADC drug.png

The linker of ADC drug [2]

Medicilon can design water-soluble linkers with sugar instead of PEG for highly cytotoxic molecules, and can quickly prepare highly cytotoxic compounds and linkers with bifunctional groups, to realize the rapid connection with toxins and antibodies.

Drug antibody ratio (DAR)

Drug antibody ratio (DAR) is the average number of payload portions attached to each mAb and can be obtained by test methods such as HPLC-MS. DAR has an impact on drug pharmacology and activity, and the DAR value is essential for the later stage of ADC drug development. ADC drugs are ingested by tumor cells in a limited amount during in vivo circulation, so generally higher Dar is beneficial to improve the efficacy. However, the small molecule drugs used in ADC drugs have strong hydrophobicity. When the DAR value is too high, it will cause the accumulation of ADC drugs, resulting in the reduction of circulating half-life in vivo and the increase of toxic and side effects, which leads to the unavailability of too high DAR. Generally, the DAR value of ADC for preclinical and clinical use is in the range of 2-8. To obtain ADC drugs with higher Dar and homogeneity, the antibody can be modified by genetic engineering to have a fixed number of efficient reaction sites for coupling small molecule drugs.

Drug antibody ratio (DAR).png

Drug antibody ratio (DAR) [3]

Summary and Outlook

As a new targeted anticancer drug, ADC combines the advantages of both antibody and small molecule drugs and has huge market prospects. With the development of antibodies, the continuous optimization of linkers, the excavation of high active loads and the continuous improvement of coupling technology, ADC drugs with high efficiency and low toxicity will emerge continuously. If we can better understand and make use of the subtleties of the interaction between ADC and tumor, the real potential of ADC technology will be better developed and more widely used, and ultimately may have a revolutionary impact on the treatment of tumor patients.

[1] Kyoji Tsuchikama, et al. Antibody-drug conjugates: recentadvances in conjugation and linker chemistries.  Protein Cell. 2018Jan; 9(1):33-46.

[2] Joshua Z Drago,et al. Unlockingthe potential of antibody-drug conjugates for cancer therapy.  Nat Rev Clin Oncol.  2021 Jun; 18(6):327-344.

[3]Dan Lu, et al. Semi-mechanistic Multiple-Analyte Pharmacokinetic Model foran Antibody-Drug-Conjugate in Cynomolgus Monkeys. Pharm Res. 2015Jun; 32(6):1907-19.



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