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The impact of antibody targets on ADC pharmacokinetics

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Tumor treatment is ushering in the era of ADC drugs.

ADC is linked by a powerful cytotoxic payload drug and tumor-targeting antibody by a chemical linker, usually the drug-antibody ratio (DAR) is 3.5-4. The design principle is to directly deliver cytotoxic drugs to the tumor part through antibodies without harming healthy cells.

ADC drugs approved by the FDA (Document 1)
ADC drugs approved by the FDA (Document 1)

ADC drug pharmacokinetics

The original intention of ADC design was to improve the therapeutic window of systemic administration of chemotherapeutics. Previously, its poor permeability and non-selective cytotoxicity resulted in a narrow therapeutic window.

When the ADC binds to the target antigen on the tumor cell surface, it is internalized through receptor-mediated endocytosis, and then degraded in the cell. The payload of the cytotoxic drug is released into the tumor cell, thereby avoiding the production of healthy cells. Kill.

For ADC, it also faces the unique characteristics and development challenges of drug metabolism. ADC molecular weight is about 150KD, distributed in plasma, interstitial fluid and lymph; it binds to FcRn and has a longer plasma retention time; intravenous injection once in 1-4 weeks; due to saturated target binding and clearance, most of them are nonlinear Pharmacokinetics and dose-dependent clearance; however, there are also dose-dependent clearance of some drugs. Theoretically, nonlinearity is directly proportional to the target load on the whole body. The binding of endogenous and exogenous antibodies to FcRn is saturated and may cause non-linearity; although this saturation requires higher doses than treatment.

ADC drugs are taken up by tissue cells through blood vessels
ADC drugs are taken up by tissue cells through blood vessels

Intravenous ADCs transport endothelial cells through pore convection or through blood vessels, and enter tissues through the walls of blood vessels. During this transport process, ADC is protected from lysosomal degradation by binding to FcRn. Passing through the interstitial matrix is slow and unstable. ADC drugs bind to target receptors on the cell membrane surface in the interstitial night and undergo receptor-mediated endocytosis. In cells that do not express FcRn, ADC drugs are internalized and then cleaved by lysosomes to release the loaded cytotoxic drugs. ADC drugs that do not bind to the receptor return to the venous circulation through the lymphatic circulation. In the circulation, macrophages, monocytes and other immune cells express FcγR and swallow ADC drugs. In tissues, ADC drugs can be degraded by non-specific proteases.

Medicilon has undertaken more than 100 IND application biopharmaceutical projects, including monoclonal antibodies, double antibodies, polyclonal antibodies, ADCs, viral vaccines and fusion proteins. As of May 2022, Medicilon has successfully helped 10 ADC drugs to be approved for clinical trails, and has multiple ADC projects under development. 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.

The classic ADC drug pharmacokinetic evaluation includes multiple drug components: conjugated antibody, total antibody (conjugated and unconjugated), free payload, anti-drug antibody (ADA), etc. Like all drugs, the plasma concentration and the effectiveness of the tumor site are only loosely linked.

Plasma protein, which is highly variable between individuals, interferes with the predictive relationship between dose and response. The plasma stability and degree of uncoupling in the circulation can be used to estimate the coupling fraction. The free loaded drug concentration can be used to assess the toxicity of the payload dependent, but this toxicity cannot distinguish the toxicity that occurs after ADC is ingested by normal tissues.

Regarding ADA, due to the use of humanized antibodies and the low immunogenicity of the loaded drugs, the immunogenicity of ADC drugs is not a big problem. In the past few decades, ADC engineering optimization has focused on target selection, Fc receptor interaction, linker technology, and payload selection.

Further development of ADC drugs requires understanding of the tumor site, the characteristics and kinetics of tumor cells, and the impact of tumors on drug distribution and elimination.


ADC antibodies are usually designed to bind to the extracellular domain of the target protein, and then are taken up by receptor-mediated endocytosis and enter tumor cells. This initial binding has a very high affinity, so the characteristics of the target affect the metabolic kinetics of ADC drugs, which is called target-mediated drug disposition (TMDD). TMDD is divided into two observation scales, a small area to observe the penetration of tumor tissue, and a large area to monitor the drug exposure of the whole body.

Key points to be considered for target selection: target expression, internalization, turnover, accessibility, binding affinity, etc.

1. Target-mediated distribution

After injection, the drug is distributed according to the target expression in normal tissues and diseased tissues. The therapeutic dose often reaches the maximum target occupancy rate in the whole body. If the dose is not saturated, the drug is preferentially distributed in the tissues with high perfusion and high permeability, as well as the tissues with high target expression. In order to obtain the best specificity, the load of the target at the tumor site is compared with the whole body load, the higher the better, but usually, the tumor target load accounts for less than 1% of the whole body load.

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Improved strategy

The new target protein of interest is concentrated on the mutated protein in the tumor, so that non-specific uptake by normal tissues will be minimized. There are also studies that pre-inject naked antibodies to patients to bind, partially saturate the target of normal tissues, and then inject ADCs to improve local specificity in tumor tissues and reduce systemic toxicity. However, with this strategy, it is necessary to ensure that after the naked antibody is used, the tumor’s target load is partially unsaturated, so that the ADC drug can reach the tumor and be ingested. This requires a very accurate understanding of tissue perfusion and drug distribution after drug injection. Moreover, the expression level of the target varies greatly from person to person, resulting in a huge difference in the amount of naked antibody used, so this scheme is somewhat impractical. Furthermore, naked antibodies also have biological functions, leading to unpredictable consequences of drug use. Therefore, this program should not be used clinically in the future.

The efficacy of ADC drugs depends on the degree of occupation of the target protein, or the degree of saturation of the target protein.

The accessibility of the target protein: cell-cell density, cell tight junctions, the target protein is a dimer, trimer, etc., will cover the epitope bound by the antibody or form a binding steric hindrance. At this time, the target protein’s Problems with accessibility and problems with drug intake.

2. Target-mediated drug elimination

Target-mediated elimination refers to ADC binding to its target, internalized through receptor-mediated endocytosis, and degradation within the cell. Saturated target-mediated elimination can cause non-linear pharmacokinetics. When the targets are saturated, the elimination follows the zero-order rate, and when they are not saturated, the elimination follows the first-order rate.

The internalization rate of the drug target complex also affects the target-mediated ADC elimination. Unlike Xiaofen drugs, high target-mediated elimination (or target-mediated drug internalization) is necessary for ADC (ADC drug efficacy is related to tumor cell internalization drugs). The size of the antibody drug and the different epitopes of the antibody drug against the antigen may affect the internalization of the antibody drug. ADC drug-mediated target internalization may be related to the initial effectiveness of the drug, but with the rapid removal of tumor cell surface targets, its continued effectiveness is affected.

The extra-cellular domain (ECD) of the membrane-bound target is found in the circulatory system of the patient. The combination of ECD in the blood circulation and the drug to form a complex will accelerate the elimination of the drug, and will accumulate in the liver, causing liver toxicity. Of course, there are also opinions that ECD is more of an indicative marker for advanced patients, rather than its mediated target drug elimination.

3. Binding site barrier effect

TMDD plays a prominent role in a small number of tumors. The barrier effect of the target binding site includes the cumulative effect of target expression, turnover, and the affinity of the drug to penetrate the entire solid tumor.

If the target is expressed abnormally in the tumor tissue and the affinity is high, a large dose of ADC is required to desaturate the available receptors at the edge of the tumor, so that the release of ADC molecules can continue to penetrate deeper layers.

Krogh cylinder radius
Krogh cylinder radius

*Krogh cylinder radius :the Krogh cylinder radius was varied—essentially, a measure of the mean intercapillary distance. Reduced RKrogh values produced tumors that were more accessible to the drug and therefore easier to target, as compared to less vascularized tumors characterized by high RKrogh values.

When the turnover of drug targets is fast, there is a quick replenishment of internalized targets. The only thing that can be modified for the barrier effect of the binding site is the binding affinity. In the tumor microenvironment, the antibody drug is more likely to be captured by the first target contact, rather than penetrate further. Therefore, to optimize the affinity according to the size of the tumor to ensure that there is sufficient affinity for the internalization of the drug, and to allow the drug to penetrate deeper into the tumor, a balance is required.

4. Circulating lymphocyte antigen

If ADC drugs target lymphocyte antigens, such as CD30, CD19, CD20, etc., the pharmacokinetics need to fully consider circulating lymphocytes, because lymphocytes may migrate or circulate to different tissues. Of course, due to the limited amount of clinical samples in Phase I, no significant pharmacokinetic difference between ADC drugs for lymphoma or hematological tumors and ADC for solid tumors has been found. In addition, ADC drugs combined with normal immune cells in the circulation may also activate complement, etc., causing the elimination of these cells.

Editor’s summary

The target of ADC drugs is very important to improve the therapeutic window of chemical drugs. The target itself has a variety of effects on the metabolism of ADC drugs, which are inseparable from drug penetration, distribution, and elimination.


1. Nicolas Joubert et al, Antibody–Drug Conjugates: The Last Decade, Pharmaceuticals 2020, 13, 245; doi:10.3390/ph13090245

2. Paul Malik et al, Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer, Pharm Res DOI 10.1007/s11095-017-2259-3

3.Han TH, Zhao B. Absorption, distribution, metabolism, and excretion considerations for the development of antibody-drug conjugates. Drug Metab Dispos Biol Fate Chem. 2014;42(11):1914–20.

4.Sun X, Ponte JF, Yoder NC, Laleau R, Coccia J, Lanieri L, et al. Effects of drug-antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibody-maytansinoid conjugates. Bioconjug Chem. 2017;28 (5):1371–81.

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