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Explain the clinical pharmacology of ADC in detail
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Explain the clinical pharmacology of ADC in detail.
Antibody-drug conjugates ( ADCs ) are formed by linking monoclonal antibodies targeting specific antigens with small-molecule cytotoxic drugs through a linker, which has both the powerful killing effect of traditional small-molecule chemotherapy and the tumor targeting of antibody drugs.
Since the first ADC ( Gemtuzumab-ozogamicin (trade name: Mylotarg) ) was approved for the treatment of CD33-positive acute myeloid leukemia, several ADCs have been developed for the treatment of cancer.
From selecting the right antibody to the final product, the entire ADC development process is a daunting and challenging task.
Clinical pharmacology is one of the most important tools in drug development, and leveraging this tool can help find the optimal dosage of a product to maintain its safety and efficacy in a patient population.
Unlike other small or large molecules that typically measure only one moiety and/or metabolite for pharmacokinetic analysis, ADCs require measurement of multiple moieties to characterize their PK properties.
Therefore, an in-depth understanding of the clinical pharmacology of ADCs is critical for the selection of safe and effective doses in the patient population.
Overview of the Pharmacokinetics of ADCs
Pharmacokinetics is an integral part of clinical pharmacology and the modern drug development process.
The main purpose of a pharmacokinetic study is to obtain information about the drug’s absorption, volume of distribution, clearance, half-life, accumulation after multiple doses, various disease states, and the effects of age, weight, and gender on drug pharmacokinetics Information.
These pharmacokinetic parameters can be used to design optimal dosing regimens for patients.
It should be recognized that, unlike small molecules and therapeutic proteins ( antibodies or fusion proteins ), the PK of ADCs is very complex because ADCs consist of several components.
Not only the PK of the mAb, but also the PK of the cytotoxic molecule and the physicochemical properties of the binding should be considered.
Since the molecular weight of monoclonal antibody accounts for more than 90%, the PK of different components of ADC is greatly affected by its PK.
The PK profile of the total antibody ( ADC+mAb ) provides the best assessment of ADC stability and integrity.
Conjugates and conjugation sites also play important roles in maintaining the stability and PK of ADCs.
The following table lists the properties of FDA-approved ADCs and their PKs.
Pharmacokinetics of ADCs
In general, following administration, four processes are involved in the body. These processes are absorption, distribution, metabolism and clearance.
Most antibodies are usually administered by the intravenous or infusion route, but antibodies can also be administered by the subcutaneous ( SC ) route.
However, for ADCs, the current route of administration is intravenous injection or infusion.
SC administration may not be suitable for ADCs due to the response to the cytotoxic payload and local deposition of cytotoxic substances.
The distribution of a drug in the body can be described by the volume of distribution.
Due to their size and polarity, the distribution of antibodies and ADCs is usually confined to the vascular and interstitial spaces.
The initial distribution of ADCs is generally limited to blood vessels, and their volume of distribution is generally equal to blood volume.
Subsequently, ADCs can be distributed to the interstitial space.
In addition, ADC distribution is also affected by target antigen expression and endocytosis.
The distribution and accumulation of ADCs in the same tissue can have adverse ( toxic ) pharmacological effects due to the release of cytotoxic drugs or metabolites following ingestion of ADCs.
The in vivo catabolism/metabolism process of ADC includes antibody catabolism process and in vivo metabolism of small molecule drugs.
Before ADCs reach tumor cells, they release effector molecules in cells ( non-cleavable linker ) or in the circulatory system ( cleavable linker ), and unbound antibodies and antibody fragments follow the metabolic pathway of antibodies to generate amino acids through enzymatic hydrolysis, which are reused by the body .
Free small-molecule drugs and/or small-molecule drugs linked to amino acid residues and/or small-molecule drug metabolites of linkers, which may be formed after ADC cleavage or catabolism, will further undergo hepatic CYP450 enzyme metabolism, and may also have potential drug-drug interactions.
In addition to the properties of the ADC itself, antigen expression, receptor/cell density, FcRn-mediated circulation, interaction with Fcγ, receptor-mediated endocytosis, and immunogenicity all affect ADC catabolism.
ADC is also eliminated by catabolism and excretion.
ADC can be degraded after entering the lysosome through a specific pathway that binds to the target, and then cleared from the body after the release of small molecule drugs; it can also be cleared through non-specific pinocytosis, which involves the neonatal receptor ( FcRn ) Participate in the recycling process.
ADCs, antibodies, polypeptides and amino acid fragments with larger molecular weights cannot be excreted by glomerular filtration, but are reabsorbed and utilized in the form of amino acids.
Free small-molecule drugs, peptides with smaller molecular weights, amino acid-linked small-molecule drugs, and antibody fragments with smaller molecular weights can be excreted by glomerular filtration.
At the same time, small molecule drugs and metabolites can also be eliminated by enzymatic metabolism or excreted into feces through transporters.
Bioanalysis of ADCs
ADCs have several components, and in order to characterize the PK profile of these components, several analytical methods are required, as described below:
- Kinetic profiles of conjugates and total antibodies determined by ELISA immunoassays;
- TFC-MS/MS, quantification of free drug/metabolite ;
- High-resolution mass spectrometry for in vivo drug-to-antibody ratio (DAR) analysis .
In addition, two types of ELISA immunoassays are used to quantitatively measure the analytes of ADCs: the first type of assay measures total antibodies, ie ADCs with a DAR greater than or equal to zero.
The second assay measures drug-binding antibodies, defined as ADCs with a DAR greater than or equal to 1.
Other analytical methods are size exclusion chromatography ( SEC ) and hydrophobic interaction chromatography ( HIC ).
SEC is the most commonly used liquid chromatography ( LC ) technique for determining the amount of aggregated antibodies, and this technique can also be used for ADCs.
While HIC is a traditional technique for protein isolation, purification and characterization, this technique is now being used for ADC characterization and analysis.
The ADC cytotoxic payload should have the following properties:
- A cytotoxic payload should have appropriate lipid solubility.
- The target of the payload should be inside the cell.
- The payload molecules should be small in size, lack immunogenicity, and be soluble in aqueous buffers so that they can be easily conjugated.
- The payload should be stable in blood.
Currently, commonly used cytotoxic drug effector molecules are microtubule inhibitors ( such as: auristatins, maytansinoids ), DNA damaging agents ( such as calicheamicin, duocarmycins, anthracyclines, pyrrolobenzodiazepine dimers ) and DNA transcription inhibitors ( Amatoxin and Quinolinealkaloid (SN-38) ).
Several ADC drugs that have been approved for marketing use a total of 6 different small molecule drugs, of which 3 ADC drugs use MMAE as a conjugated drug, 2 drugs use Calicheamicin as a conjugated drug, and MMAF has been successfully applied. , DM1, SN-38, Dxd.
Drug Antibody Ratio (DAR)
The drug-to-antibody ratio ( DAR ) refers to the average number of payload molecules attached to a single mAb, usually between 2 and 4 molecules.
In rare cases, DARs up to 8 can be safely achieved by using hydrophilic linker payloads, such as Enhertus and Trodelvys.
DAR is very important for the determination of the efficacy of ADCs, in addition, DAR may affect the stability of the drug in circulation, PK and toxicity of ADC.
Studies have shown that ADCs with high DAR values ( 7 to 14 ) have faster clearance and reduced efficacy in vivo compared with ADCs with DAR values < 6 .
The DAR value and its effect on stability and PK also depend on the coupling position and the size of the linker.
Lysine or cysteine is often modified to generate ADCs. Lysine is one of the most commonly used amino acid residues for linking substrates and antibodies, and lysines are usually present on the surface of antibodies, making them easy to couple.
Mylotargs, Kadcylas and Besponsas all use lysine bioconjugation technology.
Other amino acids such as cysteine and tyrosine can also be modified, and cysteine was modified with maleimide to synthesize ADCs such as Adcetriss, Polivys, Padcevs, Enhertus, Trodelvys and Blenreps.
Linker is an integral part of ADC, which determines the drug release mechanism, PK, therapeutic index and safety of ADC. Early ADC linkers were chemically labile, such as disulfides and hydrazones.
These linkers are unstable in circulation and have short half-lives, typically one to two days.
The latest generation of linkers are more stable in the systemic circulation, such as peptide and glucuronic acid linkers. The two most common linkers are as follows:
Cleavage-type linkers are sensitive to the intracellular environment, and release free effector molecules and antibodies, such as acid-cleavable linkers and protease-cleavable linkers, through catabolism and dissociation in cells.
They are normally stable in blood but rapidly cleave in the low pH and protease-rich lysosomal environment, releasing effector molecules.
Furthermore, if the effector molecule can transmembrane, it can destroy the tumor by exerting a potential bystander effect.
The non-cleavable linker is a new generation linker with improved plasma stability compared to the cleavable linker.
Since non-cleavable linkers can provide greater stability and tolerance than cleavable linkers, these linkers reduce off-target toxicity and also provide a larger therapeutic window.
In 11 clinical trials targeting 8 ADCs, the incidence of ADAs at baseline ranged from 1.4% to 8.1%, and the incidence of ADAs after baseline ranged from 0 to 35.8%, values in the range of therapeutic mAbs Inside.
Overall, the incidence of ADA for ADCs was lower in patients targeting hematological tumors than in patients targeting solid tumors; most ADAs were directed against the monoclonal antibody domain of ADCs.
Furthermore, in most patients, the hapten-like structures of these ADCs do not create more risk of immune responses than therapeutic monoclonal antibodies.
ADC pharmacokinetic model
The method of applying the model can integrate PK, efficacy and safety data to meet the needs of ADC drug development at different stages, such as: target selection, antibody affinity, linker stability, animal to human extracellular push, dose selection and adjustment, ER correlation studies ( exposure-response relationships ), DDI studies, etc.
The kinetic models of ADCs are also complex due to the multiple clearance pathways ( dissociation and catabolism ) of ADCs and the complex PK profile of multiple analytes.
Different models have different applications.
For example, the two-compartment model and the PBPK model can be used to describe the stability characteristics of ADCs with parameters such as clearance rate, dissociation rate, and metabolic rate.
Currently, non-compartmental models, population pharmacokinetic models, mechanism-based models, and physiological-based models are all used in ADC pharmacokinetic studies.
In the research and development process of ADC drugs, clinical pharmacology plays a very important role.
Through the continuous development of bioanalytical technology, the PK/PD characteristics of ADC drugs can be thoroughly and comprehensively elucidated. important.
ADC drugs will also show more powerful advantages in the field of tumor treatment.
1 . ClinicalPharmacology of Antibody-Drug Conjugates. Antibodies (Basel). 2021 May21;10(2):20.
Explain the clinical pharmacology of ADC in detail
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