Clinical pharmacological basis of ADC

preface

Antibody conjugated drugs (ADCs) are formed by the connection between monoclonal antibodies targeting specific antigens and small molecule cytotoxic drugs through joints, which combines the powerful killing effect of traditional small molecule chemotherapy and the tumor targeting of

From selecting the right antibody to the final product, the entire ADC development process is a difficult and challenging task

Overview of the pharmacokinetics of ADCs

Pharmacokinetics is an integral part of

It should be recognized that, unlike small molecules and therapeutic proteins (antibodies or fusion proteins), the PK of an ADC is very complex because the ADC consists of

Pharmacokinetic characteristics of ADCs

In general, after administration, four processes are involved in the

absorb

Most antibodies are usually given intravenously or infusion, and antibodies can also be given subcutaneously (SC) routes

distribution

The distribution of the drug in the body can be described

The initial distribution of ADCs is generally confined to blood vessels, and their volume of distribution is generally equal to blood volume

The distribution and accumulation of ADCs in the same tissue can produce adverse (toxic) pharmacological effects, which are due to the release

metabolism

In vivo decomposition/metabolic processes of ADCs include antibody catabolic processes and in vivo metabolism

Free small molecule drugs that may form after ADC cleavage or catabolism and/or small molecule drug metabolites with amino acid residues and / or linker small molecule drug metabolites further undergo hepatic CYP450 enzyme metabolism and may also occur with potential drug-drug interactions

In addition to the properties of the ADC itself, the expression of antigens, receptor/cell density, FcRn-mediated circulatory action, Fcγ-mediated interaction, receptor-mediated endocytosis, immunogenicity, etc.

purge

ADCs are also eliminated

ADCs, antibodies, peptides with large molecular weights and amino acid fragments cannot be filtered and excreted through glomerular filtration, but are reabsorbed and utilized in the form of amino acids

Bioanalysis of ADCs

ADCs have several components, and in order to characterize the PK characteristics of these components, several analytical methods are required, as described below:

In addition, two types of ELISA immunoassays are used to quantitatively measure the analyte of an ADC: the first type of assay measures the total antibody, i.

Other analytical methods are dimensional exclusion chromatography (SEC) and hydrophobic action chromatography (HIC

Cytotoxic payload

The ADC cytotoxic payload should have the following characteristics:

Currently, commonly used cytotoxic drug effector molecules are microtubule inhibitors (e.
g.
, auristatins, maytansinoids), DNA damaging agents (e.
g.
, calicheamicin, duocarmycins, anthracyclines, pyrrolobenzodiazepine dimers), and DNA transcription inhibitors (Amatoxin and Quinolinealkaloid).
(SN-38)）
。 Several ADC drugs that have been approved for marketing have used 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 the other successful applications are MMAF, DM1, SN-38, Dxd
.

Drug antibody ratio (DAR)

The drug-antibody ratio (DAR) refers to the average number of payload molecules attached to a single monoclonal antibody, usually between
2 and 4 molecules.
In rare cases, up to 8 DARs can be safely achieved by using hydrophilic linker payloads, such as Enhertus and Trodelvys
.
DAR is important for the determination of the efficacy of ADCs, in addition, DAR may affect the stability of the drug in circulation, PK and ADC toxicity
.

Studies have shown that ADCs with high DAR values (7 to 14) are cleared faster and have reduced
in vivo efficacy compared to ADCs with DAR values <6.
The DAR value and its effect on stability and PK also depends on the coupling position and the size of the
connector.

Lysine or cysteine is usually modified to produce an ADC
.
Lysine is one of the most commonly used amino acid residues to connect substrates and antibodies, and lysine is usually present on the antibody surface and is therefore prone to coupling
.
Mylotargs, Kadcylas, and Besponsas all use lysine biobinding techniques
.

Other amino acids such as cysteine and tyrosine can also be modified, and ADCs
such as Adcetriss, Polivys, Padcevs, Enhertus, Trodelvys, and Blenreps are synthesized with maleimide-modified cysteine.

Connect

The linker is an integral part of the ADC and determines the drug release mechanism, PK, therapeutic index, and safety of the ADC
.
Early ADC connectors were chemically unstable, such as disulfide and hydrazone
.
These hymens are unstable in the cycle and have short half-lives, typically one to two days
.
The latest generation of hymens are more stable in the systemic cycle, such as peptides and glucuronic acid connectors
.
The two most common connectors are as follows:

Lysable hymen

Lysis-type linkers are sensitive to the intracellular environment, releasing free effector molecules and antibodies such as acid lysis hyenaeon and protease lytic hyenons through catabolic and dissociative interactions within the
cell.
They are usually stable in the blood, but lysomal environments at low pH and enriched with proteases lysomal lyses rapidly, releasing effector molecules
.
In addition, if the effector molecules can transmembrane, the tumor
can be destroyed by exerting a potential bystander effect.

Non-cleavage connectors

The non-cleavage linker is a new generation of connectors that have better plasma stability
than lysable connectors.
Since non-lysable hymens can provide greater stability and tolerance than lysable hymen, these hymens reduce off-target toxicity and also provide a larger window of
treatment.

immunogenicity

In 11 clinical trials targeting 8 ADCs, the baseline incidence of ADAs ranged from 1.
4% to 8.
1%, and the incidence of ADAs after baseline was between 0 and 35.
8%, which ranged from
therapeutic monoclonal antibodies.
Overall, the incidence of ADAs in ADCs is less in patients targeting hematologic tumors than in patients targeting solid tumors; Most ADAs are specific to the monoclonal antibody domain of the
ADC.
In addition, in most patients, the hapmogen-like structure of these ADCs does not produce more risk
of immune response than therapeutic monoclonal antibodies.

ADC pharmacokinetic model

The application model method 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 extrapolation, dose selection and adjustment, E-R correlation studies (exposure-response relationships), DDI studies, and so on
.
Due to the multiple clearance pathways (dissociation and catabolism) of ADCs, as well as the presence of complex PK features of multiple analytes, their dynamic models are also complex
.

Different models have different applications, such as the two-atrioventricular model and the PBPK model can describe the stability characteristics
of the ADC with parameters such as clearance, dissociation, and metabolic rate.
At present, non-atrioventricular models, population pharmacologic models, mechanism-based models, and physiology-based models have been applied
in ADC pharmacokinetic research.

brief summary

Clinical pharmacology plays a very important role in the development process of ADC drugs, and through the continuous development of bioanalytical techniques, in-depth and comprehensive elucidating of PK/PD characteristics of ADC drugs is essential
to promote the development of more toxic and efficient ADC drugs.
ADC drugs will also show more powerful advantages
in the field of tumor treatment.

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