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Related Concept Videos

Drug Delivery: Miscellaneous Routes01:22

Drug Delivery: Miscellaneous Routes

Drug delivery methods like oral inhalation, nasal sprays, transdermal patches, eye drops, intravitreal injection,  and rectal administration provide localized effects with reduced toxicity.
Oral inhalation and nasal sprays swiftly transfer drugs across the respiratory epithelium's mucosal layer. Inhaled glucocorticoids and bronchodilators directly target lung conditions such as asthma, while fluticasone nasal spray mitigates allergic rhinitis.
Transdermal patches transport drugs through the...
Drug Accumulation During Multiple Dosing: Repetitive IV Injections01:21

Drug Accumulation During Multiple Dosing: Repetitive IV Injections

Calculating drug dosage and accumulation in multiple-dose regimens is crucial for achieving therapeutic efficacy while avoiding toxicity. This involves determining the plasma drug concentrations over time to optimize dosing schedules. The principle of superposition is fundamental in this process, allowing for the prediction of drug concentration in plasma following multiple doses based on single-dose data.The principle of superposition asserts that the plasma concentration-time curves from...
Drug Accumulation During Multiple Dosing: Intermittent IV Infusions01:24

Drug Accumulation During Multiple Dosing: Intermittent IV Infusions

Intermittent intravenous (IV) infusion is a method of drug administration where medications are delivered over short infusion periods followed by intervals of no drug delivery. This approach helps to prevent sustained high drug concentrations in the bloodstream, reducing the risk of adverse effects associated with prolonged exposure. Unlike continuous infusion, steady-state concentrations may not be achieved during a single dosing cycle but can be reached through repeated...
Modified-Release Drug Delivery Systems: Stimuli-Activated01:30

Modified-Release Drug Delivery Systems: Stimuli-Activated

Stimuli-activated drug delivery systems are designed to release drugs in response to specific physical, chemical, or biological stimuli. These systems often utilize hydrogels—three-dimensional, hydrophilic polymer networks capable of swelling in aqueous environments and retaining significant fluid volumes. Upon exposure to particular stimuli, these hydrogels undergo structural transitions that allow the embedded drug to be released. Due to this adaptive behavior, such systems are also called...
Modified-Release Drug Delivery Systems: Site-Targeted01:24

Modified-Release Drug Delivery Systems: Site-Targeted

Site-targeted drug delivery systems enhance therapeutic efficacy while minimizing systemic toxicity and treatment costs. Unlike conventional methods, these systems ensure precise drug delivery, improving bioavailability and reducing side effects. Targeted drug delivery is classified into three levels. First-order targeting directs drugs to the capillary beds of specific organs or tissues. Second-order targets specific cell types, such as tumor cells, using receptor-mediated interactions.
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Site-Targeted Drug Delivery Systems: Polymeric Carriers

Polymeric carriers enhance targeted drug delivery by increasing efficacy while minimizing off-target effects. These carriers comprise a biodegradable polymeric backbone integrated with functional elements that enable targeting, improve physicochemical properties, and regulate drug release.Targeting MechanismsThe targeting ability of polymeric carriers is mediated by a homing device, which is a molecular recognition component designed to selectively bind to specific tissues or cells. Monoclonal...

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Related Experiment Video

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Efficient and Site-specific Antibody Labeling by Strain-promoted Azide-alkyne Cycloaddition
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Site-Specific Modification of Native IgGs with Flexible Drug-Load.

Jöri E Wehrmüller1, Julia C Frei1, Torsten Hechler2

  • 1Center for Radiopharmaceutical Science, ETH-PSI-USZ, Paul Scherrer Institute, 5232, Villigen-PSI, Switzerland.

Chembiochem : a European Journal of Chemical Biology
|September 21, 2024
PubMed
Summary

Researchers developed a new method for creating antibody-drug conjugates (ADCs) by modifying native antibodies. This technique allows for precise control over drug load and offers improved efficacy and tolerability for cancer therapies.

Keywords:
ADCDual-payloadMicrobial transglutaminasePeptideRadio-immunoconjugate

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Area of Science:

  • Bioconjugation Chemistry
  • Antibody Engineering
  • Pharmacology

Background:

  • Site-specific conjugation of antibodies yields antibody-drug conjugates (ADCs) with enhanced efficacy and tolerability over stochastic methods.
  • Challenges remain in precisely controlling drug load and attaching multiple payloads to antibodies.

Purpose of the Study:

  • To demonstrate a simple, direct method for modifying native IgG antibodies at glutamine 295 (Q295) without protein engineering.
  • To achieve flexible drug-to-antibody ratios (DARs) with one or multiple payloads.

Main Methods:

  • Utilized short, lysine-containing peptides and microbial transglutaminase for conjugation to native IgG antibodies at Q295.
  • Generated HER2-targeting ADCs using trastuzumab with DARs of 2 and 4, employing orthogonal conjugation for varied payloads.
  • Conducted quantitative biodistribution studies using 111In-radiolabeled conjugates.

Main Results:

  • Successfully conjugated antibodies with flexible DARs (2 and 4) using diverse payloads.
  • Demonstrated high tumor uptake and minimal off-target tissue accumulation of radiolabeled conjugates.
  • A single dose of trastuzumab conjugated to α-Amanitin resulted in complete, durable tumor remission and was well-tolerated.

Conclusions:

  • The Q295 conjugation method offers a straightforward approach for creating homogeneous ADCs with controlled DARs.
  • This technique facilitates the development of potent ADCs with improved therapeutic profiles.
  • The demonstrated efficacy and tolerability highlight the potential of this method for novel cancer therapeutics.