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Related Concept Videos

Antibody Actions01:26

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Antibodies, or immunoglobulins, are critical players in the immune system's arsenal against invading pathogens. Produced by B cells and plasma cells, their primary role is to detect and bind to specific antigens, molecules found on the surface of pathogens like bacteria or viruses. Beyond antigen recognition, antibodies perform several vital functions that contribute to immune defense.
Neutralization
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Drug-Receptor Bonds01:25

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Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
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Phase II Conjugation Reactions: Overview01:14

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Conjugation, a key component of phase II biotransformation reactions, is a vital process in drug detoxification. It involves transferring endogenous substances like glucuronic acid, sulfate, and glycine to drugs or their metabolites formed in phase I reactions. These conjugation reactions, often catalyzed by specific enzymes, transform potentially harmful metabolites into inactive, water-soluble forms easily excreted in urine or bile. By enhancing polarity and eliminating pharmacological...
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Non-Oral Extravascular Drug Absorption Routes01:15

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Non-oral extravascular routes, which encompass sublingual, buccal, topical, intramuscular, and inhalation methods, primarily utilize passive diffusion to transport drugs into the systemic circulation. The absorption rates and effectiveness of these routes depend on the drug's physicochemical properties, as well as the patient's anatomical and pathophysiological state.
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Drug Distribution: Plasma Protein Binding01:29

Drug Distribution: Plasma Protein Binding

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Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the bound fraction. Acidic drugs form large, inactive complexes by reversibly binding to plasma albumin, which prevents them from diffusing across biological barriers. These drug-protein complexes act as reservoirs for the drugs. As the concentration of unbound drugs decreases, these complexes quickly dissociate to release the free drug, maintaining...
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Conjugated Proteins02:50

Conjugated Proteins

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Simple proteins and protein complexes contain only amino acids. In contrast, many other proteins, called conjugated proteins, covalently bond with non-protein moieties.
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Non-internalising antibody-drug conjugates.

Nicola Ashman1, Jonathan D Bargh2, David R Spring1

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New antibody-drug conjugates (ADCs) bypass cancer cell internalisation, releasing payloads extracellularly. This approach broadens therapeutic targets beyond highly expressed internalising antigens, expanding cancer treatment options.

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Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
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Initial Evaluation of Antibody-conjugates Modified with Viral-derived Peptides for Increasing Cellular Accumulation and Improving Tumor Targeting
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Area of Science:

  • Oncology
  • Drug Development
  • Bioconjugation Chemistry

Background:

  • Traditional antibody-drug conjugates (ADCs) rely on cancer cell internalisation for payload release, limiting therapeutic development.
  • This internalisation requirement necessitates high expression of internalising antigens and efficient intracellular processing, posing significant challenges.

Purpose of the Study:

  • To review recent advancements in non-internalising antibody-drug conjugates (ADCs).
  • To explore alternative strategies for ADC payload delivery that overcome internalisation-dependent limitations.
  • To highlight novel cancer targets and linking chemistries for extracellular payload release.

Main Methods:

  • Review of current literature on non-internalising ADC strategies.
  • Analysis of emerging cancer-associated cell surface and extracellular proteins as therapeutic targets.
  • Examination of linking chemistry enabling extracellular payload release.

Main Results:

  • Non-internalising ADCs offer an alternative to internalisation-dependent payload release.
  • Extracellular release broadens the scope of targetable antigens and tumor components.
  • Targeting the tumor stroma and extracellular matrix presents new therapeutic avenues.

Conclusions:

  • Non-internalising ADCs significantly expand the potential applications of antibody-drug conjugate technology.
  • This approach alleviates constraints associated with high antigen expression and inefficient internalisation.
  • Further development in this area promises to broaden the range of treatable cancers.