Anitbody-drug conjugates

Overview

An antibody-drug conjugate (ADC) consists of a cytotoxin covalently linked to a monoclonal antibody (mAb) that recognizes an antigen differentially overexpressed on tumor cells.1 This allows for sensitive discrimination between malignant and healthy cells.1


These loaded antibodies are expected to selectively deliver lethal cargoes to tumor cells and provide sustained clinical benefit to pre-selected cancer patients while, at the same time, minimizing systemic toxicity.1

ADCs Feature 3 Components: 1-3

  1. Tumor-specific monoclonal antibody
  2. Toxin
  3. Linker
diagram

ADC Proposed Mechanism of Action:1-3

ADCs are engineered to have the antibody (1) track a specific tumor antigen bind themselves to the surface of cancer cells and, upon internalization (2) and processing within endosomes or lysosomes, the ADC drug releases its lethal cargo (3) leading to tumor cell death (4).

diagram

Opportunities for ADCs1

diagram
  • Next Generation Payloads: potential for higher levels of cytotoxic drug conjugation
  • New Linkers: optimized stability of the linker between drug and antibody
  • Target Engine: tumor or tissue specificity and ability to internalize of the ADC
  • Optimized Biologics: discovery of new conjugation chemistries
  • Controlled Drug Loading: ability to mute the cytotoxicity of the drug until it reaches its destination, drug-to-antibody ratio, toxicity issues

Therapeutic Potential

Treating cancer with cytotoxic agents introduces a risk of systemic adverse events.

Binding of the ADC to the recognized antigen triggers internalization and degradation of the mAb, which releases the cytotoxin inside the cell.

Ideally, ADCs may help provide a wider therapeutic index with potentially fewer side effects than "free" cytotoxic agents.

  1. Bouchard H, Viskov C, Garcia-Echeverria C. Antibody-drug conjugates—a new wave of cancer drugs. Bioorg Med Chem Lett. 2014;24(23):5357-5363.
  2. Peters C, Brown S. Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015;35(4):e00225. doi: 10.1042/BSR20150089.
  3. Diamantis N, Banerji U. Antibody-drug conjugates—an emerging class of cancer treatment. Br J Cancer. 2016;114(4):362-367.

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