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Antibody Drug Conjugates

Antibody drug conjugates (ADCs) combine the benefits of large molecule specificity with small molecule toxicity. They are of particular oncological interest as they possess the ability to deliver the chemotherapeutic cytotoxic agent directly to the tumour site antigen, thereby dramatically reducing the degree of healthy tissue damage.

 

Figure 1: Antibody drug conjugates consist of a cytotoxic agent conjugated to a monoclonal antibody (mAb) using a stable linker.  The combination of the linker and the cytotoxic agent is the drug. For safety reasons it is imperative that the cytotoxic agent stays conjugated to the monoclonal antibody until it binds onto or is internalized by the tumour cell. [1]


Antibody drug conjugates
Figure 2: Elements of an Antibody-Drug Conjugate (ADC)

Whilst ADCs are novel and new to the market, with only three products having gained regulatory approval by the end of 2015, the first ADC, Mylotarg (gemtuzumab/ozogamicin, Pfizer), was approved by the FDA in 2000.  It has subsequently been voluntarily withdrawn from sale due to lack of efficacy over the cytotoxic delivered solely.

The remaining two antibody drug conjugates that are still available are Adcetris (bretuximab/vedontin, Seattle Genetics) which gained FDA approval in February 2011 and Kadcyla (trastuzumab/emtansine, Genentech) which was achieved regulatory approval in February 2013.
As previously discussed, the primary area of interest in antibody drug conjugate development is in oncology.  This is partially because monoclonal antibodies, relying on ADCC and CDC, have only generated moderate success in this field thus far.

There are a wide variety of linkers available for conjugating the drug onto the mAb and their inherent complexity mean they are often thought of as a drug product in their own right.  They are broadly split into two sets:

  • Cleavable – such as disulfide, hydrazone, or peptide linkers
  • Non-cleavable – such as thioether bonds

The nature and type of linker incorporated can, and does, have a significant impact on the efficacy of the antibody drug conjugate
Mylotarg incorporates an unstable hydrazone linker which is acid labile and is readily hydrolyzed under acidic lysosomic or endosomic conditions.  This is generally accepted as the primary reason for the observed lack of efficacy.

Adcetris consists of a stable dipeptide linker, via exposed cysteine residues, following mild intra-chain disulfide bond reduction. This linker provides much greater in vivo stability and only releases its warhead following internalization and degradation with lysosomal enzymes.
Emantasine is conjugated to trastuzumab in Kadcyla via lysine residues on the amino side chain, forming an amide bond.  This covalent bond keeps the payload, linker, and cytotoxic warhead associated even after internalization and degradation of the monoclonal antibody.

Another key factor that requires investigation and optimization during antibody drug conjugate development is the ratio of cytotoxic drug per monoclonal antibody.  This drug-to-antibody ratio (DAR) is critical as it has been demonstrated that too few bound cytotoxic agents lead to poor efficacy.  Whilst too many may lead to increased aggregation, loss of target binding properties, and a much reduced half-life.  The typically accepted optimal value for a drug-to-antibody ratio is in the region 3-4.

 

[1] Nicholas APS Buss et al, Monoclonal antibody therapeutics: history and future, Current Opinion in Pharmacology, Volume 12, Issue 5, October 2012, Pages 615–62

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