A Winning Combination?
Engineering more effective antibody-drug conjugates
Roisin McGuigan |
Antibody-drug conjugates (ADCs) are an emerging cancer treatment with a lot of promise – by combining the targeting ability of an antibody with a compounds cell-killing ability, it’s possible to create a highly selective – and effective – therapeutic. We spoke to Christoph Rader, part of a team from The Scripps Research Institute who have engineered antibodies using selenocysteine residues, dubbed selenomabs, which they hope will improve the utility of ADCs.
Why try to optimize ADCs?
We wanted to develop new homogeneous antibody-drug conjugates (ADCs) to overcome the current limitations of heterogeneous ADCs, which are based on randomly conjugating the drug molecule to the lysine or cysteine residues of the antibody molecule. The random conjugation results in a mixture of ADC species, with different pharmacokinetic and pharmacodynamic properties. Ideally, a homogenous ADC constitutes a single species, and has highly defined and reproducible pharmacological properties. When thinking about clinical utility, it’s a bit like comparing monoclonal and polyclonal antibodies.
Where does selenocysteine fit in?
To generate homogeneous ADCs, unique chemical reactivity has to be built into the antibody. Selenocysteine – also known as the 21st natural amino acid – has unique chemical reactivity that allows selective drug conjugation in the presence of the other >1,000 amino acids in the antibody molecule. And our team has a decade of experience working with selenocysteine, especially when it comes to engineering antibodies with selenocysteine residues.
In our current study, we built on our knowledge to make highly potent and stable selenomab-drug conjugates for models of human breast cancer and multiple myeloma.
The conjugation chemistry had to be tailored to the high reactivity of the selenocysteine residue to ensure selectivity and stability, so we collaborated closely with organic chemists. We also improved the expression of selenomabs by better harnessing the natural selenocysteine incorporation machinery of mammalian cells, which allowed us to achieve the yields necessary to carry out extensive biochemical characterization of selenomab-drug conjugates, along with in vitro and in vivo activity studies.
How did the new selenomab-drug conjugates perform?
Despite their lower drug-to-antibody ratio (DAR), the activity of our selenomab-drug conjugates outperformed the gold standard ado-trastuzumab emtansine (Kadcyla) both in vitro and in vivo.
We are particularly interested in the development of ADCs that carry more than one kind of drug. Using drug surrogates, we previously developed conditions that allow us to orthogonally conjugate two different drugs to cysteine and selenocysteine with high precision (2). We are now using this technology to conjugate drugs to these “thio-selenomabs”. We also plan to continue our work on improving the expression of selenomabs to facilitate the translation of selenomab-drug conjugates and thio-selenomab-drug conjugates into clinical trials.
- X Li et al., “Stable and potent selenomab-drug conjugates”, Cell Chem Biol, 24, 433–442 (2017). PMID: 28330604.
- X Li et al., “Site-specific dual antibody conjugation via engineered cysteine and selenocysteine residues”, Bioconjug Chem, 26, 2243–2248 (2015). PMID: 26161903.