RESEARCH

Novel aqueous chemistries for the selective modification of proteins have been described in recent years and chemical protein modification has become a key instrument in Chemical Biology and drug development. It is commonly agreed that these tools will provide major insight into basic biology and enable the development of novel protein therapeutics with unprecedented properties. Fundamental biology, for instance, should benefit from facile methods for the preparation of post translationally modified proteins. For the synthesis of protein conjugate therapeutics modern methodologies may offer increased precision, improved linkage stabilities and therapeutic efficiency. Nevertheless, conventional protein modification chemistries are still widely used. To deliver on these promises it will be key to make chemical site-selective protein modification methodologies widely available in an easily usable format.

More recently, the conjugation of monoclonal antibodies directed against tumour marker proteins with highly potent cytotoxic drugs has emerged as a powerful strategy to create antibodies with improved killing potential towards malignant cells or even turn antibodies lacking any cytotoxic activity into potent antineoplastic agents. Efforts in the field of antibody-drug conjugates (ADCs) have led to the recent approval of two ADCs as drugs: Adcetris®, for the treatment of refractory Hodgkin lymphoma and anaplastic large-cell lymphoma, and Kadcyla®, for the treatment of metastatic HER2+ breast cancer. ADCs represent the fastest growing class of next-generation antibody therapeutics and will comprise 10% of total antibody therapeutics revenues by 2016 reaching nearly $58bn. Initial work on antibody-drug conjugates (ADCs) relied on poorly site-selective conjugation strategies to attach drugs to antibodies yielding heterogeneous mixture of antibodies with different drug loading at different sites. It was soon found that both the number of drugs per antibody and the attachment site could have a profound effect on the pharmacokinetics, efficacy and toxicity of an ADC. A high ratio of drug to antibody (typically > 2) may lead to reduced thermos stability of the ADC and result in a faster clearance from the bloodstream. ADCs with high drug to antibody ratio (DAR) were also found to have a smaller therapeutic window than ADCs with low DARs. Additionally the site of drug attachment can have a profound effect on clearance kinetics and off-target ADC toxicity as well as in plasma stability and efficacy. These observations demonstrate the importance of using site-selective protein-modification chemistries for the synthesis of homogenous protein conjugate therapeutics.

The ProteinConjugates network is an innovative science & training program that aims to develop new site-selective bioconjugation methodologies that explore natural proteinogenic amino acids and their use to build protein conjugates for the treatment of serious conditions such as cancer or reumathoid arthritis, by providing advanced training to the next generation of excellent European researchers through a series of well-integrated research projects encompassing:

- The development of innovative and highly efficient site-selective protein modification reactions.
- Validation of new targeting antibodies and protein-based nanoparticle scaffolds for active targeted drug delivery.
- The construction, characterization and biological evaluation of chemically defined therapeutically useful protein conjugates.

The translation of novel tools and conjugates into novel anti-cancer therapeutics with improved selectivity, safety and efficacy.