The SIMICA Project under the GA 807281, intends to place the Instituto de Medicina Molecular João Lobo Antunes (iMM), in Lisbon within the core of a European network of laboratories that seeks to produce cutting-edge research in the field of antibody-drug conjugates (ADCs).
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 the drug development process. 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 posttranslationally-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 create chemical site-selective protein modification methodologies, which are widely available in an easily usable format.
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 antitumoral potential towards malignant cells or even turn antibodies lacking any cytotoxic activity into potent antineoplastic agents. ADCs represent the fastest growing class of next-generation antibody therapeutics. Initially, ADCs relied on insufficient site-selective conjugation strategies to attach drugs to antibodies, which yielded a 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. Indeed, off-target toxicity is a pressing problem in the clinical development of ADCs.
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