Abstract
Monoclonal antibodies (mAbs) and their derivatives are currently the fastest growing class of therapeutics. Even if naked antibodies have proven their value as successful biopharmaceuticals, they suffer from some limitations. To overcome suboptimal therapeutic efficacy, immunoglobulins are conjugated with toxic payloads to form antibody drug conjugates (ADCs) and with chelating systems bearing therapeutic radioisotopes to form radioimmunoconjugates (RICs). Besides their therapeutic applications, antibody conjugates are also extensively used for many in vitro assays. A broad variety of methods to functionalize antibodies with various payloads are currently available. The decision as to which conjugation method to use strongly depends on the final purpose of the antibody conjugate. Classical conjugation via amino acid residues is still the most common method to produce antibody conjugates and is suitable for most in vitro applications. In recent years, however, it has become evident that antibody conjugates, which are generated via site-specific conjugation techniques, possess distinct advantages with regard to in vivo properties. Here, we give a comprehensive overview on existing and emerging strategies for the production of covalent and non-covalent antibody conjugates.
Highlights
The introduction of the “magic bullet” principle by Paul Ehrlich at the very beginning of the 20th century and the following work of Köhler and Milstein on the production of the first mouse monoclonal antibodies in 1975 gave rise to the development of a novel class of therapeutics [1]
The examples of antibody drug conjugates (ADCs) development outlined in this review clearly demonstrate the necessity for sitespecificity, but a defined stoichiometry of the corresponding cargo is if not even more, important
In the future, only site- modified ADCs will be approved by regulating authorities since these techniques enable us to tightly control the conjugation reaction to produce highly defined ADCs, and, ensure batch-to-batch reproducibility
Summary
The introduction of the “magic bullet” principle by Paul Ehrlich at the very beginning of the 20th century and the following work of Köhler and Milstein on the production of the first mouse monoclonal antibodies in 1975 gave rise to the development of a novel class of therapeutics [1]. Random conjugation via amino acids is often sufficient enough for antibodies that are used for in vitro assays where it is only important to maintain the binding affinity and specificity towards an antigen. The difficulty, is to control the stoichiometry of chemical reactions with lysine or cysteine residues, which are the two most commonly targeted amino acids for bioconjugation. Some of the approaches require site-directed mutagenesis while others are more complicated as they include multiple enzymes or combine protein expression machineries from different hosts. These techniques are in general more time consuming compared to a classical chemical conjugation approach since the primary sequence of the antibody has to be altered or additional proteins have to be expressed. The nucleotide binding site (NBS) is a valuable antibody modification site for photoaffinity labeling (9) and antibodies with catalytic activity (10) can be exploited to form bioconjugates where the coupled pharmacophore, e.g., a peptide assumes the targeting function and the antibody acts as a cargo molecule
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