The mosaic puzzle of the therapeutic monoclonal antibodies and antibody fragments - A modular transition from full-length immunoglobulins to antibody mimetics

The use of monoclonal antibodies represents an important and efficient diagnostic and therapeutic tool in disease management and modern science but remains limited by several factors including the uneven distribution in diseased tissues as well as undesired activation of side immune reactions. Major scientific advancements including Recombinant DNA Technology, Hybridoma Technology, and Polymerase Chain Reaction have considerably impacted the use of monoclonal antibodies providing technical and effective solutions to overcome the shortcomings encountered with conventional antibodies. Initially, the introduction of antibody fragments allowed a more uniform and deeper penetration of the targeted tissue and reduced unwanted activation of Fc-mediated immune reactions. On another level, the immunogenicity of murine-derived antibodies was overcome by humanizing their encoding genes with specific sequences of human origin andtransgenic mice able to synthesize fully human antibodies were successfully created. Moreover, the advancement of genetic engineering techniques supported by the modular structure of antibody coding genes paved the way for the development of a new generation of antibody fragments with a wide spectrum of monospecific and bispecific agents. These later could be monovalent, bivalent, or multivalent, and either expressed as a single chain, assembled in multimeric forms or stringed in tandem. This has conferred improved affinity, stability, and solubility to antibody targetting. Lately, a new array of monoclonal antibody fragments was introduced with the engineering of nanobody and antibody mimetics as non-immunoglobulin-derived fragments with promising diagnostic and therapeutic applications. In this review, we decipher the molecular basis of monoclonal antibody engineering with a detailed screening of the antibody derivatives that provides new perspectives to expand the use of monoclonal fragments into previously unexplored fields.