Biological Therapeutics

Over the last 25 years many biological therapeutics have been approved for clinical use; and many of these for diseases where there was no other available therapy. There has been an evolution over this time period from proteins intended to be “nature identical” to the development of engineered products and use of novel protein scaffolds intended to confer a pharmacokinetic, pharmacodynamic or other advantage over the natural counterpart. In addition, protein engineering has allowed the development of monoclonal antibodies as highly potent modulators directed at specific peptides / proteins. Monoclonal antibodies are generally considered to have a long elimination half-life, due to the protective mechanism of FcRn binding; however, target mediated drug disposition (TMDD) is often observed whereby clearance changes with dose, particularly with antibodies directed against cell surface targets. This phenomenon where the kinetics of the target itself can impact the kinetic behaviour of the therapeutic protein is one of the key differences between small molecule drugs and monoclonal antibodies. Another key difference is the potential for immunogenicity with therapeutic proteins where anti-drug-antibodies are produced against what the body recognises as a “foreign” protein. Immunogenicity can impact both the pharmacokinetic (PK) and pharmacodynamic (PD) behaviour of the therapeutic protein, as well as the safety profile. Many of these molecules demonstrate exquisite species selectivity in their biological activity and the species used for preclinical safety assessment should be selected with this in mind. The ability to extrapolate to human from pre-clinical data needs to take into account this potential species specificity. Differences in potency across species can be greater than safety margins imposed on either dose or exposure and should be factored into appropriate dose selection for entry into clinical testing. For this reason, it is important to select the starting dose for first-in-human trials based on an understanding of both the toxicological and pharmacological dose / concentration-effect relationships. The latter has resulted in an increased emphasis on translational PK-PD approaches to the design of preclinical studies and the translation of PK-PD data to support early clinical development. Such approaches require the development of an integrated suite of PK, PD and immunogenicity bioanalytical assays to support preclinical and clinical development