Objective
Evaluation of a humanized Anti-Serpin B13 monoclonal antibody for potential as a developmental drug candidate.
Background Rationale
At the discovery stage, it is important to identify a therapeutic molecule with target product profile, which is usually based on clinical usage of this potential therapeutic agent. Critical quality attributes (CQAs) of the lead molecule will be further assessed to setup quality target product profile at the chemistry, manufacturing and control (CMC) stage. The cost of engineering an antibody at the discovery stage is significantly lower than the cost of optimizing process and formulation at the development stage. In addition, poor physicochemical properties of an antibody may affect its biological functions in vitro and in vivo. For example, post-translational modifications (PTMs) in complementarity-determining regions (CDRs) of an antibody can significantly reduce its potency. If an antibody is found with a developability issue in the discovery stage, it can be fixed by protein engineering. For example, deletion of two hydrophobic residues in the CDR domains of a mAb significantly reduced its tendency to precipitation and aggregation. The physicochemical properties of antibodies can be altered in the process and fixing these liabilities prior to further in vivo studies is a prudent next step and buys down the risk of failure in the clinic.
Description of Project
Research from Dr Jan Czyzyk and his team at the University of Minnesota, USA, explores the balance between proteases and serpins, and how their activity can in turn affect the inflammation and tissue regeneration of pancreatic islet cells. Their findings show that antibodies can be used to change this serpin–protease balance, with interesting impacts. Excitingly, their research opens the possibility for anti-serpin activity to be used as both a biomarker and an active mechanism of protection for individuals with type 1 diabetes. Injecting an anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of pancreatic islets in Type 1 Diabetes animal model, and led to increase in the beta cell mass. Additional data suggests that anti-serpin immunological response promotes adaptive changes in the endocrine pancreas and could potentially help impede the progression of T1D in humans.
Anticipated Outcome
In silico assessments, based on antibody sequence analysis, will narrow down the list of potential liabilities in the lead antibody. These anticipated liabilities will be tested experimentally to generate supporting evidence. An in vitro enzyme assay to evaluate direct inhibition of Serpin B13 cleavage of its de novo substrate Cathepsin L in the presence and absence of the lead antibody will be established to show mechanism of action.
Based on the totality of findings critical liabilities can be fixed using mutagenesis to generate a second-generation molecule that is more attractive for further development in a subsequent proposal.
Relevance to T1D
Research from Dr Jan Czyzyk and his team at the University of Minnesota, USA, explores the balance between proteases and serpins, and how their activity can in turn affect the inflammation and tissue regeneration of pancreatic islet cells. Their findings show that antibodies can be used to change this serpin–protease balance, with interesting impacts. Excitingly, their research opens the possibility for anti-serpin activity to be used as both a biomarker and an active mechanism of protection for individuals with type 1 diabetes. Injecting an anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of pancreatic islets in Type 1 Diabetes animal model, and led to increase in the beta cell mass. Additional data suggests that anti-serpin immunological response promotes adaptive changes in the endocrine pancreas and could potentially help impede the progression of T1D in humans.