Comparability: what we can learn from the review of advanced therapy medicinal products.

Publicly available summaries from Marketing Authorization Applications for gene and cell therapy products (advanced therapies) were evaluated to explore data expectations for product characteristics pre and post changes (comparability). Public assessment reports were used to analyze trends in information requests from regulators concerning comparability from current commercial advanced therapies. In the analysis, 12 products approved in the USA and EU were included. Inadequacies were highlighted for comparability data (six products); additional information requests (five products) and major objections were identified relating to comparability (two products, EU). Postapproval authorization obligations were imposed for six products. Comparability data are essential component for regulatory applications and public assessment reports provide a valuable source of insight into regulators' expectations.

Probing a protein-protein interaction by in vitro evolution.

In this study, we used in vitro protein evolution with ribosome and phage display to optimize the affinity of a human IL-13-neutralizing antibody, a therapeutic candidate for the treatment of asthma, >150-fold to 81 pM by using affinity-driven stringency selections. Simultaneously, the antibody potency to inhibit IL-13-dependent proliferation in a cell-based functional assay increased 345-fold to an IC50 of 229 pM. The panoply of different optimized sequences resulting from complementarity-determining region-targeted mutagenesis and error-prone PCR using ribosome display was contrasted with that of complementarity-determining region-targeted mutagenesis alone using phage display. The data highlight the advantage of the ribosome-display approach in identifying beneficial mutations across the entire sequence space. A comparison of mutation hotspots from in vitro protein evolution to knockout mutations from alanine scanning demonstrated that in vitro evolution selects the most appropriate positions for improvements in potency without mutating any of the key residues within the functional paratope.