Monoclonal antibodies play an increasingly important role for the development of new drugs across multiple therapy areas. The term 'developability' encompasses the feasibility of molecules to successfully progress from discovery to development via evaluation of their physicochemical properties. These properties include the tendency for self-interaction and aggregation, thermal stability, colloidal stability, and optimization of their properties through sequence engineering. Selection of the best antibody molecule based on biological function, efficacy, safety, and developability allows for a streamlined and successful CMC phase. An efficient and practical high-throughput developability workflow (100 s-1,000 s of molecules) implemented during early antibody generation and screening is crucial to select the best lead candidates. This involves careful assessment of critical developability parameters, combined with binding affinity and biological properties evaluation using small amounts of purified material (<1 mg), as well as an efficient data management and database system. Herein, a panel of 152 various human or humanized monoclonal antibodies was analyzed in biophysical property assays. Correlations between assays for different sets of properties were established. We demonstrated in two case studies that physicochemical properties and key assay endpoints correlate with key downstream process parameters. The workflow allows the elimination of antibodies with suboptimal properties and a rank ordering of molecules for further evaluation early in the candidate selection process. This enables any further engineering for problematic sequence attributes without affecting program timelines.
The 'fast rotational matching' method (an approach to find the three rotational degrees of freedom in matching problems using just one three-dimensional FFT) is extended to the full six-dimensional (rotation and translation) matching scenario between two three-dimensional objects. By recasting this problem into a formulation involving five angles and just one translational parameter, it was possible to accelerate, by means of fast Fourier transforms, five of the six degrees of freedom of the problem. This method was successfully applied to the docking of atomic structures of components into three-dimensional low-resolution density maps. Timing comparisons performed with our method and with 'fast translational matching' (the standard way to accelerate the translational parameters utilizing fast Fourier transforms) demonstrates that the performance gain can reach several orders of magnitude, especially for large map sizes. This gain can be particularly advantageous for spherical- and toroidal-shaped maps, since the scanning range of the translational parameter would be significantly constrained in these cases. The method can also be harnessed to the complementary surface (or 'exterior docking') problem and to pattern recognition in image processing.
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