title: Rational Design of Biobetters with Enhanced Stability.
abstract: Biotherapeutics are the fastest growing class of pharmaceutical with a rapidly evolving market facing the rise of biosimilar and biobetter products. In contrast to a biosimilar, which is derived from the same gene sequence as the innovator product, a biobetter has enhanced properties, such as enhanced efficacy or reduced immunogenicity. Little work has been carried out so far to increase the intrinsic stability of biotherapeutics via sequence changes, even though, aggregation, the primary degradation pathway of proteins, leads to issues ranging from manufacturing failure to immunological response and to loss of therapeutic activity. Using our spatial aggregation propensity tool as a first step to a rational design approach to identify aggregation-prone regions, biobetters of rituximab have been produced with enhanced stability by introducing site-specific mutations. Significant stabilization against aggregation was achieved for rituximab with no decrease in its binding affinity to the antigen.
authors.affiliation: Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Courtois
authors.affiliation: Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139.
authors.forename: Curtiss P
authors.initials: CP
authors.lastname: Schneider
authors.affiliation: Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139.
authors.forename: Neeraj J
authors.initials: NJ
authors.lastname: Agrawal
authors.affiliation: Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139.
authors.forename: Bernhardt L
authors.initials: BL
authors.lastname: Trout
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000915:Antibody Affinity; D018951:Antigens, CD20 / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D004355:Drug Stability; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D066329:Protein Aggregates; D015202:Protein Engineering; D055550:Protein Stability; D011994:Recombinant Proteins / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000069283:Rituximab / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D050505:Mutant Proteins; D066329:Protein Aggregates; D011994:Recombinant Proteins; D000069283:Rituximab
keywords: SAP; biobetter; drug design; molecular modeling; monoclonal antibody; mutation; protein aggregation; rituximab; stabilization