caa a22 4500 445313870 CHVBK 20180317142639.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s11095-011-0414-9 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0414-9 Coupling of Aggregation and Immunogenicity in Biotherapeutics: T- and B-Cell Immune Epitopes May Contain Aggregation-Prone Regions [Elektronische Daten] [Sandeep Kumar, Satish Singh, Xiaoling Wang, Bonita Rup, Davinder Gill] ABSTRACT: Biotherapeutics, including recombinant or plasma-derived human proteins and antibody-based molecules, have emerged as an important class of pharmaceuticals. Aggregation and immunogenicity are among the major bottlenecks during discovery and development of biotherapeutics. Computational tools that can predict aggregation prone regions as well as T- and B-cell immune epitopes from protein sequence and structure have become available recently. Here, we describe a potential coupling between aggregation and immunogenicity: T-cell and B-cell immune epitopes in therapeutic proteins may contain aggregation-prone regions. The details of biological mechanisms behind this observation remain to be understood. However, our observation opens up an exciting potential for rational design of de-immunized novel, as well as follow on biotherapeutics with reduced aggregation propensity. Springer Science+Business Media, LLC, 2011 aggregation nationallicence biotherapeutics nationallicence cross β motif nationallicence drug development nationallicence immunogenicity nationallicence 3D : three-dimensional nationallicence ADA : anti-drug antibody nationallicence APC : antigen-presenting cell nationallicence APR : aggregation-prone region nationallicence CDR : complementarity-determining region nationallicence CMC : chemistry manufacturing and control nationallicence Fab : fragment antigen binding nationallicence Fc : fragment crystallizable nationallicence IgG : immunoglobulin G nationallicence Igm : immunoglobulin M nationallicence mAb : monoclonal antibody nationallicence MHC : major histocompatibility complex nationallicence TH-cell : T-helper cell nationallicence Treg-cell : T-regulatory cell nationallicence Kumar Sandeep Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., MC6S, 575 Maryville Centre Drive, 63141, St. Louis, Missouri, USA aut Singh Satish Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., BB3D, 700 Chesterfield Parkway West, 63017, Chesterfield, Missouri, USA aut Wang Xiaoling Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., MC6S, 575 Maryville Centre Drive, 63141, St. Louis, Missouri, USA aut Rup Bonita Protein Bioanalytics, Pfizer, Inc., G2001A, One Burtt Road, 08100, Andover, Massachussets, USA aut Gill Davinder Global Biotherapeutic Technologies, Pfizer Inc., W1009, 87 Cambridge Park Drive, 02139, Cambridge, Massachussets, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/5(2011-05-01), 949-961 0724-8741 28:5<949 2011 28 11095 https://doi.org/10.1007/s11095-011-0414-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0414-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kumar Sandeep Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., MC6S, 575 Maryville Centre Drive, 63141, St. Louis, Missouri, USA aut NATIONALLICENCE 700 1- Singh Satish Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., BB3D, 700 Chesterfield Parkway West, 63017, Chesterfield, Missouri, USA aut NATIONALLICENCE 700 1- Wang Xiaoling Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., MC6S, 575 Maryville Centre Drive, 63141, St. Louis, Missouri, USA aut NATIONALLICENCE 700 1- Rup Bonita Protein Bioanalytics, Pfizer, Inc., G2001A, One Burtt Road, 08100, Andover, Massachussets, USA aut NATIONALLICENCE 700 1- Gill Davinder Global Biotherapeutic Technologies, Pfizer Inc., W1009, 87 Cambridge Park Drive, 02139, Cambridge, Massachussets, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/5(2011-05-01), 949-961 0724-8741 28:5<949 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer