Coupling of Aggregation and Immunogenicity in Biotherapeutics: T- and B-Cell Immune Epitopes May Contain Aggregation-Prone Regions

  • Sandeep Kumar
  • Satish K. Singh
  • Xiaoling Wang
  • Bonita Rup
  • Davinder Gill


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.


aggregation biotherapeutics cross β motif drug development immunogenicity 





anti-drug antibody


antigen-presenting cell


aggregation-prone region


complementarity-determining region


chemistry manufacturing and control


fragment antigen binding


fragment crystallizable


immunoglobulin G


immunoglobulin M


monoclonal antibody


major histocompatibility complex


T-helper cell


T-regulatory cell



We thank Drs. Patrick Buck, Mark Mitchell, Ned M. Mozier, Herbert A. Runnels, Bruce Thompson, Phoebe Baldus and Vesselin Mitaksov for several helpful discussions regarding the aggregation-immunogenicity coupling. Drs. Sandeep Nema, Kevin King and Graeme Bainbridge are thanked for their interest in applications of computational modeling towards biotherapeutics discovery and development. A postdoctoral fellowship to Xiaoling Wang from Pfizer Biotherapeutics Pharmaceutical Sciences Research and Development is gratefully acknowledged. Sandeep Kumar acknowledges discussions with participants of the Buzz Session entitled “The relationship between aggregation and immunogenicity” on Tuesday 11 January 2011 during CHI’s Pep Talk: The Protein Science Week at Hotel Del Coronado in San Diego, CA. His discussions with Dr. Bjoern Peters of IEDB on the side lines of the above conference are also deeply appreciated. Dr. Neeti Sinha is acknowledged for critical reading of the manuscript.


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Sandeep Kumar
    • 1
  • Satish K. Singh
    • 2
  • Xiaoling Wang
    • 1
  • Bonita Rup
    • 3
  • Davinder Gill
    • 4
  1. 1.Biotherapeutics Pharmaceutical SciencesPfizer Inc.St. LouisUSA
  2. 2.Biotherapeutics Pharmaceutical SciencesPfizer Inc.ChesterfieldUSA
  3. 3.Protein BioanalyticsPfizer, Inc.AndoverUSA
  4. 4.Global Biotherapeutic TechnologiesPfizer Inc.CambridgeUSA

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