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
Perspective

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.

KEY WORDS

aggregation biotherapeutics cross β motif drug development immunogenicity 

ABBREVIATIONS

3D

three-dimensional

ADA

anti-drug antibody

APC

antigen-presenting cell

APR

aggregation-prone region

CDR

complementarity-determining region

CMC

chemistry manufacturing and control

Fab

fragment antigen binding

Fc

fragment crystallizable

IgG

immunoglobulin G

Igm

immunoglobulin M

mAb

monoclonal antibody

MHC

major histocompatibility complex

TH-cell

T-helper cell

Treg-cell

T-regulatory cell

Notes

ACKNOWLEDGMENTS

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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