The AAPS Journal

, Volume 16, Issue 1, pp 48–64

High-Throughput Biophysical Analysis of Protein Therapeutics to Examine Interrelationships Between Aggregate Formation and Conformational Stability

  • Rajoshi Chaudhuri
  • Yuan Cheng
  • C. Russell Middaugh
  • David B. Volkin
Mini-Review Theme: Aggregation and Interactions of Therapeutic Proteins

DOI: 10.1208/s12248-013-9539-6

Cite this article as:
Chaudhuri, R., Cheng, Y., Middaugh, C.R. et al. AAPS J (2014) 16: 48. doi:10.1208/s12248-013-9539-6

Abstract

Stabilization and formulation of therapeutic proteins against physical instability, both structural alterations and aggregation, is particularly challenging not only due to each protein’s unique physicochemical characteristics but also their susceptibility to the surrounding milieu (pH, ionic strength, excipients, etc.) as well as various environmental stresses (temperature, agitation, lyophilization, etc.). The use of high-throughput techniques can significantly aid in the evaluation of stabilizing solution conditions by permitting a more rapid evaluation of a large matrix of possible combinations. In this mini-review, we discuss both key physical degradation pathways observed for protein-based drugs and the utility of various high-throughput biophysical techniques to aid in protein formulation development to minimize their occurrence. We then focus on four illustrative case studies with therapeutic protein candidates of varying sizes, shapes and physicochemical properties to explore different analytical challenges in monitoring protein physical instability. These include an IgG2 monoclonal antibody, an albumin-fusion protein, a recombinant pentameric plasma glycoprotein, and an antibody fragment (Fab). Future challenges and opportunities to improve and apply high-throughput approaches to protein formulation development are also discussed.

KEY WORDS

aggregationbiophysicalconformationformulationmini-reviewmonoclonal antibodyproteinstabilitystructure

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  • Rajoshi Chaudhuri
    • 1
    • 2
  • Yuan Cheng
    • 1
  • C. Russell Middaugh
    • 1
  • David B. Volkin
    • 1
  1. 1.Department of Pharmaceutical Chemistry, Macromolecule and Vaccine Stabilization CenterUniversity of KansasLawrenceUSA
  2. 2.Vaccine Production Program Laboratory, Vaccine Research Center/NIAIDNational Institutes of Health, DHHSGaithersburgUSA