A scalable low-cost cGMP process for clinical grade production of the HIV inhibitor 5P12-RANTES in Pichia pastoris

Protein Expr Purif. 2016 Mar;119:1-10. doi: 10.1016/j.pep.2015.10.011. Epub 2015 Oct 24.

Abstract

In the continued absence of an effective anti-HIV vaccine, approximately 2 million new HIV infections occur every year, with over 95% of these in developing countries. Calls have been made for the development of anti-HIV drugs that can be formulated for topical use to prevent HIV transmission during sexual intercourse. Because these drugs are principally destined for use in low-resource regions, achieving production costs that are as low as possible is an absolute requirement. 5P12-RANTES, an analog of the human chemokine protein RANTES/CCL5, is a highly potent HIV entry inhibitor which acts by achieving potent blockade of the principal HIV coreceptor, CCR5. Here we describe the development and optimization of a scalable low-cost production process for 5P12-RANTES based on expression in Pichia pastoris. At pilot (150 L) scale, this cGMP compliant process yielded 30 g of clinical grade 5P12-RANTES. As well as providing sufficient material for the first stage of clinical development, this process represents an important step towards achieving production of 5P12-RANTES at a cost and scale appropriate to meet needs for topical HIV prevention worldwide.

Keywords: 5P12-RANTES; Biopharmaceutical; CCR5; Chemokine; HIV; Microbicide; Pichia; Process development; Yeast; cGMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / isolation & purification
  • Anti-HIV Agents / metabolism*
  • Anti-HIV Agents / pharmacology
  • Bioreactors / economics
  • Bioreactors / standards
  • Chemokines, CC / biosynthesis*
  • Chemokines, CC / isolation & purification
  • Chemokines, CC / pharmacology
  • Chromatography, High Pressure Liquid
  • Chromatography, Ion Exchange
  • Fermentation
  • HIV / drug effects*
  • HIV Infections / drug therapy*
  • Humans
  • Inhibitory Concentration 50
  • Pichia*
  • Pilot Projects
  • Virus Internalization / drug effects

Substances

  • 5P12-RANTES
  • Anti-HIV Agents
  • Chemokines, CC