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

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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
Process development, Pichia, Microbicide, 5P12-RANTES, cGMP, MICROBICIDES, RANTES, EXPRESSION, CCR5, Biopharmaceutical, HIV, Chemokine, Yeast, VAGINAL TRANSMISSION, ENTRY INHIBITORS, RHESUS MACAQUES, HIGHLY POTENT, CHEMOKINES, PROTEIN, PROTECTION

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MLA
Cerini, Fabrice et al. “A Scalable Low-cost cGMP Process for Clinical Grade Production of the HIV Inhibitor 5P12-RANTES in Pichia Pastoris.” PROTEIN EXPRESSION AND PURIFICATION 119 (2016): 1–10. Print.
APA
Cerini, F., Gaertner, H., Madden, K., Tolstorukov, I., Brown, S., Laukens, B., Callewaert, N., et al. (2016). A scalable low-cost cGMP process for clinical grade production of the HIV inhibitor 5P12-RANTES in Pichia pastoris. PROTEIN EXPRESSION AND PURIFICATION, 119, 1–10.
Chicago author-date
Cerini, Fabrice, Hubert Gaertner, Knut Madden, Ilya Tolstorukov, Scott Brown, Bram Laukens, Nico Callewaert, et al. 2016. “A Scalable Low-cost cGMP Process for Clinical Grade Production of the HIV Inhibitor 5P12-RANTES in Pichia Pastoris.” Protein Expression and Purification 119: 1–10.
Chicago author-date (all authors)
Cerini, Fabrice, Hubert Gaertner, Knut Madden, Ilya Tolstorukov, Scott Brown, Bram Laukens, Nico Callewaert, Jay C Harner, Anna M Oommen, John T Harms, Anthony R Sump, Robert C Sealock, Dustin J Peterson, Scott K Johnson, Stephan B Abramson, Michael Meagher, Robin Offord, and Oliver Hartley. 2016. “A Scalable Low-cost cGMP Process for Clinical Grade Production of the HIV Inhibitor 5P12-RANTES in Pichia Pastoris.” Protein Expression and Purification 119: 1–10.
Vancouver
1.
Cerini F, Gaertner H, Madden K, Tolstorukov I, Brown S, Laukens B, et al. A scalable low-cost cGMP process for clinical grade production of the HIV inhibitor 5P12-RANTES in Pichia pastoris. PROTEIN EXPRESSION AND PURIFICATION. 2016;119:1–10.
IEEE
[1]
F. Cerini et al., “A scalable low-cost cGMP process for clinical grade production of the HIV inhibitor 5P12-RANTES in Pichia pastoris,” PROTEIN EXPRESSION AND PURIFICATION, vol. 119, pp. 1–10, 2016.
@article{7102653,
  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.},
  author       = {Cerini, Fabrice and Gaertner, Hubert and Madden, Knut and Tolstorukov, Ilya and Brown, Scott and Laukens, Bram and Callewaert, Nico and Harner, Jay C and Oommen, Anna M and Harms, John T and Sump, Anthony R and Sealock, Robert C and Peterson, Dustin J and Johnson, Scott K and Abramson, Stephan B and Meagher, Michael and Offord, Robin and Hartley, Oliver},
  issn         = {1046-5928},
  journal      = {PROTEIN EXPRESSION AND PURIFICATION},
  keywords     = {Process development,Pichia,Microbicide,5P12-RANTES,cGMP,MICROBICIDES,RANTES,EXPRESSION,CCR5,Biopharmaceutical,HIV,Chemokine,Yeast,VAGINAL TRANSMISSION,ENTRY INHIBITORS,RHESUS MACAQUES,HIGHLY POTENT,CHEMOKINES,PROTEIN,PROTECTION},
  language     = {eng},
  pages        = {1--10},
  title        = {A scalable low-cost cGMP process for clinical grade production of the HIV inhibitor 5P12-RANTES in Pichia pastoris},
  url          = {http://dx.doi.org/10.1016/j.pep.2015.10.011},
  volume       = {119},
  year         = {2016},
}

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