Rentschler tie-up with XL-protein expands CDMO’s growing biotechnological toolbox

By Jane Byrne

- Last updated on GMT

© GettyImages/Reptile8488
© GettyImages/Reptile8488

Related tags protein therapeutics Mammalian cell culture Autoimmune disease

Rentschler Biopharma and XL-protein have teamed up on the manufacture of what they say is a long-acting, hyperactive recombinant human deoxyribonuclease I (DNase I) that may open better treatment options for patients suffering from inflammation, chronic or autoimmune diseases.

The results of their tie-up pave the way for high yield manufacturing of other PASylated proteins and peptide drugs using mammalian cell culture on the bioprocessing platform of the Munch headquartered contract development and manufacturing organization (CDMO).

Dr Cora Kaiser, spokesperson for Rentschler, told this publication:

“In this collaboration, we were able to bring together XL-Protein’s know-how in PASylation, a biological alternative to PEGylation, with Rentschler Biopharma’s expertise in mammalian cell culture. The result is a hyperactive DNase I, which shows substantial benefits compared to existing, therapeutic DNase I.

“PASylation is a recombinant alternative to the established process of PEGylation and may offer clinical benefits like lower immunogenicity or extended biological availability.

“The main purpose of protein PASylation is to increase the protein’s hydrodynamic diameter. This will slow down metabolization of the protein by the kidney.

“The process developed at Rentschler Biopharma may serve as a platform for similar kinds of protein formats. Only slight adaptations in the downstream processing would be required based on different protein characteristics.”

Biopharmaceuticals based on mammalian cell culture might also benefit from this new technology, she added. “We this new technology potentially becoming a valuable new tool in an ever-expanding biotechnological toolbox.”

Improved patient adherence

Therapeutic DNase I has been used for more than 20 years to treat cystic fibrosis and holds the potential to be a promising treatment option for chronic as well as autoimmune diseases or inflammation. However, the short half-life of conventional DNase I requires high dosing frequency, which may result in low patient compliance and, in the case of cystic fibrosis, can lead to an elevated risk of lung infections.

The partners said the improved DNase I that they manufactured collaboratively demonstrated both extended systemic half-life in an animal model and increased enzymatic activity. “While its DNA-degrading activity is associated with a burden for the producing cell line, the high titer of recombinant protein achieved in the bioprocess is a remarkable success. The clinical application of this PASylated hyperactive DNase I could potentially offer improved patient adherence and better quality of life.”

Genetic fusion 

Arne Skerra, PhD, professor, chairman of the board and founder of XL-protein, who developed PASylation, explained that it involves the genetic fusion of a pharmacologically active protein or peptide with a polypeptide comprising several hundred Pro/Ala/Ser residues in defined sequence.

“This study has demonstrated thus such gene constructs can be stably integrated into a eukaryotic cell and lead to high expression yields, despite the large size of the resulting secreted protein,” ​he told us.

The PASylated DNase I with extended half-life and enhanced activity enhances the series of superior biopharmaceutical drug candidates designed with the help of PASylation technology, developed as part of XL-protein's in-house pipeline or with its external partners in the biopharmaceutical industry as well as by a growing number of academic research laboratories, commented Dr Skerra.

Processing promise

Apart from the obvious utility of a hyperactive PASylated DNase I with extended half-life as a second-generation therapy, he said the partnership with Rentschler Biopharma highlights broader prospects for PASylation technology:

  • High yield expression of PASylated proteins or peptides in a mammalian cell culture system; this opens new avenues for biopharmaceuticals that require structural disulfide bonds and/or native glycosylation (such as in the case of human DNase I) or other post-translational modifications which are not readily accessible via microbial expression systems.
  • Fast cell line generation paves the way for production of many other PASylated proteins or peptides in mammalian cell culture under tight timelines.
  • Quick development of an efficient downstream process yielding highly pure PASylated protein suitable for application in preclinical animal models, also providing a basis for biopharmaceutical production according to good manufacturing practice (GMP) as a prerequisite for subsequent clinical studies.

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