Rentschler Biopharma and XL-protein demonstrate efficient production of a hyperactive PASylated DNase I with extended half-life

  • Hyperactive DNase I modified with XL-protein’s PASylation® technology demonstrated significantly extended systemic half-life in vivo, potentially offering improved treatment options for autoimmune diseases and cystic fibrosis.
  • Potential for high-yield manufacturing of other PASylated protein therapeutics in mammalian cell culture on Rentschler Biopharma’s bioprocessing platform.

Laupheim and Freising, Germany, October 26, 2021 – Rentschler Biopharma SE, a leading global contract development and manufacturing organization (CDMO) for biopharmaceuticals, and XL-protein GmbH, a privately owned biopharmaceutical company located in Germany, announce a successful collaboration to manufacture a long-acting, hyperactive recombinant human deoxyribonuclease I (DNase I). Combining XL-protein’s proprietary PASylation® technology and Rentschler Biopharma’s expertise in bioprocess development, a process was developed with enhanced yield for a modified DNase I showing both strongly increased activity and an extended pharmacokinetic profile. This PASylated DNase I may open better treatment options for patients suffering from inflammation, chronic or autoimmune diseases.

“This highly successful collaboration was due to Rentschler Biopharma’s strong expertise along the entire biopharmaceutical value chain ranging from cell line development, upstream and downstream processes to drug substance manufacturing in combination with XL-protein’s know-how and longstanding experience in the design of proteins with enhanced stability using its proprietary PASylation technology. The strong results from this case study pave the way for high yield manufacturing of other PASylated proteins and peptide drugs using mammalian cell culture on Rentschler Biopharma’s bioprocessing platform,” said Thilo Grob, Vice President Process Science at Rentschler Biopharma SE.

Dr. Michaela Gebauer, Co-Managing Director at XL-protein, commented: “PASylation technology is compatible with efficient production in diverse expression hosts, and we now have shown that it can be applied to Rentschler Biopharma’s robust high titer mammalian cell line development platform which also allows for native post-translational modification of recombinant human proteins. This success further demonstrates the strength and flexibility of our technology platform and its potential to support biopharmaceutical partners seeking to develop recombinant protein or peptide drugs with extended half-life and low immunogenicity.”

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 improved DNase I manufactured collaboratively by Rentschler Biopharma and XL-protein has 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.

Meet Rentschler Biopharma at PEGS Europe, Protein & Antibody Engineering Summit, November 2 – 4, 2021, Barcelona, Spain

  • A poster titled “Development of a Production Cell Line for PASylated Human DNase I with Extended Half-life” will be presented by Serge M. Stamm, Group Leader Production
  • A talk titled “Unleashing the full potential of therapeutic protein production with a state-of the-art expression platform” will be presented by Lucia Kirchgeorg, Director Business Development, on November 3 in the track Optimizing Expression Platforms at 9:30 a.m. CET
  • Federico Pollano, Senior Vice President Business Development, and his team are looking forward to meeting you at booth 304

About PASylated DNase I and PASylation® technology
PASylation® technology offers a biological alternative to PEGylation. The PASylated DNase I was generated using gene constructs encoding a hyperactive DNase I fused with an N-terminal PAS polypeptide comprising the small natural L-amino acids Pro, Ala and Ser in a defined sequence. The resulting modified DNase I demonstrated expanded hydrodynamic volume and a strongly extended pharmacokinetic profile in an animal model.

About Rentschler Biopharma SE
Rentschler Biopharma is a leading contract development and manufacturing organization (CDMO) focused exclusively on client projects. The company offers process development and manufacturing of biopharmaceuticals as well as related consulting activities, including project management and regulatory support. Rentschler Biopharma’s high quality is proven by its long-standing experience and excellence as a solution partner for its clients. A high-level quality management system, a well-established operational excellence philosophy and advanced technologies ensure product quality and productivity at each development and manufacturing step. In order to offer best-in-class formulation development along the biopharmaceutical value chain, the company has entered into a strategic alliance with Leukocare AG. Rentschler Biopharma is a family-owned company with about 1,100 employees, headquartered in Laupheim, Germany, with a second site in Milford, MA, USA. In Stevenage, UK, Rentschler Biopharma has launched a company dedicated to cell and gene therapies, Rentschler ATMP Ltd. For further information, please visit www.rentschler-biopharma.com.

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About XL-protein GmbH
XL-protein is a German biotech company commercializing its ground-breaking PASylation® technology, which enables the design of biopharmaceuticals with extended half-life and enhanced pharmacological action. Based on a strong proprietary technology position, XL-protein focuses at the preclinical as well as clinical development of PASylated proteins in diverse disease areas. XL-protein is engaged in a growing number of partnerships with international pharmaceutical and biotech companies at various levels.

For more information, please visit: www.xl-protein.com.

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XL-protein announces the Avi-PA(S)™ MAb platform to boost the preclinical and clinical development of therapies using its PASylation® technology

FREISING, GERMANY, July 12, 2021 – XL-protein GmbH, a German biotech company specialised in the development of biopharmaceuticals with extended half-life, announced today that key scientific data have been published in the Journal of Molecular Biology (2021, Vol. 433, Pub. no. 167113). The Open Access Publication “Molecular recognition of structurally disordered Pro/Ala-rich sequences (PAS) by antibodies involves an Ala residue at the hot spot of the epitope” is also available for download at XL-protein’s web site (http://www.xl-protein.com/key-publications).

PASylation® technology is based on the conjugation of pharmaceutically active compounds with a conformationally disordered polypeptide of defined sequence comprising the small natural amino acids Pro, Ala, and/or Ser, resulting in drastically enhanced stability in vivo. With its ground-braking technology XL-protein addresses a major limitation of biopharmaceutical proteins and peptides that often show fast clearance from circulation via kidney filtration, which strongly hampers efficacy in human therapy. PAS sequences are hydrophilic, uncharged, genetically encodable amino acid polymers. These PAS chains are conformationally disordered and occupy highly expanded hydrodynamic volume, thus showing biophysical properties very similar to poly-ethylene glycol (PEG) whose conjugation to drugs is a well-known method for plasma half-life extension.

PASylation® can be applied via genetic fusion or chemical coupling to many classes of pharmacologically active compounds, including proteins, peptides and low molecular weight drugs as well as nanoparticles, both for therapeutic purposes and in vivo diagnostics. PAS-drug conjugates show retarded kidney filtration and drastically prolonged pharmacokinetics (PK) in vivo. Likewise, PASylation leads to extended residence in the eye, where elimination of biopharmaceuticals also is strongly size-dependent, thus offering prospects for ophthalmology. The intrinsically uncharged PAS polypeptides do not interfere with the pharmacological activity of the drug component and show high stability in plasma as well as poor immunogenicity, while undergoing quick degradation and metabolization after cellular uptake. Therefore, PASylation® offers an attractive solution in applications with increased risk of PEG hypersensitivity.

With multiple projects heading towards clinical application and increasing interest from scientists in the biomedical area (as documented by a growing number of publications reporting the beneficial use of PASylation®) XL-protein succeeded in developing Avi-PA(S)™ MAbs as useful antibody tools for the preclinical as well as clinical development of PASylated drug candidates. XL-protein now offers these valuable immunochemical reagents to promote broader research on applications of PASylation® technology: https://xl-protein.com/shop

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About XL-protein GmbH

XL-protein is a German biotech company commercializing its ground-breaking PASylation® technology, which enables the design of biopharmaceuticals with extended in vivo half-life and enhanced action. Based on a strong proprietary technology position, XL-protein focuses at the preclinical as well as clinical development of PASylated drug candidates in diverse disease areas. XL-protein is engaged in a growing number of partnerships with international pharmaceutical and biotech companies at various levels.

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Akari Therapeutics Presents New Preclinical Data Highlighting Potential of Long-Acting PASylated Nomacopan to Treat Retinal Diseases, Including Age-Related Macular Degeneration (AMD) and Uveitis

NEW YORK and LONDON, Feb. 25, 2021 (GLOBE NEWSWIRE) — Akari Therapeutics, Plc (Nasdaq: AKTX), a late-stage biopharmaceutical company focused on innovative therapeutics to treat orphan autoimmune and inflammatory diseases where complement (C5) and/or leukotriene (LTB4) systems are implicated, announced today the publication of new data in the journal CELLS. The paper, entitled “Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis,” highlights the importance of the LTB4-VEGF axis in the development of sight-threatening retinal inflammation. In a non-infectious allergic uveitis animal model, PAS-nomacopan reduced VEGF by more than 50% compared to saline control, equivalent to the inhibition caused by an anti-VEGF antibody. In addition, PAS-nomacopan was significantly more effective in reducing retinal inflammation than the anti-VEGF antibody.

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XL-protein and Antlia Bioscience Announce Collaboration to Develop Long-acting Peptide Therapy of Chronic Heart Failure using PASylation® Technology

SAN DIEGO, U.S.A., and FREISING, Germany, 15th October, 2020: Antlia Bioscience, Inc., a privately owned biopharmaceutical company located in San Diego, California, and XL-protein GmbH, a privately owned biopharmaceutical company located in Germany, are pleased to announce a Strategic Alliance using XL-protein’s proprietary PASylation® technology for plasma half-life extension to develop a novel, long-acting, peptide therapeutic treatment for chronic heart failure. Brian Johnson, Antlia Bioscience’s CEO commented, “chronic heart failure is a significantly unaddressed medical condition and a major public health concern. XL-protein’s PASylation® technology will allow us to safely and effectively translate our peptide into a meaningful therapeutic option for patients with chronic heart failure. “PASylation® is an excellent biological solution for plasma-half extension of therapeutic peptides, and we believe that PASylation® offers a simpler manufacturing process and superior pharmacological properties,” commented Claus Schalper, CEO of XL-protein. “We are excited to work with Antlia Bioscience to further exploit the potential of our technology and to develop new therapeutic options for the treatment of chronic heart failure.” Financial terms of the agreement have not been disclosed.

About PASylation® Technology

‘PASylation’ involves the genetic fusion or chemical conjugation of a therapeutic protein or pharmaceutically active compound with a conformationally disordered polypeptide of defined sequence comprising the small natural amino acids Pro, Ala, and/or Ser. Due to the biophysical size effect, the typically rapid clearance via renal filtration of the original drug can be retarded by a factor 10-100, depending on the length of the PAS chain. PAS sequences are highly soluble while lacking charges, they are biochemically inert, non-toxic and non-immunogenic, they offer efficient recombinant protein production in a variety of biotechnological host organisms, and they show high stability in blood plasma but are biodegradable by intracellular proteases.

About XL-protein GmbH

XL-protein is a German biotech company commercializing its ground-breaking PASylation® technology, which enables the design of biopharmaceuticals with extended plasma half-life and enhanced action. Based on a strong proprietary technology position, XL-protein focuses at the preclinical as well as clinical development of PASylated proteins in diverse disease areas. XL-protein is engaged in a growing number of partnerships with international pharmaceutical and biotech companies at various levels.

For more information, please visit: www.xl-protein.com

About Antlia Bioscience, Inc.

Antlia Bioscience is a San Diego-based biotech developing groundbreaking peptide-based therapies to treat cardiovascular and metabolic diseases. Using PASylation® and other state-of-the-art techniques, we turn promising peptides into groundbreaking therapies. We are driven to make a profound difference in the treatment of cardiovascular and metabolic diseases and believe that our efforts will result in a paradigm shift in how cardiovascular and metabolic diseases will be treated in the future.

For more information, please visit: antliabio.com

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XL-protein and DNX Biopharmaceuticals Announce Collaboration to Develop Novel Inflammasome-Directed Therapeutics using PASylation® Technology

Freising, Germany and San Diego, CA, February 25, 2020 — XL-protein has extended its existing partnership with DNX Biopharmaceuticals, a biopharmaceutical company developing nonimmunogenic, long-acting therapeutic proteins for the treatment of patients with life-long diseases, to develop novel inflammasome-directed therapeutics for the treatment of diseases linked to inflammation, autoinflammation and oncology. DNX has exercised an option for an exclusive license to research, develop and commercialize a novel antagonist from within the DNX portfolio, modified by XL-protein’s PASylation® technology. Financial terms of the collaboration were not disclosed.

The Inflammasome is involved in the initiation and regulation of innate and acquired immunity, sterile inflammation, tissue remodeling, cell death, hypoxia-ischemia and organ failure. Dysfunctional signaling related to the inflammasome complex leads to smoldering or chronic inflammation, which is implicated in a wide range of pathological conditions, including cancer, heart disease, several systemic autoinflammatory conditions such as cryopyrin-associated periodic syndromes (CAPS), type II diabetes, rheumatoid arthritis (RA) and gout.

“We are pleased that DNX has chosen PASylation® technology for the design of biopharmaceuticals with extended plasma half-life and enhanced action,” comments Claus Schalper, CEO of XL-protein, adding that “DNX’s deal with Johnson & Johnson provides another validation of our proprietary platform.”

“We are delighted to be collaborating with XL-protein and the use of their PASylation® technology to progressing DNX’s novel receptor antagonists into clinical development,” said Rajiv Datar, Co-Founder and CEO of DNX.

About PASylation® Technology
‘PASylation’ involves the genetic fusion or chemical conjugation of a therapeutic protein or pharmaceutically active compound with a conformationally disordered polypeptide of defined sequence comprising the small natural amino acids Pro, Ala, and/or Ser. Due to the biophysical size effect, the typically rapid clearance via renal filtration of the original drug can be retarded by a factor 10-100, depending on the length of the PAS chain. PAS sequences are highly soluble while lacking charges, they are biochemically inert, non-toxic and non-immunogenic, they offer efficient recombinant protein production in a variety of biotechnological host organisms, and they show high stability in blood plasma but are biodegradable by intracellular proteases.

About XL-protein GmbH
XL-protein is a German biotech company commercializing its ground-breaking PASylation® technology, which enables the design of biopharmaceuticals with extended plasma half-life and enhanced action. Based on a strong proprietary technology position, XL-protein focuses at the preclinical as well as clinical development of PASylated proteins in diverse disease areas. XLprotein is engaged in a growing number of partnerships with international pharmaceutical and biotech companies at various levels.

For more information, please visit: www.xl-protein.com

About DNX Biopharmaceuticals, Inc.
DNX is a biopharmaceutical company developing long-acting therapeutic proteins for the treatment of patients with life-long diseases. Founded in 2014 and headquartered in San Diego, CA, USA, DNX is pursuing the development of new therapeutic proteins designed to target pathways in the autoinflammation-inflammation spectrum aiming to block key mediators of immunity and inflammation for treating diseases and disorders. DNX is a resident of Johnson and Johnson Innovation – JLABS, Shanghai, a JLABS QuickFire Challenge (QFC) winner and has just closed a deal with the Lung Cancer Initiative at Johnson and Johnson.

For more information, please visit: www.dnxbio.com

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DNX Biopharmaceuticals Announces Collaboration With Lung Cancer Initiative at Johnson & Johnson

San Diego, California–(Newsfile Corp. – February 18, 2020) – DNX Biopharmaceuticals, a biopharmaceutical company developing long-acting therapeutic proteins for the treatment of patients with life-long diseases and a resident of Johnson & Johnson Innovation – JLABS, Shanghai, announced today that it has entered into a strategic collaboration with the Lung Cancer Initiative at Johnson & Johnson*. Under terms of the agreement, the Lung Cancer Initiative has taken an exclusive license to research, develop and commercialize novel molecules from within the DNX portfolio. Financial terms of the collaboration were not disclosed.

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Akari Therapeutics Announces Preclinical Ophthalmic Data Showing Nomacopan Reduces Both Vascular Endothelial Growth Factor (VEGF) and Retinal Inflammation Supporting Nomacopan as a Potential Treatment Option for Back-of-the-Eye Diseases

NEW YORK and LONDON, Jan. 27, 2020 (GLOBE NEWSWIRE) — Akari Therapeutics, Plc (Nasdaq: AKTX), a biopharmaceutical company focused on innovative therapeutics to treat autoimmune and inflammatory diseases where the complement and/or leukotriene systems are implicated, announces new preclinical data indicating that nomacopan significantly reduced both retinal inflammation and intraocular VEGF.

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Akari Therapeutics Announces Expanded Ophthalmology Program Based on Positive Emerging Data on LTB4-C5 Dual Action in Surface and Back of the Eye Diseases

NEW YORK and LONDON, April 26, 2019 (GLOBE NEWSWIRE) — Akari Therapeutics, Plc (Nasdaq: AKTX), a biopharmaceutical company focused on innovative therapeutics to treat orphan autoimmune and inflammatory diseases where the complement and/or leukotriene systems are implicated, announced encouraging new data in both the surface and the back of the eye.

“This positive initial data from our ophthalmology program supports the potential efficacy of LTB4 and C5 inhibition in eye surface and back-of-the-eye diseases. Nomacopan as a dual action inhibitor of LTB4 and C5 has the potential to be a novel eye therapy in multiple ophthalmic indications,” said Clive Richardson, Interim Chief Executive Officer of Akari Therapeutics. “Akari intends to continue development of nomacopan and long acting nomacopan variants using both topical and intravitreal administration.”

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Ajinomoto and XL-protein forge Strategic Alliance to develop PASylated therapeutics applying the Corynex® platform

SAN DIEGO, U.S.A., and FREISING, Germany, 18th December, 2018: Ajinomoto Bio-Pharma Services, a fully owned subsidiary of Ajinomoto Co. Inc. (TSE: 2802), and XL-protein GmbH, a privately owned German biopharmaceutical company, are pleased to announce a Strategic Alliance. Ajinomoto will apply its proprietary Corynex® expression system together with XL-protein’s proprietary PASylation® technology for plasma half-life extension to develop a series of therapeutic compounds.

Ajinomoto and XL-protein have established the efficient production of a PASylated proprietary GLP-1 variant with extended half-life at laboratory scale yielding >3 grams soluble protein per liter bacterial culture including facile purification from the supernatant. The PASylated GLP-1 variant maintains high receptor affinity. In vivo pharmacokinetic studies in mice have revealed a drastically prolonged half-life, suggesting potentially weekly or biweekly dosing in human patients. Ajinomoto has started a partnering process for this molecule.

Michiya Kanzaki, Associate General Manager / Business Development of Ajinomoto commented, “We are very happy and excited about this strategic alliance. The alliance combining PASylation® and Corynex® expression technology will provide novel drug candidates with a prolonged half-life and cGMP ready production system with high yield, widening our offerings to the pharmaceutical companies and eventually a meaningful therapeutic option for patients.”

“PASylation® technology is the biological solution for plasma-half extension of therapeutic proteins and peptides. We believe that PASylation® offers a simpler manufacturing process and superior pharmacological properties,” commented Claus Schalper, CEO of XL-protein. “We are excited to work with Ajinomoto as a leading Japanese life science company to further exploit the potential of our technology and to develop new therapeutic options for the treatment of metabolic diseases.”

Financial terms of the agreement have not been disclosed.

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Horizon Pharma plc and XL-protein GmbH have entered into a collaboration agreement on a potential next-generation biologic for uncontrolled gout using PASylation® technology

FREISING, January 9, 2018 /XL-protein/ — Horizon Pharma plc (NASDAQ:HZNP) yesterday announced that it has entered into a collaboration agreement with XL-protein GmbH to identify clinical-stage program candidates that could use PASylation® technology to construct a next-generation gout biologic.

PASylation® technology is a biological alternative to synthetic PEGylation and is intended to extend both the half-life of uricase and the duration of treatment for people living with uncontrolled gout, and also has the potential for subcutaneous dosing.

If the agreement yields a clinical-stage candidate, Horizon Pharma will have the right to license the candidate.

About XL-protein GmbH
XL-protein is a German biotech company commercializing its ground-breaking PASylation® technology, which enables the design of biopharmaceuticals with extended plasma half-life and enhanced action. Based on a strong proprietary technology position, XL-protein focuses at the preclinical as well as clinical development of PASylated proteins in diverse disease areas. XL-protein is engaged in a growing number of partnerships with international pharmaceutical and biotech companies at various levels. For more information, please visit www.xl-protein.com

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