Development and characterization of fused human arginase I for cancer therapy

Development and characterization of fused human arginase I for cancer therapy

Recombinant human arginase I (rhArg I) have emerged as a potential candidate for the treatment of varied pathophysiological conditions ranging from arginine-auxotrophic cancer, inflammatory conditions and microbial infection. However, rhArg I have a low circulatory half-life, leading to poor pharmac...

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Bibliographic Details
Published in:Investigational new drugs Vol. 41; no. 5; pp. 652 - 663
Main Authors: Jawalekar, Snehal Sainath, Kawathe, Priyanka Sugriv, Sharma, Nisha, Anakha, J, Tikoo, Kulbhushan, Pande, Abhay H.
Format: Journal Article
Language:English
Published: New York Springer US 01-10-2023
Springer Nature B.V
Subjects:
Anticancer properties
Antitumor activity
Arginase
Cancer
Cancer therapies
Half-life
Human serum albumin
Inflammation
Life extension
Medicine
Medicine & Public Health
Microorganisms
Oncology
Pharmaceutical industry
Pharmaceuticals
Pharmacodynamics
Pharmacokinetics
Pharmacology/Toxicology
Polyethylene glycol
Proteins
Serum albumin
Tumor cell lines
Human arginase I
Auxotrophy
Fusion protein technology
Cancer
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Summary:Recombinant human arginase I (rhArg I) have emerged as a potential candidate for the treatment of varied pathophysiological conditions ranging from arginine-auxotrophic cancer, inflammatory conditions and microbial infection. However, rhArg I have a low circulatory half-life, leading to poor pharmacokinetic and pharmacodynamic properties, which necessitating the rapid development of modifications to circumvent these limitations. To address this, polyethylene glycol (PEG)ylated-rhArg I variants are being developed by pharmaceutical companies. However, because of the limitations associated with the clinical use of PEGylated proteins, there is a dire need in the art to develop rhArg I variant(s) which is safe (devoid of limitations of PEGylated counterpart) and possess increased circulatory half-life. In this study, we described the generation and characterization of a fused human arginase I variant (FHA-3) having improved circulatory half-life. FHA-3 protein was engineered by fusing rhArg I with a half-life extension partner (domain of human serum albumin) via a peptide linker and was produced using P. pastoris expression system. This purified biopharmaceutical (FHA-3) exhibits (i) increased arginine-hydrolyzing activity in buffer, (ii) cofactor - independency, (iii) increased circulatory half-life (t 1/2 ) and (iv) potent anti-cancer activity against human cancer cell lines under in vitro and in vivo conditions.
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ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-023-01387-y