Treating liver cancer through arginine depletion.

Liver cancer, the sixth most common cancer globally and the second-leading cause of cancer-related deaths, presents a critical public health threat. Diagnosis often occurs in advanced stages of the disease, aligning incidence with fatality rates. Given that established treatments, such as stereotactic body radiation therapy and transarterial radioembolization, face accessibility and affordability challenges, the emerging focus on cancer cell metabolism, particularly arginine (Arg) depletion, offers a promising research avenue. Arg-depleting enzymes show efficacy against Arg-auxotrophic cancers, including hepatocellular carcinoma (HCC). Thus, in this review, we explore the limitations of current therapies and highlight the potential of Arg depletion, emphasizing various Arg-hydrolyzing enzymes in clinical development.

Towards development of biobetter: L-asparaginase a case study.

BACKGROUND: L-asparaginase (ASNase) has played a key role in the management of acute lymphoblastic leukaemia (ALL). As an amidohydrolase, it catalyzes the hydrolysis of L-asparagine, a crucial step in the treatment of ALL. Various ASNase variants have evolved from diverse sources since it was first used in paediatric patients in the 1960s. This review describes the available ASNase and approaches being used to develop ASNase as a biobetter candidate. SCOPE OF REVIEW: The review discusses the Glycosylation and PEGylation techniques, which are frequently used to develop biobetter versions of the majority of the therapeutic proteins. Further, it explores current ASNase biobetters in therapeutic use and discusses the protein engineering and chemical modification approaches that were employed to reduce immunogenicity, extend protein half-life, and enhance protease stability of ASNase. Emerging strategies like immobilization and encapsulation are also highlighted as potential pathways for improving ASNase properties. MAJOR CONCLUSIONS: The purpose of the development of ASNase biobetter is to achieve a novel therapeutic candidate that could improve catalytic efficiency, in vivo stability with minimum glutaminase (GLNase) activity and toxicity. Modification of ASNase by immobilization and encapsulation or by fusion technologies like Albumin fusion, Fc fusion, ELP fusion, XTEN fusion, etc. can be exploited to develop a novel biobetter candidate suitable for therapeutic approaches. GENERAL SIGNIFICANCE: This review emphasizes the importance of biobetter development for therapeutic proteins like ASNase. Improved ASNase molecules have the potential to significantly advance the treatment of ALL and have broader implications in the pharmaceutical industry.

Recombinant human endostatin as a potential anti-angiogenic agent: therapeutic perspective and current status.

Angiogenesis is the physiological process that results in the formation of new blood vessels develop from pre-existing vasculature and plays a significant role in several physiological and pathological processes. Inhibiting angiogenesis, a crucial mechanism in the growth and metastasis of cancer, has been proposed as a potential anticancer therapy. Different studies showed the beneficial effects of angiogenesis inhibitors either in patients suffering from different cancers, alone or in combination with conventional therapies. Even though there are currently a number of efficient anti-angiogenic drugs, including monoclonal antibodies and kinase inhibitors, the associated toxicity profile and their affordability constraints are prompting researchers to search for a safe and affordable angiostatic agent for cancer treatment. Endostatin is one of the endogenous anti-angiogenic candidates that have been extensively pursued for the treatment of cancer, but even over three decades after its discovery, we have not made much advancement in employing it as an anticancer therapeutic despite of its remarkable anti-angiogenic effect with low toxicity profile. A recombinant human endostatin (rh-Es) variant for non-small cell lung cancer was approved by China in 2006 and has since been used effectively. Several other successful clinical trials related to endostatin for various malignancies are either ongoing or have already been completed with promising results. Thus, in this review, we have provided an overview of existing anti-angiogenic drugs developed for cancer therapy, with a summary of tumour angiogenesis in the context of Endostatin, and clinical status of rh-Es in cancer treatment. Furthermore, we briefly discuss the various strategies to improve endostatin features (poor pharmacokinetic properties) for developing rh-Es as a safe and effective agent for cancer treatment.

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 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 (t1/2) and (iv) potent anti-cancer activity against human cancer cell lines under in vitro and in vivo conditions.

Human arginase I: a potential broad-spectrum anti-cancer agent.

With high rates of morbidity and mortality, cancer continues to pose a serious threat to public health on a global scale. Considering the discrepancies in metabolism between cancer and normal cells, metabolism-based anti-cancer biopharmaceuticals are gaining importance. Normal cells can synthesize arginine, but they can also take up extracellular arginine, making it a semi-essential amino acid. Arginine auxotrophy occurs when a cancer cell has abnormalities in the enzymes involved in arginine metabolism and relies primarily on extracellular arginine to support its biological functions. Taking advantage of arginine auxotrophy in cancer cells, arginine deprivation, which can be induced by introducing recombinant human arginase I (rhArg I), is being developed as a broad-spectrum anti-cancer therapy. This has led to the development of various rhArg I variants, which have shown remarkable anti-cancer activity. This article discusses the importance of arginine auxotrophy in cancer and different arginine-hydrolyzing enzymes that are in various stages of clinical development and reviews the need for a novel rhArg I that mitigates the limitations of the existing therapies. Further, we have also analyzed the necessity as well as the significance of using rhArg I to treat various arginine-auxotrophic cancers while considering the importance of their genetic profiles, particularly urea cycle enzymes.

Human arginase 1, a Jack of all trades?

Arginine, a conditionally essential amino acid, plays a crucial role in several metabolic and signalling pathways. Arginine metabolism in the body can be significantly increased under stress or during certain pathological conditions. Depletion of circulating arginine by administering arginine-hydrolysing enzyme has been shown to mitigate varied pathophysiological conditions ranging from cancer, inflammatory conditions, and microbial infection. This review provides an overview of such intriguing expanse of potential applications of recombinant human arginase 1 for different pathological conditions and its status of development.