Abstract
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.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Arginine is a semi-essential, cationic amino acid that serves as a precursor for the synthesis of peptides, proteins, polyamines, nitric oxides, and urea, among other things. As a result, it plays a role in a variety of metabolic activities including ammonia detoxification, hormone secretion, and immunomodulation (Morris 2006; Stasyuk et al. 2017). The urea cycle enzymes argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL) catalyse conversion of citrulline to arginine, which is an intermediate product of urea cycle. Arginase 1 (Arg 1), ornithine transcarbamylase (OTC), and ASS1 (found in liver cells), on the other hand, catabolise arginine to ornithine and urea, citrulline, and argininosuccinate, respectively (Lam et al. 2018). A few arginine-hydrolysing enzymes are being developed as a therapeutic agent for a variety of diseases and conditions. Arginine deiminase (ADI) converts l-arginine to l-citrulline and ammonia; nitric oxide synthase (NOS) converts l-arginine to l-citrulline and nitric oxide (NO); and arginine decarboxylase converts l-arginine to agmatine and carbon dioxide (Morris 2006; Caldwell et al. 2015). However, arginase 1 has emerged as a most promising candidate, owing to a slew of efficacy and toxicology-related factors.
Human arginase (Arg)
Arg (EC 3.5.3.1) is a metalloenzyme that hydrolyses arginine to ornithine and urea (Fig. 1; Caldwell et al. 2015). It is a homotrimeric enzyme with a molecular weight of 105 kDa and each subunit contains a Mn2+ metal ion centre (Khangulov et al. 1998). Mn2+ plays a role in catalysis by forming a metal-bound hydroxyl ion (from a water molecule) that serves as a nucleophile, attacking the guanidium carbon of the substrate arginine (Stone et al. 2010; Romero et al. 2012). The two isoforms of the enzyme, Arg 1 and Arg 2, are found mostly in the cytosol of hepatocytes and the mitochondrial compartment of non-hepatic organs, respectively, in humans (Srivastava et al. 2013; Burrage et al. 2015). Both the isoforms have a 60% amino acid sequence similarity, although they differ in gene location and function. Arginase 1 eliminates nitrogen via urea production, and its gene is found on chromosome 6. (6q.23; Ash 2004). Arginase 2, on the other hand, is primarily engaged in cellular development and proliferation, with its gene located on chromosome 14 (14q.24.1; Romero et al. 2012).
The deficiency of arginase 1 leads to a rare hyperargininaemia disorder, which is caused due to a point mutation (R291X) in its gene that results in a truncated protein. This leads to stunted growth and hyperammonia condition in humans (Lavulo et al. 2001). Several types of tumorigenic cells are auxotrophic to arginine due to the lower expression of OTC and/or ASS1 enzymes, and rely on extracellular arginine pool for their growth and survival. Similarly, numerous inflammatory and other disorders have been reported to arise from the imbalance of arginase expression and activity (Clemente et al. 2020). Thus, recombinant human arginase 1 (rhArg 1) is being developed for the treatment of a wide variety of pathophysiological conditions (Fig. 2).
Beneficial effects of recombinant human arginase 1 (rhArg 1) in various disorders/conditions
Arginase 1 deficiency
Arginase 1 deficiency is also known as hyperargininemia or argininemia. It is an autosomal recessive urea cycle disorder. It is a rare and progressive disorder resulting in excessive accumulation of arginine and other guanidine compounds in the blood. Loss of activity of arginase 1 protein due to mutation in ARG1 gene is a main reason for arginase 1 deficiency (Fig. 3; Terheggen et al. 1969; Böger 2007). The patients with arginase 1 deficiency essentially suffer from acute mental issues, neuro-cognitive deficiencies, and loss of ambulation, despite treatment with nitrogen scavenger drugs (Crombez and Cederbaum 2005; Helman et al. 2014; Asrani et al. 2018). In this context, Aeglea Biotherapeutics, a biotechnology company developing next-generation human enzyme to mitigate conditions with unmet medical needs, has achieved US-FDA approval, granting ‘Breakthrough Therapy Designation’ to Pegzilarginase for the mitigation of arginase 1 deficiency (Rowilson et al. 2019). Pegzilarginase is a PEGylated, cobalt substituted rhArg1 enzyme (Co-rhARG1-PEG) with average molecular weight of ~ 284 kDa and is believed to be superior to native enzyme with increased half-life, stability and catalytic activity. The first open label clinical trial of pegzilarginase was conducted on 16 patients with arginase 1 deficiency and it was found that plasma arginine level of 50% patients was effectively reduced to normal range, with no or less hypersensitivity reaction (Rowilson et al. 2019; Diaz et al. 2021).
Arginine-auxotrophic cancers
Amino acids are known to govern essential cellular processes in both normal and cancer cells, in addition to being involved in the production of peptides and proteins (Andersen et al. 2014). Because of their fast growth and multiplication, cancer cells require more nutrients, particularly amino acids, than typical healthy cells. In addition, certain cancer cells lose the ability to synthesise one or more amino acids (Fernandes et al. 2017). As a result, cancer cells become reliant on exogenous amino acid supplies to maintain their development and metabolism, i.e. cancerous cells become 'auxotrophic' for such amino acids. Thus, amino acid auxotrophy is being explored to develop amino acid deprivation therapy in which the supply of amino acids is inhibited, and this leads to the death of cancer cells (Wang et al. 2021). The use of the l-asparaginase enzyme in the treatment of paediatric acute lymphoblastic leukaemia (ALL) introduced the rationale of amino acid depletion for cancer therapy (Pieters et al. 2011; Phillips et al. 2013). In this regard, it is discovered that more than 30 malignancies are arginine auxotrophic (Jahani et al. 2018). Deficiency in synthesis of arginine from citrulline due to silencing of ASS1 gene or otherwise is a common cause of arginine auxotrophy (Fig. 3; Srivastava et al. 2013). ASS1 may operate as a carcinogenic agent (Tsai et al. 2018) or tumour suppressor (Miyamoto et al. 2017) or as a pro-metastatic factor (Shan et al. 2015) in different carcinomas; hence, its function in tumour biology remains uncertain. It is reported that the direct transactivation of ASS1 by p53 in response to genotoxic stress is the basis for its tumour suppressor function. ASS1 functions as an intrinsic Akt (protein kinase B) repressor by inhibiting the phosphorylation of Akt that is driven by arginine deprivation, though the process by which Akt detects the arginine availability as well as the connection of ASS1 to p53, a major tumour suppressor, is yet to be elucidated (Fig. 4; Miyamoto et al. 2017).
Methylation induced transcriptional silencing has been known to mediate ASS1 loss in some cancer cases (Delage et al. 2012). These include hepatocellular carcinoma (HCC), squamous cell carcinoma, cervical carcinoma, ovarian carcinoma, breast carcinoma, prostate carcinoma, colon carcinoma, lung carcinoma, osteosarcoma, glioblastoma, pre-myelocytic leukaemia and lymphoblastic leukaemia, acute myeloid leukaemia (AML), malignant melanoma, Hodgkin’s and non-Hodgkin’s lymphoma (Jahani et al. 2018). However, mechanisms like repression of the ASS1 promoter by hypoxia-inducible factor-1 alpha also may play a role in this (Tsai et al. 2009; Datta et al. 2020). Utilisation of this auxotrophy, via the employment of extracellular arginine depleting agents like recombinant human arginase 1, ameliorates such cancerous conditions keeping the normal functional host cells unaffected to a considerable extent (Datta et al. 2020). Even though conventional therapy such as radiotherapy and chemotherapy are available in the market for treatment of numerous cancer types, these treatments fail to get rid of cancer completely and recurrence of cancer is most likely to be seen during the treatment. Thus, there is a dire need to have targeted and efficacious therapy or combination of therapies. Numerous formulations of arginase 1, such as BCT-100, pegzilarginase (AEB1102) and pegtomarginase (PT01) have successfully entered clinical trials while other forms of arginase 1 are under pre-clinical studies (Schaubber et al. 2015; Rowilson et al. 2019; Leung and Shum 2019; Yu et al. 2021). Cheng and Chen disclose a formulation comprising of PEGylated rhArg1 and chemotherapeutic/target therapeutic drug (oxaliplatin, everolimus, paclitaxel or sorafenib) for treating liver or prostate cancer. Also, they have used BCT-100 for the treatment of leukaemia in combination with doxorubicin (Cheng et al. 2014). Further, BCT-100 in combination with chemical drugs such as capecitabine and oxaloplatin, 5-flurouracil or autophagy inhibitors (chloroquine) have shown promising results in clinical trials (Datta et al. 2020).
Viral infection
Several steps in the viral lifecycle of SARS-CoV-2 have been reported to depend on arginine (Grimes et al. 2020). A low arginine environment goes on to affect the production of the nucleocapsid protein (containing 6.9% arginine residues), that plays a significant role in interacting with the negatively charged ribonucleic acid (RNA) strands, enabling efficient virion packing (McBride et al. 2014). In fact, arginine residues on the spike protein are crucial enough to stabilise interaction of the virus with the host cell angiotensin-converting enzyme 2 (ACE2) receptor to facilitate viral entry (Saha et al. 2020). In this regard, studies on other viruses, such as the ribonucleic acid (RNA) influenza virus and the vaccinia virus, also revealed that arginine is essential for both DNA (Deoxyribonucleic acid) synthesis and virion packaging processes of these viruses (Schierhorn et al. 2017; Grimes et al. 2020). Depletion of arginine by utilising pegzilarginase has been reported to inhibit SARS-CoV-2 replication in Vero cells (Grimes et al. 2020). Additionally, arginine deprivation via the employment of arginase 1 has also been found to attenuate pulmonary inflammation, one of the threatening consequences of COVID-19 (Xu et al. 2020). By limiting the availability of arginine for production of nitric oxide (NO) especially via inducible NOS, it might be possible to restrict the hyper-inflammatory response in COVID-19 infection to a considerable extent (Saha et al. 2020). However, such findings are subject to further internal and external grades of validation. In fact, arginine deprivation has been examined as a potential therapeutic strategy against viral infections at the in vitro level of studies, with more success in the context of herpesviridae and adenoviridae families (Becker et al. 1967; Inglis 1968; Sanchez et al. 2016). In herpes simplex virus (HSV)-1-infected cells, treatment with a PEGylated form of native arginase 1 was found to hinder viral replication and restrict production of viral progeny with minimisation of cell-to-cell transmission, thereby blocking the classical cytopathic effects of HSV-1 (Sanchez et al. 2016). It has been reported that the utilisation of PEGylated rhArg1 is effective in acyclovir (a first-line medication for HSV infection) resistant HSV-1 infection (Timothy et al. 2013). In support of the effectiveness and safety of therapeutic arginine depletion as an anti-viral therapy, a clinical trial employing ADI-PEG20 on patients with hepatitis C virus (HCV) serotype 1B showed a viral load decrease of more than 90% (Yang et al. 2010).
Immune-related conditions
Immune system is a highly developed, pervasive system which helps to maintain the integrity of host body by recognising the self and ‘foreign’ cells. Immune-related diseases are caused by either hypoactive immune system, in which it fails to defend against the foreign antigens and gives rise to immune-deficient conditions, or hyperactive immune system, where it causes autoimmune disorders due to loss of ability to recognise self-cells (Chaplin et al. 2010). Schabbauer et al. have highlighted the use of PEGylated form of rhArg 1 in treating inflammatory autoimmune diseases (rheumatoid arthritis, multiple sclerosis), supresses the immune response by inhibiting T-cell polarisation, modulate cytokine (IL-6, IFN-γ) release, bone dysfunction (osteoporosis), and organ transplant rejection (Schabbauer et al. 2015). Attention on the role of arginase 1 in immune response increased enormously when it was reported that activated murine macrophages utilise l-arginine with the help of Th2 cytokine induced arginase 1 to form downstream arginine metabolites such as l-ornithine, polyamines and l-proline. These metabolites play a major role in cell proliferation, immune system as well as neuronal regeneration (Munder 2009; Martí and Reith 2021). l-arginine, upon hydrolysis by arginase 1, produces ornithine and urea. Ornithine has essential role in biosynthesis of polyamines. Arginase and ornithine decarboxylase enzymes are rate limiting for production of polyamines (Shosha et al. 2018). Further in vitro and in vivo studies showed that PI3K/PTEN-regulated extracellular arginase 1 in macrophage has regulatory role in immunity and inflammation (Cheng et al. 2008; Sahin et al. 2014). Based on this aspect, BCT-100 was used for immune system modulation studies in cultured cells and mouse models, which showed anti-inflammatory effect by reducing pro-inflammatory cytokines. Pre-incubation of dendritic cells with BCT-100 (30 μg/ml) showed reduced levels of T-helper cells (Th1 and Th17), which induce the secretion of pro-inflammatory cytokines interferon-γ (IFN-γ) and interleukines-17A (IL-17A). This shows the aptness of rhArg 1 to inhibit T-cell polarisation, thereby being an effective solution for T-cell-mediated autoimmune condition like acute disseminated encephalomyelitis (ADEM). Schabbauer et al. (2015) ADEM is an auto-immune condition resulting in inflammation of brain, spinal cord and demyelination of nerves of central nervous system (CNS; Garg 2003). In this context, administration of BCT-100 (10 mg/kg) in experimental autoimmune encephalomyelitis mouse model showed reduced level of IFN-γ and IL-17A cytokines, particularly in lymph nodes, which led to significant reduction in severity and disease progression (Schabbauer et al. 2015).
Multiple sclerosis is an autoimmune chronic disease related to central nervous system where immune cells attack nerve fibre and degrade myelin sheath in CNS, leading to neurodegeneration (Corraliza et al. 1995). This condition can be treated by reducing formation of NO and reactive oxygen species (ROS) which aids in reducing oxidative stress and inflammation (Lange et al. 2004). It was reported that loss of arginase 1 in myeloid cells worsens retinal ischaemia–reperfusion (IR) injury, and macrophages lacking arginase 1 have impaired inflammatory response (Fouda et al. 2018). IR of the retina causes cellular damage in a variety of ocular diseases, such as retinal vascular occlusions, glaucoma, as well as in diabetic retinopathy (Hartsock et al. 2016). Interestingly, administration of PEGylated rhArg 1 in macrophages isolated from mouse retinal IR injury model showed that recombinant human arginase 1 therapy lowered retinal IR injury and suppressed the inflammatory response of macrophages (Qualls et al. 2010; Fouda et al. 2018).
Osteoporosis is a condition with increased risk of fractures, which develops due to the reduction of bone density, that makes bones fragile (Lin and Lane 2004). Bone homeostasis is necessary for bone remodelling, which is accomplished by proper co-ordination between formation of bone by osteoblast and its resorption by osteoclast (Matsuoka et al. 2014). One of the major causes of osteoporosis is the imbalance of osteoclast–osteoblast interaction during chronic inflammation, that results in increased rate of osteoclast differentiation through receptor activator of nuclear factor kappa-Β ligand (RANKL) signalling, which is produced by immune cells such as dendritic cells, neutrophils and T lymphocytes (Pietschmann et al. 2016). Bone marrow cells from mice were treated with RANKL and Macrophage colony-stimulating factor (M-CSF) were subjected to dose-dependent administration of BCT-100 ranging from 1 to 1000 ng/ml. It was found that a high dosage of recombinant arginase 1 can inhibits osteoclastogenesis and reduce the expression of RANK, TRAP and NFAT c1 genes which are necessary for osteoclast formation. This pre-clinical study using BCT-100 also demonstrated the therapeutic potential of recombinant arginase 1 in osteoporosis (Schabbauer et al. 2015). Rheumatoid arthritis is an autoimmune chronic inflammatory disease mainly affecting joints, bones, and causing pain, inflammation and swelling of affected organs. Collagen induced mice were used to see the effect of recombinant human arginase 1. It was observed that blood level of inflammatory cytokines such as IL-17A, ILP2/23 and IL-6 decreased drastically. These studies manifest the importance of arginase 1 in inflammatory conditions (Leung et al. 2010).
Metabolic disorders
Obesity is a disorder resulting from the accumulation of excessive amount of body fat, which leads to many metabolic disorders such as insulin resistance, dyslipidaemia, hypertension, type-2 diabetes mellitus, cardiovascular diseases and cancer which are considered as some of the major global health challenges of this century (Engin 2017). It was reported that intermittent fasting is an effective method against obesity and related metabolic disorders, as it can induce autophagic flux in cells. Autophagy is a catabolic process which gets activated due to amino acid starvation during intermittent fasting with the help of mechanistic target of rapamycin (mTOR) complex 1, which senses amino acid availability in cells (Fig. 5; Goberdhan et al. 2016; Zachari et al. 2017). Hong Kong Polytechnic University disclosed an ‘arginase 1-albumin binding domain fusion protein’ (N-ABD094-rhArg) which is capable of mimicking intermittent fasting and inducing autophagic flux. Their studies showed anti-obesity effect of arginase 1-albumin binding domain fusion protein (600U) in C57BL/6J mouse strain. Within 6–7 weeks itself effective weight loss was observed and the animals showed improvement in insulin responsiveness as well as glucose tolerance, which highlighted its therapeutic potential in insulin-resistance diseases. They have also reported that fusion (cobalt substituted rhArg-N-ABD094-rhArg-Co2+) and PEGylated form (PEG-His-rhArg) of arginase 1 showed reverse adiposity and reduction in fat mass in high fat diet (HFD) fed mouse model (Leung et al. 2021). Furthermore, it was observed that HFD induced obesity mouse model administered with N-ABD094-rhArg (500U) can reduce lipogenesis, thereby decreasing triglyceride content and lipotoxicity in organs such as liver, heart and pancreas. This demonstrates the possibility of using rhArg 1 for the treatment of steatosis, an abnormal accumulation of lipids inside the cells. The pre-clinical study in mouse model also showed that N-ABD094-rhArg can downregulate the expression of pro-inflammatory adipokine monocyte chemoattractant protein 1 (Mcp1) in white adipose tissues, which is responsible for obesity-induced inflammation (Leung et al. 2020). All these results indicate the significance of modified/fusion recombinant human arginase 1 as a therapeutic drug in obese-related disorders.
Development of rhArg 1 for therapeutic use
Native hArg 1 has an optimal pH of 9.6, making it less effective at physiological pH. Furthermore, arginase 1 shows Km value of 10.5 mM for arginine substrate, implying that a substantial amount of the enzyme is required to achieve the desired results. Also, arginase 1 has circulation half-life of ~ 30 min resulting in inferior pharmacokinetic and pharmacodynamic features. This aspect limits the applicability of the native form of arginase 1, necessitating the urgent development of modifications to overcome these constraints (Patil et al. 2016; Datta et al. 2020). Two of these modified enzymes are discussed below.
PEGylated rhArg 1
The Hong Kong-based Bio-cancer Treatment International Limited (BCT) has been working on the development of rhArg 1 for therapeutic usage (Hsueh et al. 2012; Cheng et al. 2014). BCT has announced that microbial expression systems, such as Bacillus subtilis and Escherichia coli, can be used to make recombinant human arginase 1. The rhArg 1 is linked to PEG-5000 using a succinamide propionic acid linker (BCT-100) to increase its circulatory half-life (Cheng et al. 2007). BCT-100 was shown to be functionally active, with a half-life of 3 days in vivo, and to be efficacious against a variety of arginine auxotrophic malignancies, including melanoma, prostate cancer, acute myeloid leukaemia, and HCC (Xiong et al. 2016). Apart from it, Aeglea BioTherapeutics at Austin in the United States has been developing rhArg 1 for therapeutic applications. They discovered that replacing two Mn2+ ions in the active region of the native enzyme with Co2+ results in a significant increase in the enzyme affinity for arginine (Georgiou and Stone 2014; Wang et al. 2016; Iyengar et al. 2019). At physiological pH, the combination of these effects is reported to result in a ten-fold increase in the enzyme's total catalytic activity. The addition of Co2+ enhances the serum stability of the enzyme, resulting in a 12–15 times reduction in the IC50 value for killing HCC and melanoma cell lines (Stone et al. 2010). US-FDA has approved the investigational new drug (IND) application of pegtomarginase, which is a site-specific linear PEGylated rhArg1, for the treatment of patients with advance stage carcinomas (Datta et al. 2020).
Regardless of the efficacy of PEGylation in the modification of therapeutic proteins, clinical use of PEGylated proteins is recognised to have a few numbers of drawbacks, prompting bio-therapeutic companies to find more cost-effective and safer ways for the modification of therapeutic proteins. PEG toxicity, immunogenicity, and hypersensitivity to PEG are all aspects to consider, as are challenges emerging from the heterogeneity of PEGylated proteins and the cost of generating PEGylated proteins (Langenheim and Chen 2009; Fee and Alstine 2011; Li et al. 2013; Haeckel et al. 2016).
Fusion rhArg 1
The fused protein undergoes either neonatal fragment crystallizable receptor (FcRn)-mediated recycling and/or reduced glomerular clearance when rhArg 1 is genetically fused to the IgG Fc domain (Sockolosky et al. 2012). IgG1, IgG2, and IgG4 have been found to have nominal circulatory half-lives of ~ 480 h, whereas IgG3 has a half-life of ~ 144 h (Strohl 2015). It is reported that other properties of fusion proteins, such as solubility and stability are also improved by Fc fusion (Levin et al. 2015). Furthermore, anti-cancer activity of IgG1 Fc fused to rhArg 1 (rhArg 1-Fc), with a circulatory half-life of 4 days, has been investigated and found that it can be used as a therapeutic candidate for malignancies (Li et al. 2013). According to in vitro mutagenesis and related binding studies, it is observed that the conserved H166 residue of the human FcRn heavy chain, positioned opposite the FcRn-IgG contact site, plays a key role in the pH-dependent FcRn–albumin interaction (Zhao et al. 2013). A patent also describes engineering and characterisation of rhArg 1 albumin binding domain fusion protein, with a claimed circulatory half-life of 7 days (Leung et al. 2019). Using protein engineering approach, we have also engineered fusion variants of hArg1 in which the hArg1 enzyme is fused to a variety of half-life extension partners (HLEPs) via peptide linker. The lead engineered human arginase 1 (EHA) variant exhibited not only enhanced in vivo circulatory half-life but also desirable anti-cancer activity in a mouse xenograft model of hepatic cancer (data not published).
Conclusion
Arginine is a versatile amino acid that is essential to many physiological and pathological processes. Moreover, arginine plays a crucial hub role in the viral lifecycle of several viruses, including SARS-CoV-2, herpesviridae, and adenoviridae families. Arginine requirement in the body can be substantially increased during conditions such as rapid growth, stress or pathological circumstances. Thus, the import of arginine from the extracellular fluid is necessary for cells lacking the enzyme(s) necessary for its biosynthesis. Also, many malignant cells depend on the body pool of arginine for growth and maintenance because they lack or produce inadequate levels of the enzyme(s) required for arginine synthesis. Hence, depletion of arginine by administering arginine-hydrolysing enzyme has emerged as a powerful approach to selectively target and destroy such pathophysiological conditions. rhArg 1 is a potential candidate, not only for the treatment of a variety of cancers but also for a vast expanse of other pathological conditions including viral infections, multiple sclerosis, rheumatoid arthritis, autoimmune diseases, congenital hyperargininaemia, inflammation, obesity, and metabolic disorders and related complications and comorbidities (either alone or in combination with other drugs). However, issues concerning its pharmacokinetic profile do threaten to compromise its therapeutic functionality. The successful development of fusion variant(s) of rhArg 1 with increased circulatory half-life, therefore, is an important leap towards developing a safer and longer acting arginase 1 molecule for clinical use.
Abbreviations
- ACE2:
-
Angiotensin-converting enzyme 2
- ADEM:
-
Acute disseminated encephalomyelitis
- ADI:
-
Arginine deiminase
- ALL:
-
Acute lymphoblastic leukaemia
- AML:
-
Acute myeloid leukaemia
- Arg:
-
Arginase
- ARG1:
-
Arginase 1
- ASL:
-
Argininosuccinate lyase
- ASS1:
-
Argininosuccinate synthetase
- CNS:
-
Central nervous system
- DNA:
-
Deoxyribonucleic acid
- Fc:
-
Fragment crystallizable
- FcRn:
-
Neonatal Fc receptor
- FDA:
-
Food and Drug Administration
- EHA:
-
Engineered human arginase
- HCC:
-
Hepatocellular carcinoma
- HCV:
-
Hepatitis C virus
- HFD:
-
High fat diet
- HLEP:
-
Half-life extension partners
- HSV-1:
-
Herpes simplex virus-1
- IFN-γ:
-
Interferon-γ
- Ig:
-
Immunoglobulin
- IL-17A:
-
Interleukines-17A
- IND:
-
Investigational new drug
- iNOS:
-
Inducible nitric oxide synthase
- IR:
-
Ischaemia–reperfusion
- Mcp1:
-
Monocyte chemoattractant protein
- M-CSF:
-
Macrophage-colony-stimulating factor
- mTOR:
-
Mechanistic target of rapamycin
- NFAT c1:
-
Nuclear factor of activated T cells, cytoplasmic 1
- NO:
-
Nitric oxide
- NOS:
-
Nitric oxide synthase
- OTC:
-
Ornithine transcarbamylase
- PEG:
-
Polyethylene glycol
- PI3K:
-
Phosphoinositide 3-kinase
- PTEN:
-
Phosphatase and Tensin Homolog
- RANK:
-
Receptor activator of nuclear factor κ B
- RANKL:
-
Receptor activator of nuclear factor kappa-Β ligand
- rhArg 1:
-
Recombinant human arginase 1
- RNA:
-
Ribonucleic acid
- SARS-COV-2:
-
Severe acute respiratory syndrome coronavirus 2
- Th 1/17:
-
T-helper cell 1/17
- TRAP:
-
TNF receptor-associated protein
References
Andersen JT, Dalhus B et al (2014) Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding. J Biol Chem 289(19):13492–13502. https://doi.org/10.1074/jbc.M114.549832
Ash DE (2004) Structure and function of arginases. J Nutr 134:2760–2764. https://doi.org/10.1093/jn/134.10.2760S
Asrani KH, Cheng L et al (2018) Arginase I mRNA therapy—a novel approach to rescue arginase 1 enzyme deficiency. RNA Biol 15:914–922. https://doi.org/10.1080/15476286.2018.1475178
Becker Y, Olshevsky U et al (1967) The role of arginine in the replication of herpes simplex virus. J Gen Virol 1:471–478. https://doi.org/10.1099/0022-1317-1-4-471
Böger RH (2007) The pharmacodynamics of l-arginine. J Nutr 137:1650–1655. https://doi.org/10.1093/jn/137.6.1650S
Burrage LC, Sun Q et al (2015) Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. Hum Mol Genet 24:6417–6427. https://doi.org/10.1093/hmg/ddv352
Caldwell RB, Toque HA et al (2015) Arginase: an old enzyme with new tricks. Trends Pharmacol Sci 36:395–405. https://doi.org/10.1016/j.tips.2015.03.006
Chaplin DD (2010) Overview of the immune response. J Allergy Clin Immunol 125(3–23):1. https://doi.org/10.1016/j.jaci.2009.12.980
Cheng PN, Lam TL et al (2007) Pegylated recombinant human arginase (rh-Arg-peg5, 000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion. Can Res 67:309–317. https://doi.org/10.1158/0008-5472
Cheng NM (2013) Use of pegylated recombinant human arginase for treatment of leukemia. US 2013/0295073 A1
Cheng NM, Chen L (2014) Combinational use of pegylated recombinant human arginase with chemotherapeutic/target therapeutic drug in cancer treatment. WO 2014/001956 A2
Cheng NM, Leung YC, et al (2008) Use of arginase in combination with 5FU and other compounds for treatment of human malignancies. 20080292609A1
Cheng NM, Leung YC et al (2014) Pharmaceutical preparation and method of treatment of human malignancies with arginine deprivation. US 008679810B2
Clemente S, van Waarde A et al (2020) Arginase as a potential biomarker of disease progression: a molecular imaging perspective. Int J Mol Sci 21:5291. https://doi.org/10.3390/ijms21155291
Corraliza IM, Soler G et al (1995) Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages. Biochem Biophys Res Commun 206:667–673. https://doi.org/10.1006/bbrc.1995.1094
Crombez EA, Cederbaum SD (2005) Hyperargininemia due to liver arginase and metabolism. Mol Genet Metab 84:243–251. https://doi.org/10.1016/j.ymgme.2004.11.004
Datta S, Kawathe P, et al (2020) Human arginase I (Arg I)—a potential broad-spectrum anti-cancer agent: perspectives and the road ahead. Res Rev J Oncol Hematol 9:23–35. https://doi.org/10.37591/rrjooh.v9i3.2312
Delage B, Luong P et al (2012) Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis 3:342. https://doi.org/10.1038/cddis.2012.83
Diaz GA, Schulze A et al (2021) Clinical effect and safety profile of pegzilarginase in patients with arginase 1 deficiency. J Inherit Metab Dis 44:847–856. https://doi.org/10.1002/jimd.12343
Engin A (2017) The definition and prevalence of obesity and metabolic syndrome. Adv Exp Med Biol 960:1–17. https://doi.org/10.1007/978-3-319-48382-5_1
Fee CJ, Van Alstine JM (2011) Purification of pegylated proteins. Methods Biochem Anal 54:339–362. https://doi.org/10.1002/9780470939932.ch14
Fernandes HS, Silva Teixeira CS et al (2017) Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections. Expert Opin Therap Patents 27(3):283–297. https://doi.org/10.1080/13543776.2017.1254194
Fouda AY, Xu Z et al (2018) Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses. Cell Death Dis 9:1001. https://doi.org/10.1038/s41419-018-1051-6
Friedman JM (2000) Obesity in the millennium. Nature 404:632–634. https://doi.org/10.1038/35007504
Garg RK (2003) Acute disseminated encephalomyelitis. Postgrad Med J 79:11–27. https://doi.org/10.1136/pmj.79.927.11
Georgiou E, Stone E (2014) Composition of engineered human arginases and methods for treating cancer. 20140242060A1
Goberdhan DC, Wilson C et al (2016) Amino acid sensing by mTORC1: intracellular transporters mark the spot. Cell Metab 23:580–589. https://doi.org/10.1016/j.cmet.2016.03.013
Grimes JM, Khan S et al (2020) Arginine depletion as a therapeutic approach for patients with COVID-19. Int J Infect Dis. https://doi.org/10.1016/j.ijid.2020.10.100
Haeckel A, Appler F et al (2016) XTEN as biological alternative to PEGylation allows complete expression of a protease-activatable killin-based cytostatic. PLoS ONE 11:e0157193. https://doi.org/10.1371/journal.pone.0157193
Hartsock MJ, Cho H et al (2016) A mouse model of retinal ischemia-reperfusion injury through elevation of intraocular pressure. J Vis Exp 113:54065. https://doi.org/10.3791/54065
Helman G, Pacheco-Colón I et al (2014) The urea cycle disorders. Semin Neurol 34(3):341–349. https://doi.org/10.1055/s-0034-1386771
Hsueh EC, Knebel SM et al (2012) Deprivation of arginine by recombinant human arginase in prostate cancer cells. J Hematol Oncol 5:17. https://doi.org/10.1186/1756-8722-5-17
Inglis VB (1968) Requirement of arginine for the replication of herpes virus. J Gen Virol 3:9–17. https://doi.org/10.1099/0022-1317-3-1-9
Iyengar AS, Gupta S et al (2019) Protein chimerization: a new frontier for engineering protein therapeutics with improved pharmacokinetics. J Pharmacol Exp Ther 370:703–714. https://doi.org/10.1124/jpet.119.257063
Jahani M, Noroznezhad F et al (2018) Arginine: challenges and opportunities of two-faced molecule in cancer therapy. Biomed Pharmacother 102:594–601. https://doi.org/10.1016/j.biopha.2018.02.109
Khangulov SV, Sossong TM et al (1998) l-arginine binding to liver arginase requires proton transfer to gateway residue His141 and coordination of the guanidinium group to the dimanganese (II, II) center. Biochemistry 37:8539–8550. https://doi.org/10.1021/bi972874c
Lam SK et al (2018) Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models. Oncol Rep 40:1994–2004. https://doi.org/10.3892/or.2018.6598
Lange PS, Langley B et al (2004) Novel roles for arginase in cell survival, regeneration, and translation in the central nervous system. J Nutr 134:2812–2827. https://doi.org/10.1093/jn/134.10.2812S
Langenheim JF, Chen WY (2009) Improving the pharmacokinetics/pharmacodynamics of prolactin, GH, and their antagonists by fusion to a synthetic albumin-binding peptide. J Endocrinol 203:375–387. https://doi.org/10.1677/JOE-09-0211
Lavulo LT, Sossong TM et al (2001) Subunit–subunit interactions in trimeric arginase: generation of active monomers by mutation of a single amino acid. J Biol Chem 276:14242–14248. https://doi.org/10.1074/jbc.M010575200
Leung S, Liu X et al (2010) The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease. Cell Mol Immunol 7:182–189. https://doi.org/10.1038/cmi.2010.22
Leung YC, Shum AS (2019) Composition and application of arginine-depleting agents for cancer, obesity, metabolic disorders, and related complications and comorbidities. WO2019228510A1
Leung YC, Shum AS (2020) Composition and application of arginine-depleting agents for cancer, obesity, metabolic disorders, and related complications and comorbidities. 20200181597A1
Leung YC, Shum AS, et al (2021) Methods for inducing intermittent fasting and modulating autophagy. WO 2021/110071 A1
Levin D, Golding B et al (2015) Fc fusion as a platform technology: potential for modulating immunogenicity. Trends Biotechnol 33:27–34. https://doi.org/10.1016/j.tibtech.2014.11.001
Li L, Wang Y et al (2013) An engineered arginase FC protein inhibits tumor growth in vitro and in vivo. Evidence-Based Complementary and Alternative Medicine. https://doi.org/10.1155/2013/423129
Lin JT, Lane JM (2004) Osteoporosis: a review. Clin Orthop Relat Res 425:126–134
Martí AA, Reith W (2021) Arginine-dependent immune responses. Cell Mol Life Sci 78:5303–5324. https://doi.org/10.1007/s00018-021-03828-4
Matsuoka K, Park KA et al (2014) Osteoclast-derived complement component 3a stimulates osteoblast differentiation. J Bone Miner Res 29:1522–1530. https://doi.org/10.1002/jbmr.2187
McBride R, Van Zyl M et al (2014) The coronavirus nucleocapsid is a multifunctional protein. Viruses 6:2991–3018. https://doi.org/10.3390/v6082991
Miyamoto T, Lo PHY et al (2017) Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53. Sci Adv 3(5):e1603204. https://doi.org/10.1126/sciadv.1603204
Morris SM Jr (2006) Arginine: beyond protein. Am J Clin Nutr 8:508–512. https://doi.org/10.1093/ajcn/83.2.508S
Munder M (2009) Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol 158:638–651. https://doi.org/10.1111/j.1476-5381.2009.00291.x
Patil MD, Bhaumik J et al (2016) Arginine dependence of tumor cells: targeting a chink in cancer’s armor. Oncogene 35:4957–4972. https://doi.org/10.1038/onc.2016.37
Phillips MM, Sheaff MT et al (2013) Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges. Cancer Res Treatment 45(4):251. https://doi.org/10.4143/crt.2013.45.4.251
Pieters R, Hunger SP et al (2011) l-Asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer 117(2):238–249. https://doi.org/10.1002/cncr.25489
Pietschmann P, Mechtcheriakova D et al (2016) Immunology of osteoporosis: a mini-review. Gerontology 62:128–137. https://doi.org/10.1159/000431091
Qualls JE, Neale G et al (2010) Arginine usage in mycobacteria-infected macrophages depends on autocrine–paracrine cytokine signaling. Sci Signal 3:135. https://doi.org/10.1126/scisignal.2000955
Romero PA, Stone E et al (2012) SCHEMA-designed variants of human arginase I and II reveal sequence elements important to stability and catalysis. ACS Synth Biol 1:221–228. https://doi.org/10.1021/sb300014t
Rowilson SW, Austin TX et al (2019) Methods and composition for treating Arginase 1 deficiency. 20190167770A1
Saha P, Banerjee AK et al (2020) A virus that has gone viral: amino acid mutation in S protein of Indian isolate of Coronavirus COVID-19 might impact receptor binding, and thus, infectivity. Biosci Rep 40:5. https://doi.org/10.1042/BSR20201312
Sahin E, Haubenwallner S et al (2014) Macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses. J Immunol 193:1717–1727. https://doi.org/10.4049/jimmunol.1302167
Sanchez MD, Ochoa AC et al (2016) Development and evaluation of a host-targeted antiviral that abrogates herpes simplex virus replication through modulation of arginine-associated metabolic pathways. Antiviral Res 132:13–25. https://doi.org/10.1016/j.antiviral.2016.05.009
Schabbauer G, Bluml S et al (2015) Methods and compositions for modulating the immune system with arginase 1. 20150315561A1
Schierhorn KL, Jolmes F et al (2017) Influenza A virus virulence depends on two amino acids in the N-terminal domain of its NS1 protein to facilitate inhibition of the RNA-dependent protein kinase PKR. J Virol 91(10):e00198-e217. https://doi.org/10.1128/JVI.00198-17
Shan YS, Hsu HP et al (2015) Argininosuccinate synthetase 1 suppression and arginine restriction inhibit cell migration in gastric cancer cell lines. Sci Rep 5(1):9783. https://doi.org/10.1038/srep09783
Shosha E, Fouda A et al (2018) Mechanisms of retinal ischemia/reperfusion injury: arginase and the mitochondria. FASEB J 32:824–833. https://doi.org/10.1096/fasebj.2018.32.1_supplement.824.3
Sockolosky JT, Tiffany MR et al (2012) Engineering neonatal Fc receptor-mediated recycling and transcytosis in recombinant proteins by short terminal peptide extensions. Proc Natl Acad Sci 109:16095–16100. https://doi.org/10.1073/pnas.1208857109
Srivastava S, Ratha BK (2013) Unique hepatic cytosolic arginase evolved independently in ureogenic freshwater air-breathing teleost, Heteropneustes fossilis. PLoS One. https://doi.org/10.1371/journal.pone.0066057
Stasyuk N, Gayda G et al (2017) Fluorometric enzymatic assay of l-arginine. Spectrochim Acta A Mol Biomol Spectrosc 170:184–190. https://doi.org/10.1016/j.saa.2016.07.019
Stone EM, Glazer ES et al (2010) Replacing Mn2+ with Co2+ in human arginase I enhances cytotoxicity toward l-arginine auxotrophic cancer cell lines. ACS Chem Biol 5:333–342. https://doi.org/10.1021/cb900267j
Strohl WR (2015) Fusion proteins for half-life extension of biologics as a strategy to make biobetters. BioDrugs 29:215–239. https://doi.org/10.1007/s40259-015-0133-6
Terheggen HG, Schwenk A et al (1969) Arginimaemia with arginase deficiency. Lancet 2:748–749
Timothy PF, James MH et al (2013) Methods for treatment of inflammatory and infectious diseases. US20140112902A1
Tsai W-B, Aiba I et al (2009) Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF-1α/Sp4. Mol Cancer Ther 8:3223–3233. https://doi.org/10.1158/1535-7163.MCT-09-0794
Tsai CY, Chi HC et al (2018) Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy. FASEB J 32(5):2601–2614. https://doi.org/10.1096/fj.201700094r
Wang B, Wang X et al (2016) Production of a therapeutic protein by fusing it with two fragments of the carboxyl-terminal peptide of human chorionic gonadotropin β-subunit in Pichia pastoris. Biotech Lett 38:801–807. https://doi.org/10.1007/s10529-016-2038-y
Wang Z, Xie Q et al (2021) Amino acid degrading enzymes and autophagy in cancer therapy. Front Pharmacol. https://doi.org/10.3389/fphar.2020.582587
Xiong L, Teng JL et al (2016) Arginine metabolism in bacterial pathogenesis and cancer therapy. Int J Mol Sci 17:363. https://doi.org/10.3390/ijms17030363
Xu Z, Shi L, Wang Y et al (2020) Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 8:420–422. https://doi.org/10.1016/S2213-2600(20)30076-X
Yang TS, Lu SN et al (2010) A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br J Cancer 103(7):954–960. https://doi.org/10.1038/sj.bjc.6605856
Yu KM, Pang TP et al (2021) Rational design, engineer, and characterization of a novel pegylated single isomer human arginase for arginine depriving anti-cancer treatment. Life Sci. 264:118674. https://doi.org/10.1016/j.lfs.2020.118674
Zachari M, Ganley IG (2017) The mammalian ULK1 complex and autophagy initiation. Essays Biochem 61(6):585–596. https://doi.org/10.1042/EBC20170021
Zhao S, Zhang Y et al (2013) Extending the serum half-life of G-CSF via fusion with the domain III of human serum albumin. Biomed Res Int 2013:107238. https://doi.org/10.1155/2013/107238
Acknowledgements
The authors thank Dr. Ipsita Roy, Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar for her valuable assistance in critical evaluation of the manuscript.
Funding
The authors thank the Department of Science and Technology (Grant No. CRG/2020/000865) and the National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (NPLC-AHP) for providing financial support.
Author information
Authors and Affiliations
Contributions
AJ and PSK contributed equally. AJ, PSK, SD and SSJ involved in conceptualization, data curation and writing the manuscript. UCB involved in reviewing and editing of the manuscript. AHP involved in conceptualization, visualisation, investigation, supervision, reviewing and editing. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Anakha, J., Kawathe, P.S., Datta, S. et al. Human arginase 1, a Jack of all trades?. 3 Biotech 12, 264 (2022). https://doi.org/10.1007/s13205-022-03326-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s13205-022-03326-9