pegylated recombinant human arginase (BCT-100) / BCT international - LARVOL DELTA

PEG-BCT-100 and canavanine synergistically induce apoptosis in arginine biosynthetic enzyme-deficient pancreatic cancer. (PubMed, Cancer Res Commun) - "From our in-house cohort and online database analysis, we found that the majority of the pancreatic cancer patients exhibited deficiencies in both ASS1 and OTC enzymes, suggesting that the combination of arginine deprivation and canavanine could be particularly effective in these patients. The ASS1- and OTC-negativity could also serve as predictive biomarkers for the response in other arginine-dependent cancers."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • ASS1

Treating liver cancer through arginine depletion. (PubMed, Drug Discov Today) - "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. Teaser: While pegylated recombinant human arginase 1 variants have demonstrated efficacy in treating cancers, including hepatocellular carcinoma, their toxicity limitations drive researchers to investigate safer solutions, with fused recombinant human arginase 1 variants emerging as a promising, affordable, effective, and safe option against liver cancer."

Journal • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

PARC: a phase I/II study evaluating the safety and activity of pegylated recombinant human arginase BCT-100 in relapsed/refractory cancers of children and young adults. (PubMed, Front Oncol) - P1/2 | "The RP2D of BCT-100 in children with relapsed/refractory cancers is established at 1600U/kg intravenously weekly and can lead to sustained disease stability in this hard to treat population. EudraCT, 2017-002762-44; ISRCTN, 21727048; and ClinicalTrials.gov, NCT03455140."

Journal • P1/2 data • Brain Cancer • CNS Tumor • Hematological Disorders • Oncology • Pediatrics • Solid Tumor

Intranasal EP4 agonist and Arginase-1 therapy in a murine model of asthma. (PubMed, Eur J Pharmacol) - "IV therapy with L-902,688 and BCT-100, a human pegylated arginase-1, ameliorated lung inflammatory features in a murine model of asthma...Asthmatic mice that received IN L-902,688 showed improved in vivo lung function. In conclusion, our results underline the potential of modulating MDSCs systemically or locally as a future therapeutic option in airway inflammatory diseases such as asthma."

Journal • Preclinical • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells. (PubMed, EMBO Rep) - "Moreover, BCT-100 is highly efficacious in a patient-derived xenograft model, causing > 90% reduction in the number of human leukaemic stem cells (LSCs). These findings indicate arginine depletion to be a promising and novel strategy to eradicate therapy resistant LSCs."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ASS1 • CD34

Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment. (PubMed, Int J Mol Sci) - "To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal."

Journal • Review • Oncology • ASS1

Radiation doses and accuracy of navigated pedicle screw placement in cervical and thoracic spine surgery: a comparison of sliding gantry CT and mobile cone-beam CT in a homogeneous cohort. (PubMed, J Neurosurg Spine) - "The applied radiation doses were significantly lower using SGCT for navigated pedicle screw placement in spinal instrumentation. A modern CT scanner on a sliding gantry leads to lower radiation doses, especially through automated 3D radiation dose adjustment."

Journal • Surgery • Orthopedics

A randomised evaluation of low-dose Ara-C plus pegylated recombinant arginase BCT-100 versus low dose Ara-C in older unfit patients with acute myeloid leukaemia: Results from the LI-1 trial. (PubMed, Br J Haematol) - "The survival of acute myeloid leukaemia (AML) patients aged over 60 has been suboptimal historically, whether they are treated using hypomethylating agents, low-dose cytarabine (LDAC) or venetoclax-based regimens. No significant difference in overall or median survival between treatment arms was seen. The addition of BCT-100 to LDAC was well tolerated."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Randomised Evaluation of Low-Dose Ara-C Plus BCT-100 Versus Low Dose Ara-C in Older Patients with Acute Myeloid Leukaemia: Results from the LI-1 Trial (ASH 2021) - "Between September 2018 and December 2020, 83 patients were randomised. The trial was prematurely closed due to the COVID pandemic and did not reach the pre-planned first evaluation. Median age was 76.7 years (range 62-88)."

Clinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Novel Coronavirus Disease • Oncology

Arginine Deprivation in SCLC: Mechanisms and Perspectives for Therapy. (PubMed, Lung Cancer (Auckl)) - "Small cell lung cancer (SCLC) displays marked arginine auxotrophy due to inactivation of the rate-limiting enzyme argininosuccinate synthetase 1 (ASS1), and as a consequence may be targeted with pegylated arginine deiminase or ADI-PEG20 (pegargiminase) and human recombinant pegylated arginases (rhArgPEG, BCT-100 and pegzilarginase). Moreover, recent work has identified an intriguing role for targeting arginine in combination with PD-1/PD-L1 immune checkpoint inhibitors and clinical trials are in progress. Thus, future studies of arginine-depleting agents with chemoimmunotherapy, the current standard of care for SCLC, may lead to enhanced disease control and much needed improvements in long-term survival for patients."

IO biomarker • Journal • Review • Immune Modulation • Inflammation • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • ASS1 • PD-1

Human arginase 1, a Jack of all trades? (PubMed, 3 Biotech) - "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."

Journal • Review • Infectious Disease • Oncology

PARC: A Study Evaluating the Safety and Activity of Pegylated Recombinant Human Arginase (BCT-100) (clinicaltrials.gov) - P1/2 | N=49 | Completed | Sponsor: University of Birmingham | Unknown status ➔ Completed | Trial completion date: Apr 2021 ➔ Jul 2022 | Trial primary completion date: Apr 2021 ➔ Jul 2022

Trial completion • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Brain Cancer • Hematological Malignancies • Oncology • Pediatrics • Sarcoma • Solid Tumor

Less Time Is Less Motion: Analysis of Practical Efficiencies Gained With a Modified Workflow Integrating Planar kV Midimaging With CBCT for Spine Stereotactic Body Radiation Therapy. (PubMed, Adv Radiat Oncol) - "Patient motion, detected as out-of-tolerance shifts on planar kV midimaging, occurred during 6 of 25 fractions (24%) and were validated on repeat CBCT 100% of the time...Accurate patient positioning was effectively achieved with use of multiple 2-dimensional-3-dimensional kV images and an average of 1 verification CBCT scan per fraction. Integration of planar kV midimaging can effectively reduce treatment time associated with spine SBRT delivery and minimize the potential dosimetric effect of intrafraction motion on target coverage and spinal cord dose."

Journal

Characterisation of Expression the Arginine Pathway Enzymes in Childhood Brain Tumours to Determine Susceptibility to Therapeutic Arginine Depletion. (PubMed, Biomed Res Int) - "Pegylated arginase (BCT-100) is currently in phase I/II trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in other tumour types and IHC analysis of patient tumour samples could help identify patients likely to benefit from this treatment."

Journal • Brain Cancer • Ependymoma • Glioblastoma • Glioma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • ARG2 • ASS1

Pegylated arginase isolated from beef liver tissue inhibited cell proliferation, induced apoptosis & inhibits induced mammary tumors in human breast cancer in vitro & in vivo (AACR 2022) - "Furthermore, the results also revealed a significant reduction in activities of ALT, AST, and ALP in the Peg-Arginase group compared to MNU untreated or native-Arginase groups, suggesting that Peg-Arginase may eliminate the hepatotoxic effect of the MNU. All in all, our results suggested that the arginine-depleting enzyme, Peg-Arginase, exerted an anticancer effect against both T-47D and MDA-MB-231 breast cancer cell lines through cell proliferation inhibition and apoptosis induction."

Preclinical • Breast Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CCND1 • CTNNB1 • MIR23A • TP53

Arginine- depleting enzyme, pegylated arginase, isolated from beef-liver tissue induces growth inhibition, apoptosis, cell cycle arrest and inhibits induced mammary tumors: A promising strategy for human breast cancer treatment in vitro and in vivo (SABCS 2021) - "Furthermore, Peg-Arginase treatment reduced the localization and expression of oncogenic β-catenin in the nucleus compared to MNU-untreated and native-Arginase groups. All in all, our results suggested that the arginine-depleting enzyme, Peg-Arginase, exerted an anticancer effect against both luminal A and triple-negative breast cancer cell lines, through cell proliferation inhibition and apoptosis induction, which might provide a promising alternative strategy targeting oncometabolite in human breast cancer."

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CCND1 • MIR23A • TP53

A phase 1 study of pegylated recombinant arginase (PEG-BCT-100) in combination with systemic chemotherapy (capecitabine and oxaliplatin)[PACOX] in advanced hepatocellular carcinoma patients. (PubMed, Invest New Drugs) - "The PACOX regimen demonstrated good anti-cancer activity and survival advantage in advanced pre-treated HCC with favourable safety profile. It warrants further phase II/III studies."

Clinical • Combination therapy • Journal • P1 data • Dermatology • Gastrointestinal Cancer • Hepatocellular Cancer • Mucositis • Oncology • Solid Tumor • Stomatitis

Efficacy Study of Pegylated Recombinant Human Arginase 1 as a Second-line Therapy in Patients With Advanced Liver Cancer (clinicaltrials.gov) - P2; N=27; Completed; Sponsor: Bio-Cancer Treatment International Limited; Terminated ➔ Completed

Trial completion • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Safety, PK/PD and preliminary anti-tumor activities of pegylated recombinant human arginase 1 (BCT-100) in patients with advanced arginine auxotrophic tumors. (PubMed, Invest New Drugs) - "Conclusions BCT-100 is safe in a non-Chinese population and has anti-tumor activities in both MM and CRPC. Weekly BCT-100 at 2.7 mg/kg is defined as the optimal biological dose for future clinical phase II studies."

Clinical • Journal • PK/PD data • Genito-urinary Cancer • Melanoma • Oncology • Prostate Cancer • Solid Tumor

A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma. (PubMed, Invest New Drugs) - P1/2 | "PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers."

Biomarker • Clinical • Journal • P2 data • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • ASS1

Pegylated Recombinant Human Arginase 1 Induces Autophagy and Apoptosis via the ROS-Activated AKT/mTOR Pathway in Bladder Cancer Cells. (PubMed, Oxid Med Cell Longev) - "While N-acetyl-L-cysteine was shown to alleviate BCT-100-induced apoptosis and autophagy, chloroquine, MK-2206, and rapamycin were found to potentiate BCT-100-triggered apoptosis. Finally, BCT-100 was demonstrated to induce autophagy and apoptosis via the ROS-mediated AKT/mTOR signaling pathway in bladder cancer cells."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

Pharmacological screening identifies SHK242 and SHK277 as novel arginase inhibitors with efficacy against allergen-induced airway narrowing in vitro and in vivo. (PubMed, J Pharmacol Exp Ther) - "The reference compound 2(S)-amino-6-boronohexanoic acid (ABH) and >200 novel arginase inhibitors were tested for their ability to inhibit recombinant human arginase 1 and 2 in vitro...We have identified promising novel arginase inhibitors for the potential treatment of allergic asthma that were able to protect against allergen-induced early and late asthmatic reactions. Our new inhibitors show protective effects in reducing airway narrowing in response to allergens and reductions in the early and late asthmatic response."

Journal • Asthma • Immunology • Inflammation • Pneumonia • Respiratory Diseases

Contactin 1 modulates pegylated arginase resistance in small cell lung cancer through induction of epithelial-mesenchymal transition. (PubMed, Sci Rep) - "Silencing CNTN-1 rather than CDH17 or IGF2BP1 in H446-BR and H526-BR cells re-sensitized resistant cells to BCT-100 treatment and attenuated the epithelial-mesenchymal transition (EMT) phenotype. The AKT signaling pathway was activated in H446-BR and H526-BR cells accompanied by EMT progression, and AKT inhibitor LY294002 reversed the EMT progression in resistant cells."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer

Cytotoxicity of [HuArgI (co)-PEG5000]-induced arginine deprivation to ovarian Cancer cells is autophagy dependent. (PubMed, Invest New Drugs) - "In this study, we assess arginine auxotrophy in ovarian cancer cells and attempt to target them using arginine deprivation induced by a pegylated recombinant human Arginase I cobalt [HuArgI (Co)-PEG5000]...[HuArgI (Co)-PEG5000]-induced arginine deprivation led to extensive and prolonged activation of autophagy, which proved to be deleterious to cell survival since its inhibition led to a significant decrease in cytotoxicity. This indicates that the activation of autophagy following arginine-deprivation, rather than being protective, mediates cell cytotoxicity leading to death by autophagy."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Preclinical safety and antitumor activity of the arginine-degrading therapeutic enzyme pegzilarginase, a PEGylated, cobalt-substituted recombinant human arginase 1. (PubMed, Transl Res) - "This is consistent with the known autophagy-inducing effects of arginine depletion, and the link between autophagy and major histocompatibility complex antigen presentation to T cells. Our work supports the ongoing clinical investigations of pegzilarginase in solid tumors and clinical combination of pegzilarginase with immune checkpoint inhibitors."

IO Biomarker • Journal • Immune Modulation • Inflammation • Lung Cancer • Melanoma • Merkel Cell Carcinoma • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer