BrevaRex (AR20.5) / Quest PharmaTech, CanariaBio - LARVOL DELTA

Isolated auto-citrullinated regions of PADI4 associate to the intact protein without altering their disordered conformation. (PubMed, Biophys Chem) - "PADI4 auto-citrullinates in several regions of its sequence, namely in correspondence of residues Arg205, Arg212, Arg218, and Arg383...The affinities of PADI4 for unmodified peptides were slightly larger than those of the corresponding citrullinated ones in the two series, but they were all within the same range, indicating that there were no relevant variations in the thermodynamics of binding due to sequence effects. These results highlight details of the self-citrullination of PADI4 and, more generally, of possible auto-catalytic mechanisms taking place in vivo for other citrullinating enzymes or, alternatively, in proteins undergoing citrullination passively."

Journal • CNS Disorders • Dermatology • Immunology • Inflammatory Arthritis • Multiple Sclerosis • Oncology • Psoriasis • Rheumatoid Arthritis • Rheumatology

CanariaBio Achieves Significant Milestone with FDA's Orphan Drug Designation for MAb-AR20.5 Targeting Pancreatic Cancer (PRNewswire) - "CanariaBio Inc...announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to its investigational drug product, MAb-AR20.5, an IgG1k type murine monoclonal antibody that binds specifically to the circulating and tumor-associated antigen (MUC1) expressed ubiquitously on pancreatic cancer cells....CanariaBio Inc. is planning to initiate clinical trials to assess the safety and efficacy of MAb-AR20.5 in patients with pancreatic cancer. More details about the upcoming studies and trial sites will be made available in the coming months."

New trial • Orphan drug • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Orphan Designation: Treatment of pancreatic cancer (FDA) - Date Designated: 08/10/2023

Orphan drug • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment. (PubMed, Biomedicines) - "Two granulysin (GRNLY) based immunotoxins were generated, one containing the scFv of the SM3 mAb (SM3GRNLY) and the other the scFv of the AR20.5 mAb (AR20.5GRNLY)...Histological studies of tumors obtained from treated mice demonstrated reduced cellularity, nuclear morphology compatible with apoptosis induction and active caspase-3 detection by immunohistochemistry. Overall, our results exemplify that these immunotoxins are potential drugs to treat Tn-expressing cancers."

Journal • Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • CASP3 • MUC1

Novel Mutations in GPR68 and SLC24A4 Cause Hypomaturation Amelogenesis Imperfecta. (PubMed, J Pers Med) - "Family 2 had a novel homozygous nonsense mutation in SLC24A4 gene (NM_153646.4:c.613C>T, NP_705932.2:p.(Arg205*)). Family 3 also had a homozygous missense mutation in SLC24A4 gene which was reported previously (c.437C>T, p.(Ala146Val)). This report not only expands the mutational spectrum of the AI-causing genes but also improves our understanding of normal and pathologic amelogenesis."

Journal • Musculoskeletal Diseases • Orthopedics

The first Two non-Finnish HYLS1 Variants: expanding the phenotypic spectrum of Hydrolethalus Syndrome. (PubMed, Clin Genet) - "The first allele carries the same Finnish missense variant (NM_145014.2: c.632A>G, p.(Asp211Gly)) in both fetuses and the second allele carries a new missense variant (c.662G>C, p.(Arg221Pro)) in the first fetus, and a new nonsense variant (c.613C>T, p.(Arg205*)) in the second fetus. This is the first report of HYLS1 mutated cases outside Finland. Both cases presented here are consistent with HLS with additional malformations, allowing expansion of the phenotypic presentation previously described."

Journal • CNS Disorders • Ventriculomegaly

NPR2 variants are frequent among children with familiar short stature and respond well to growth hormone therapy. (PubMed, J Clin Endocrinol Metab) - "NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy."

Clinical • Journal • Orthopedics

Comparative ligand structural analytics illustrated on variably glycosylated MUC1 antigen-antibody binding. (PubMed, Beilstein J Org Chem) - "We illustrate this informatics approach by investigating the in-silico binding of a peptide and glycopeptide epitope of the glycoprotein Mucin 1 (MUC1) binding with the antibody AR20.5. Although the bound conformation of peptide and glycopeptide is similar, the glycopeptide fluctuates less and resides in specific conformers for more extended periods. This structural analysis which gives a high-level view of the features in the system under observation, could be readily applied to other binding problems as part of a general strategy in drug design or mechanistic analysis."

Journal • MUC1

Engineered high-affinity zinc binding site reveals gating configurations of a human proton channel. (PubMed, J Gen Physiol) - "The lower affinity of Zn2+ in open channels is consistent with the idea that structural rearrangements within the transmembrane region bring Arg205 near position 116, electrostatically expelling Zn2+. This phenomenon provides direct evidence that Asp185 opposes position 116 in closed channels and that Arg205 moves between them when the channel opens."

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Characterization of the sortase A from Lactobacillus acidophilus ATCC 4356 involved in adherence to intestinal cells. (PubMed, Future Microbiol) - "The active sites of SrtA include His137, Cys198 and Arg205...The adhesion ability of L. acidophilus was also decreased resulting from the inhibition of SrtA activity. The unique properties of SrtA of L. acidophilus can provide some insights into the development of high adhesion lactobacillus strains in the GI tract."

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Zr-Labeled AR20.5: A MUC1-Targeting ImmunoPET Probe. (PubMed, Molecules) - "In subsequent in vivo experiments in athymic nude mice bearing subcutaneous MUC1-expressing ovarian cancer xenografts, [Zr]Zr-DFO-AR20.5 clearly delineated tumor tissue, producing a tumoral activity concentration of 19.1 ± 6.4 percent injected dose per gram (%ID/g) at 120 h post-injection and a tumor-to-muscle activity concentration ratio of 42.4 ± 10.6 at the same time point. Additional PET imaging experiments in mice bearing orthotopic MUC1-expressing ovarian cancer xenografts likewise demonstrated that [Zr]Zr-DFO-AR20.5 enables the visualization of tumor tissue-including metastatic lesions-with promising tumor-to-background contrast."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • CA 15-3 • MUC1

Revealing the positive binding cooperativity mechanism between the orthosteric and the allosteric antagonists of CCR2 by Metadynamics and Gaussian Accelerated Molecular Dynamics Simulations. (PubMed, ACS Chem Neurosci) - "The charged residues Arg2065.43 of TM5 and Glu2917.39 of TM7 play key roles in stabling the TM7 and TM6...Our results illustrate the conformational details about the effect of the orthosteric antagonist on allosteric antagonist of CCR2. The conformational dynamics of CCR2 upon binding different ligands can provide a rational basis for development of allosteric ligands of CCR2."

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