YS110 / Kissei, Y's Therap - LARVOL DELTA

Anti-tumor effect and mechanism of action of a nuclear transportable antibody drug conjugate Y-TR-1: Anti CD26 antibody conjugated with RNA polymerase II inhibitor triptolide (AACR 2025) - "We established the humanized anti-CD26 monoclonal antibody YS110, which has a direct anti-tumor effect through nuclear translocation of CD26 and transcriptional suppression of the POLR2A gene, a subunit of RNA polymerase II (Pol II)... Y-TR-1 is an ADC with a novel mechanism of action, i.e., nuclear translocation and subsequent Pol II inhibition. Transcriptional repression of POLR2A expression by nuclear-localized CD26 and Pol II inhibition by internalized triptolide are expected to have additive effects. Y-TR1 exhibited potent antitumor activity against CD26-positive cancer cells in vitro and in vivo."

Oncology • DPP4

Pre-clinical research of ZHB015, an anti-CD26/CD3 bispecific T-cell-engaging antibody (AACR 2025) - "Although FDA approved axitinib in combination with avelumab as the first-line treatment for PD-L1 positive advanced renal cell carcinoma in 2019, the problems still exist such as individual differences and drug tolerance. ZHB015 simultaneously binds to tumor CD26 and T cell CD3, inducing T cell mediated antitumor effects. ZHB015 has an outstanding anti-tumor activity in vitro and in vivo, which is superior to YS110 and the current first line treatment. Thus, ZHB015 is being further developed as a potential therapy for CD26 positive solid tumor."

IO biomarker • Preclinical • Genito-urinary Cancer • Kidney Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • DPP4 • PD-L1

Development of a Novel CD26-Targeted Chimeric Antigen Receptor T-Cell Therapy for CD26-Expressing T-Cell Malignancies. (PubMed, Cells) - "One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110...Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies."

CAR T-Cell Therapy • IO biomarker • Journal • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Transplantation • CD19 • CD69 • CXCL8 • DPP4 • GZMB • IFNG • TNFA

Phase 2 Study of YS110, a Recombinant Humanized Anti-CD26 Monoclonal Antibody, in Japanese Patients With Advanced Malignant Pleural Mesothelioma. (PubMed, JTO Clin Res Rep) - "The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated."

Clinical • Journal • P2 data • Interstitial Lung Disease • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • DPP4

Serum soluble CD26/DPP4 titer variation is a potential prognostic biomarker in cancer therapy with a humanized anti-CD26 antibody. (PubMed, Biomark Res) - "Our study indicates that serum sCD26/DPP4 titer variation in the early phase of YS110 treatment is a predictive biomarker for evaluating therapeutic efficacy."

Biomarker • Journal • Oncology

Structure of Blood Coagulation Factor VIII in Complex with an Anti-C1 Domain Pathogenic Antibody Inhibitor. (PubMed, Blood) - "This study reports the first structure of an anti-C1 domain antibody inhibitor and the first fVIII:inhibitor complex with a therapeutically active fVIII construct. Further structural understanding of fVIII immunogenicity may result in the development of more effective and safe fVIII replacement therapies."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

Overexpression of histone H3.1 induced cell malignant transformation and mutation of H3.1 C96/110A further induced chromatin instability (AACR 2018) - "...Histone H3.1 and H3.2 are canonical histones and they differ by only one amino acid, Ser96 on H3.2 compared with Cys96 on H3.1, and both of them have a Cys110...In addition, the RNA-seq assay revealed a total of 678 genes that were oppositely expressed between H3.1 and H3.1 C96/110A ectopically expressed cells. These findings emphasize the importance of a balance among histone variants in the cell and an essential role of cysteines in histone H3.1."

Oncology

Clinical Study of YS110 in Patients With Malignant Pleural Mesothelioma (clinicaltrials.gov) - P1/2; N=40; Completed; Sponsor: Kissei Pharmaceutical Co., Ltd.; Active, not recruiting ➔ Completed; Trial completion date: Dec 2020 ➔ Feb 2020; Trial primary completion date: Dec 2020 ➔ Feb 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date • Lung Cancer • Mesothelioma • Oncology • Solid Tumor

Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma. (PubMed, Lung Cancer) - "YS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study."

Clinical • Journal • P1 data • Lung Cancer • Mesothelioma • Oncology • Solid Tumor • Thoracic Cancer

Zinc Binds and Regulates the Activity of the Natural Anticoagulant Protein Z (ISTH 2017) - "Collectively our observation suggests that Zn2+ binds PZ and regulates its anticoagulant activity."

Biomarker • Clinical • Biosimilar

"UK says 110,000 applied for self-employed income scheme after launch https://t.co/rRPWFcLI1N" (@Reuters)

Prediction of cytotoxic activity of a series of 1H-pyrrolo[2,3-b]pyridine derivatives as possible inhibitors of c-Met using molecular fingerprints. (PubMed, J Recept Signal Transduct Res) - "Two hydrogen bonds between Lys1110, Met1160, and 7g-cl were stable during the equilibrium time range. The suggested modifications might be considered in future studies to design more efficient anticancer agents."

Journal

Characterization of an intertidal zone metagenome oligoribonuclease and the role of the intermolecular disulfide bond for homodimer formation and nuclease activity. (PubMed, FEBS Open Bio) - "Substitution of the Cys110 residue with either Gly or Ala hampered the dimer formation and severely affected the enzyme's ability to act on RNA. A conserved loop containing His128-Tyr129-Arg130 in the neighboring monomer is probably involved in efficient binding and processing of longer RNA substrates than diribonucleotides."

Journal

Biodistribution of a CD3/EpCAM bispecific T-cell engager is driven by the CD3 arm. (PubMed, J Nucl Med) - "PET images and ex-vivo biodistribution in immunocompetent mice with 89Zr-muS110, targeting mouse CD3 (Kd = 2.9 nM) and mouse EpCAM (Kd = 21 nM), and 89Zr-hyS110, targeting only mouse CD3 (Kd = 2.9 nM), showed uptake in tumor, spleen and other lymphoid organs, while the human-specific control BiTE 89Zr-AMG 110 showed similar tumor uptake but lacked spleen uptake. Significance: 89Zr-muS110 biodistribution is mainly dependent on the T-cell targeting arm with limited contribution of its second arm, targeting EpCAM. These findings highlight the need for extensive biodistribution studies of novel bispecific constructs as results might have implications for their respective drug development and clinical translation."

Journal

In silico studies of the inhibition mechanism of dengue with papain. (PubMed, J Biomol Struct Dyn) - "The salt bridge formation between the Asp103 and Lys110 residues are the important stabilizing factor in E-protein(Ala54-Ile129)…Papain(Cys25) complex. This result can extend our knowledge of the functional behaviour of Papain and provides structural insight to target Envelope protein as forthcoming drug targets in Dengue."

Journal

Development of novel monoclonal antibodies with specific binding affinity for denatured human CD26 in formalin-fixed paraffin-embedded and decalcified specimens. (PubMed, PLoS One) - "Specifically, these mAbs display strong binding affinity to denatured human CD26 rather than undenatured human CD26, and are capable of detecting denatured human CD26 in decalcified specimens. These novel anti-CD26 mAbs are potentially useful for the analysis of CD26 expression in cancer patients with bony metastasis, and may help decide the appropriateness of YS110 therapy for future cancer patients."

Journal

A comprehensive study on levan nanoparticles formation: kinetics and self-assembly modeling. (PubMed, Int J Biol Macromol) - "This model was built by taking into account enzyme poisoning effect (also demonstrated experimentally) and a diffusion limited cluster model for the aggregation phenomenon. Simulation results fit properly experimental data and catalytic parameters as well as predicting accurately the value of CAC for producing its reorganization into nanoparticles by self-assembly."

Journal

Novel Antibody-Drug Conjugate with Anti-CD26 Humanized Monoclonal Antibody and Transcription Factor IIH (TFIIH) Inhibitor, Triptolide, Inhibits Tumor Growth via Impairing mRNA Synthesis. (PubMed, Cancers (Basel)) - "In conclusion, the novel compound Y-TR1 showed antitumor properties against CD26-positive cancer cell lines both in vitro and in vivo without toxicity. The Y-TR1 is a unique antitumor ADC and functions against Pol II."

Journal

Inflammation-mediated fetal injury by maternal granulocyte-colony stimulating factor and high-dose intraamniotic endotoxin in the caprine model. (PubMed, Turk J Obstet Gynecol) - "...Pregnant goats (n=4) were given 50 microg/day G-CSF into the maternal jugular vein through gestational days 110-115 (term, 150 days)...Necrotizing funisitis with abundant leukocyte infiltration and fetal brain injury was induced in all the fetuses in the experimental group. Maternal i.v. G-CSF for 5 days followed by 20 mg of IA endotoxin is a feasible caprine model to exacerbate intrauterine inflammation."

Journal

PET-imaging of 89Zr-labeled bispecific T-cell engagers in syngeneic tumor bearing mice (AACR 2019) - "MuS110, a BiTE® with affinity for murine CD3 (KD= 2.9 nM) and murine EpCAM (KD= 21 nM), was radiolabeled with positron emission tomography (PET) isotope zirconium-89 (89Zr) to study its pharmacokinetics and involvement of the immune system in an immunocompetent mouse model bearing a syngeneic tumor.METHODS MuS110 and two control BiTE® antibody constructs (hyS110 and AMG110) were radiolabeled with 89Zr. In addition, in nude BALB/c mice, tumor uptake was the same for 89Zr-muS110 and 89Zr-AMG110 (1.5 vs 1.7 %ID/g, P>0.05). 89Zr-muS110 uptake was lower in spleen and mesLNs following 5 days of 10 µg muS110 iv compared to control mice(spleen: 4.2 vs 8.2 %ID/g, P<0.01; mesLNs: 1.9 vs 3.5, P<0.01), likely representing target saturation.CONCLUSION Distribution of BiTE® 89Zr-muS110 is predominantly mediated by the affinity for CD3, resulting in uptake in lymphoid tissues."

Preclinical

Clinical Study of YS110 in Patients With Malignant Pleural Mesothelioma (clinicaltrials.gov) - P1/2; N=48; Active, not recruiting; Sponsor: Kissei Pharmaceutical Co., Ltd.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Percent Body Fat Cut-Off Points for Diagnosing Metabolic Syndrome in Korean Adolescents. (PubMed, Iran J Public Health) - "...The subjects (n=2120; boys=1107, girls=1013) were middle and high school students aged 12-17 yr who participated in the Korean National Fitness Award Project in 2013...Age- and sex-specific percent body fat cut-off points were identified in relation to the metabolic syndrome status of Korean adolescents. These percent body fat cut-offs might be useful for identifying metabolic abnormality due to obesity in Korean adolescents."

Journal

Electrostatic explanation of D1228V/H/N-induced c-Met resistance and sensitivity to type I and type II kinase inhibitors in targeted gastric cancer therapy. (PubMed, J Mol Model) - "...In DFG-in conformation, the wild-type Asp1228 is surrounded by a number of positively charged residues within its first and second shells, which can also form a hydrogen-bonding network with its vicinal residues Phe1089, Lys1110, Asp1222, and Met1229 in the first shell...Graphical abstract The molecular mechanism of D1228V/H/N mutation-induced inhibitor resistance and sensitivity in c-Met kinase is investigated. The mutation electrostatically destabilizes the DFG-in conformation of kinase A-loop and induces its spontaneous transition to DFG-out state, which reshapes kinase active site and influences the site interactions with inhibitor ligands."

Journal