tigatuzumab (CS-1008) / Daiichi Sankyo - LARVOL DELTA

CD4+ mucosal-associated invariant T cells express highly diverse T cell receptors. (PubMed, J Immunol) - "To specifically characterize this TCR repertoire, we analyzed VDJ sequences across 2 datasets and identified distinct TCR usage among CD4+ MAIT cells including TRAV21, TRAV8 (TRAV8-1, TRAV8-2, TRAV8-3), and TRAV12 families (TRAV12-2, TRAV12-3), as well as more variable J segment, CDR3α, and TRBV sequences. TRAV1-2- MAIT cell TCRs were also enriched after in vitro culture with interleukin-2 and Mycobacterium tuberculosis. These results indicate that mature human CD4+ MAIT cells adopt distinct TCR usage from the canonical TRAV1-2+ CD8+ subset and suggest that alternative MR1 ligands in addition to riboflavin intermediates may select for them."

Journal • Infectious Disease • Oncology • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD4 • CD8 • IL2

Gene expression profiling of peripheral blood identifies systemic T-cell and neutrophilic immune response in paediatric bronchiectasis (WBC 2025) - "The top significantly upregulated genes included T-cell receptor genes TRBJ2-4, TRBJ2-3 and TRAV8-5 (all FC >2.6 and adjusted p<0.05), which all play a crucial role in adaptive immunity... The BAL GE in children with bronchiectasis at the time of diagnosis reflects a generic immune-inflammatory response. In contrast, blood GE markers included T-cell receptor and neutrophilic-associated genes. Both BAL and blood hold specific and different biological information and provide data on biological processes."

Gene expression profiling • IO biomarker • Bronchiectasis • Cough • Infectious Disease • Influenza • Pediatrics • Pneumococcal Infections • Pneumonia • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CRP • IFNA1 • IFNG

CD4 + Mucosal-associated Invariant T (MAIT) cells express highly diverse T cell receptors. (PubMed, bioRxiv) - "To specifically characterize this TCR repertoire, we analyzed VDJ sequences of single MR1-5-OP-RU tetramer + MAIT cells across two datasets and identified distinct TCR usage among CD4 + MAIT cells including TRAV21, TRAV8 (TRAV8-1, TRAV8-2, TRAV8-3), and TRAV12 families (TRAV12-2, TRAV12-3), as well as more variable J chain and CDR3 sequences. Non-TRAV1-2 MAIT cell TCRs were also enriched after in vitro expansion, including with Mycobacterial tuberculosis . These results indicate that mature human CD4 + MAIT cells adopt distinct TCR usage from the canonical TRAV1-2 + CD8 + subset and suggest that alternative MR1 ligands in addition to riboflavin intermediates may select them."

Journal • Infectious Disease • Oncology • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD4 • CD8

Phase I-IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies. (PubMed, Int J Mol Sci) - "Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations."

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

SINGLE-CELL MULTI-OMIC EVALUATION OF DIFFERENCES IN T CELL POPULATIONS IN PROGRESSION OF SLE (EULAR 2024) - "TCR analysis indicates both CTL and CD8+ cytotoxic T cells have largest fraction of expanded clonotypes, with increased levels of TRAV19 , TRAV8 , TRAV38... Dysregulation of signaling in T cell activation appears to be manifesting in increased oxidative phosphorylation, dysregulation of MAPK kinases or alterations in apoptotic pathways and might be suggestive of a preclinical autoimmunity development trajectory and associated with clonal expansion. Alterations of these processes vary by ancestral background, reflecting the heterogeneity of SLE presentation."

Clinical • Inflammatory Arthritis • Lupus • Metabolic Disorders • Systemic Lupus Erythematosus • CD4 • CD8 • GZMB • IFNG • IKZF1 • IL10 • MAP2K6 • MAP3K5 • NKG7 • PRF1 • STAT3 • TBX21 • TMSB4X • TXNIP • ZEB2

Peg-lipid-modified agonistic antibody against tumor necrosis factor receptor family elicits superior apoptosis-inducing activity against human carcinoma. (PubMed, Bioorg Med Chem Lett) - "The chemically modified TRA-8 antibody [anti-death receptor 5 (DR5) antibody] with PEG-lipid (DSPE-PEG) demonstrated significant cytotoxic activity in vitro without the need for crosslinking with a secondary antibody, which is typically required...Nevertheless, by designing new PEG-lipids that are intended to be resistant to enzymatic degradation, we were able to prevent this degradation and restore the cytotoxic activity of the modified antibody. These findings provide valuable insights for the design of PEG-lipid-modified antibodies and suggest their potential effectiveness in enhancing cancer therapy."

Journal • Oncology • TNFA • TNFRSF10B

T-cell receptor diversity and allergen sensitivity in childhood asthma and atopic dermatitis. (PubMed, Pediatr Allergy Immunol) - "Integrated TCR repertoires analysis provides clinical insights into the diverse TCR genes linked to antigen specificity, offering potential for precision immunotherapy in childhood allergies."

IO biomarker • Journal • Allergy • Asthma • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Pulmonary Disease • Respiratory Diseases

Neutrophils as potential therapeutic targets for breast cancer. (PubMed, Pharmacol Res) - P2 | "Clinical trials are evaluating neutrophil-targeted therapies, including Reparixin (NCT02370238) and Tigatuzumab (NCT01307891); however, their clinical efficacy remains suboptimal. This review summarizes the evidence regarding the close relationship between neutrophils and BC, emphasizing the critical roles of neutrophils in regulating metabolic and immune pathways. Additionally, we summarize the existing therapeutic approaches that target neutrophils, highlighting the challenges, and affirming the rationale for continuing to explore neutrophils as a viable therapeutic target in BC management."

Journal • Review • Breast Cancer • Oncology • Solid Tumor

Identification and validation of an immune-relevant risk signature predicting survival outcome and immune infiltration in uveal melanoma. (PubMed, Int Ophthalmol) - "The identified immune risk signature was demonstrated to be associated with the favorable immune infiltration, prognosis and immunotherapeutic efficacy, which may provide clues for survival evaluation and immune treatment."

IO biomarker • Journal • Tumor mutational burden • Eye Cancer • Genito-urinary Cancer • Melanoma • Oncology • Solid Tumor • Urothelial Cancer • Uveal Melanoma • TMB

Genes Encoding Adaptive Immune Receptor Repertoire Might Be Associated With The Risk Of Graves' Disease And Antithyroid Drug-induced Agranulocytosis (ENDO 2023) - "Our results identified several gAIRR alleles that were more prevalent in GD cases than in controls, including IGLV1-41*02N (a novel allele with the sequence closest to IGLV1-41*02, 20.3% in GD patients vs. 7.7% in controls, p=0.008), IGHV1-69*04N (12.5% vs. 3.8%, p=0.02), TRGV4*01 (46.9% vs. 31.7%, p=0.022), and several other alleles (such as TRBV6-6*03, IGKV1/OR22-5*01N, TRVB12-2*01N, TRAV8-4*01N, IGHV3-71*02, IGHV2-70*04N, etc.) We also found several gAIRR alleles that were less prevalent in GD cases than in controls, including IGLV5-45*03N, IGLV2-14*04, IGLV(V)-66*01, IGLV3-13*01N, TRBV20/OR9-2*02N, TRBD2*01, TRAV6*02, among others...Future studies with larger sample sizes are necessary. Furthermore, a joint analysis of HLA and gAIRR genotypes might provide valuable insight into the pathogenesis of GD and TiA."

IO biomarker • Late-breaking abstract • Agranulocytosis • Endocrine Disorders • Granulocytopenia • Grave’s Disease • Immunology

Specific Genetic Polymorphisms Contributing in Differential Binding of Gliadin Peptides to HLA-DQ and TCR to Elicit Immunogenicity in Celiac Disease. (PubMed, Biochem Genet) - "SNP rs12722069 at HLA-DQ8 that codes Arg76α forms three H-bonds with Glu12 and two H-bonds with Asn13 of DQ2 restricted gliadin in the presence of TRAV8-3/TRBV6...Highly polymorphic sites of HLA alleles and TCR variable regions could be utilized for better risk prediction models in CD. Therapeutic strategies by identifying inhibitors or blockers targeting specific gliadin:HLA-DQ:TCR binding sites could be investigated."

IO biomarker • Journal • Celiac Disease • Immunology

Genetic Interactions Between T-Cell Receptor Polymorphisms and HLA Amino Acids Contribute to the Risk of Rheumatoid Arthritis (ACR Convergence 2022) - "rs1076861 is an intergenic SNP located between TRDV3 and TRAJ61, and rs7150263 is also an intergenic SNP located between TRAV7 and TRAV8. This study has identified statistical interactions between TCR polymorphisms and HLA-A amino acids. Replication will be performed within a large transethnic dataset including > 200,000 samples (RA international genetics consortium)"

IO biomarker • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Genetic Interactions Between T-Cell Receptor Polymorphisms and HLA Amino Acids Contribute to the Risk of Rheumatoid Arthritis (ACR Convergence 2022) - "rs1076861 is an intergenic SNP located between TRDV3 and TRAJ61, and rs7150263 is also an intergenic SNP located between TRAV7 and TRAV8. This study has identified statistical interactions between TCR polymorphisms and HLA-A amino acids. Replication will be performed within a large transethnic dataset including > 200,000 samples (RA international genetics consortium)"

IO biomarker • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Molecular Basis for the Recognition of HIV Nef138-8 Epitope by a Pair of Human Public T Cell Receptors. (PubMed, J Immunol) - "The gene use of the variable domain for TD08 and H25-11 is TRAV8-3, TRAJ10 for the α-chain and TRBV7-9, TRBD1*01, TRBJ2-5 for the β-chain...Then, we revealed the molecular basis of the public TCR binding to the peptide HLA, which mostly relies on the interaction between the TCR and HLA and can tolerate the mutation in the Nef138-8 peptide. These findings promote the molecular understanding of T cell immunity against HIV epitopes and provide an important basis for the engineering of TCRs to develop T cell-based immunotherapy against HIV infection."

IO biomarker • Journal • Human Immunodeficiency Virus • Infectious Disease

MFN1 and MFN2 Are Dispensable for Sperm Development and Functions in Mice. (PubMed, Int J Mol Sci) - "Spermatogenesis was normal in Mfn double knockout mice, in which properly developed TRA98+ germ cells, SYCP3+ spermatocytes, and TNP1+ spermatids/spermatozoa were detected in seminiferous tubules, indicating that sperm formation was not disrupted upon MFN deficiency. Collectively, our findings reveal that both MFN1 and MFN2 are dispensable for sperm development and functions in mice."

Journal • Preclinical

ZDHHC19 Is Dispensable for Spermatogenesis, but Is Essential for Sperm Functions in Mice. (PubMed, Int J Mol Sci) - "Spermatogenesis was not disrupted in Zdhhc19 knockout mice, in which properly developed TRA98+ germ cells, SYCP3+ spermatocytes, and TNP1+ spermatids/spermatozoa were detected in seminiferous tubules...All of these led to the inability of Zdhhc19 mutant sperm to fertilize oocytes in IVF assays. Taken together, our results support the fact that Zdhhc19 is a testis enriched gene dispensable for spermatogenesis, but is essential for sperm functions in mice."

Journal • Preclinical • Infertility

Identification and characterization of the antigen recognized by the germ cell mAb TRA98 using a human comprehensive wet protein array. (PubMed, Genes Cells) - "Although NKAP is a ubiquitously expressed protein, NKAP recognized by mAb TRA98 in mouse testis was SUMOylated. These results suggest that NKAP undergoes modifications, such as SUMOylation in the testis, and plays an important role in spermatogenesis."

Journal

[VIRTUAL] Three-dimensional H-scan ultrasound imaging for acute detection of breast cancer response to neoadjuvant treatment - Initial results using a preclinical animal model (SABCS 2020) - "Animals were then US imaged at baseline and before receiving intraperitoneal injections, namely: (1) 0.3 mg sterile saline (control), (2) 0.2 mg of agnostic TRA-8 monoclonal antibody to human death receptor 5 (DR5) + 0.1 mg sterile saline, (3) 0.1 mg paclitaxel + 0.2 mg sterile saline, and (4) 0.1 mg TRA-8 + 0.2 mg paclitaxel. 3D H-scan US imaging is a promising technique that allows visualization of the heterogenous tissue microenvironment and improves the evaluation of treatment at an early stage of therapy as validated by histologic findings."

Breast Cancer • Oncology • Solid Tumor • CASP3 • PARP1

Regulation of pancreatic cancer TRAIL resistance by protein O-GlcNAcylation. (PubMed, Lab Invest) - "With gain- and loss-of-function of the O-GlcNAc-adding enzyme, O-GlcNActransferase (OGT), we determined that increasing O-GlcNAcylation rendered TRAIL-sensitive cells more resistant to TRA-8-induced apoptosis, while inhibiting O-GlcNAcylation promoted TRA-8-induced apoptosis in TRAIL-resistance cells...We further defined that DR5 O-GlcNAcylation was independent of FADD, the adapter protein for the downstream death-inducing signaling. These studies have demonstrated an important role of protein O-GlcNAcylation in regulating TRAIL resistance of pancreatic cancer cells; and uncovered the contribution of O-GlcNAcylation to DR5 oligomerization and thus mediating DR-inducing signaling."

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

Oral recombinant methioninase increases TRAIL receptor-2 expression to regress pancreatic cancer in combination with agonist tigatuzumab in an orthotopic mouse model. (PubMed, Cancer Lett) - "MR, effected by o-rMETase, enabled the efficacy of the TRAIL-R2 agonist tigatuzumab by increasing TRAIL-R2 expression in pancreatic cancer. Our results suggest that o-rMETase has clinical potential for treating pancreatic cancer."

Combination therapy • Journal • CNS Disorders • Gastrointestinal Cancer • Melanoma • Oncology • Pancreatic Cancer • Solid Tumor

Shared T cell receptor chains in blood memory CD4 T cells of narcolepsy type 1 patients. (PubMed, J Autoimmun) - "We detected a bias in the usage of TRAV3 and TRAV8 families, with public CDR3α motifs only present in CD4 T cells from patients with NT1. These findings may offer a unique tool to identify disease-relevant antigens."

Clinical • Journal • Sleep Disorder

[VIRTUAL] Biogeographical differences in gene segment usage (SID 2020) - "Specifically, TRAV8-5 was overexpressed in hip skin in comparison to peripheral blood (FDR = 1.97e-35), a finding that was independent of HLA haplotype...Analysis of BCR genes revealed that IgHA1 was poorly expressed in the palm when compared to the hip (relative fold change = 0.06, FDR = 2.02e-05). These findings are relevant because diseases such as palmoplantar psoriasis, hand dermatitis, and palmoplantar pustulosis have a predilection for palmar skin, which according to these results has differential expression of both TCR and BCR receptors."

Atopic Dermatitis • Dermatitis • Dermatology • Dermatopathology • Immunology • Psoriasis

Reduced retinoic acid synthesis accelerates prophase I and follicle activation. (PubMed, Reproduction) - "WIN 18,446 significantly accelerated the progression of prophase I; this was seen as early as 48 hours post treatment using meiotic chromosome spreads, and was still evident after 12 days of culture using Tra98/Msy2 immunostaining. Furthermore, ovaries treated with WIN 18,446 at e13.5 but not at P0 had a higher proportion of growing follicles compared to vehicle controls, thus showing evidence of increased follicle activation. These data therefore indicate that retinoic acid is not necessary for meiotic progression but may have a role in the regulation of its progression and germ cell survival at that time, and provide evidence for a link between meiotic arrest and follicle growth initiation."

Journal • P1 data • Ophthalmology

TBCRC 019: An open label, randomized, phase II trial of nanoparticle albumin-bound paclitaxel (nab-PAC) with or without the anti-death receptor 5 (DR5) monoclonal antibody tigatuzumab (TIG) in patients with metastatic triple negative breast cancer (TNBC) (ASCO 2013) - Presentation time: Saturday, Jun 1, 1:15 PM - 5:00 PM; Abstract #1052; P2, N=60; TBCRC 019 (NCT01307891); ""Of the 39 in the combination arm, there were 2 CR, 9 PR (1 near CR, 96% tumor reduction), 11 SD and 17 PD; ORR 28% (95% CI 14%-42%). Of the 21 in the single agent arm, there were no CR, 8 PR, 4 SD and 9 PD; ORR 38% (95% CI 17%-59%). Higher ORRs were seen in the chemotherapy naïve patients (58% vs. 15% combination and 42% vs. 35% single agent)"

P2 data • Breast Cancer

CS-1008 with carboplatin/paclitaxel in chemotherapy naïve subjects with metastatic or unresectable non-small cell lung cancer (NSCLC) (clinicaltrials.gov) - P2, N=109; Sponsor: Daiichi Sankyo Inc; Active, not recruiting -> Completed

Trial completion • Non Small Cell Lung Cancer