otelixizumab (ChAglyCD3) / GSK - LARVOL DELTA

Environmentally relevant concentrations of polystyrene nanoplastics induce Parkinson's-like neurotoxicity in C. elegans via oxidative stress. (PubMed, Environ Int) - "Co-treatment with N-acetylcysteine (NAC) attenuated PS-NP-induced paralysis, lowering the rate from 51.33 % to 29.47 %, though rescue failure in trx-4 mutants indicated mechanistic complexity and the indispensable role of endogenous defense systems. Critically, neurotoxicity occurred even at 0.1 μg/L PS-NPs, a level relevant to environmental contamination. These findings establish PS-NPs as potent inducers of PD-like neurodegeneration via complex oxidative stress cascades, validated by genetic and antioxidant interventions at environmentally realistic exposure levels, and highlight the urgency of monitoring nanoplastic pollution and developing antioxidant-based interventions."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • SOD3

Immunomodulatory interventions in type 1 diabetes: a systematic review and meta-analysis revealing paradoxical dissociation between beta-cell preservation and glycemic control. (PubMed, BMC Endocr Disord) - "Immunomodulation provides modest, temporary beta-cell preservationwithout consistent glycemic improvement. The C-peptide-HbA1c disconnect likelyreflects intensive insulin management masking treatment benefits. IL-2'sparadoxical HbA1c improvement without beta-cell preservation warrants mechanistic investigation. Time-dependent benefit attenuation suggests maintenance therapy may be necessary. Safety profiles favor Treg Enhancementover WBCs Clearance approaches. Future trials should employ continuous glucosemonitoring endpoints, longer follow-up, and combination strategies to optimizedisease-modifying therapy development."

Clinical • IO biomarker • Journal • Retrospective data • Review • Diabetes • Immunology • Metabolic Disorders • Type 1 Diabetes Mellitus

Immunotherapy as a treatment for type 1 diabetes mellitus in children and young adults: A comprehensive systematic review and meta-analysis. (PubMed, PLoS One) - "This meta-analysis aimed to assess the effectiveness of immunotherapy in treating T1DM by examining its effects on the patients' required dose of insulin, C-peptide, and HbA1c levels. While some studies failed to show desired results, the overall effect was an increase in C-peptide levels and a decrease in HbA1c levels. However, the study did not achieve statistical significance for insulin dosing. The main study's strength is its focus on randomized clinical trials which is considered among the highest levels of epidemiological evidence. Therefore, further research is required to minimize the gaps and to explore immunotherapy-based drugs as potential treatments for T1DM."

Clinical • Journal • Retrospective data • Review • Diabetes • Hypoglycemia • Immunology • Metabolic Disorders • Type 1 Diabetes Mellitus

Identifying Promising Immunomodulators for Type 1 Diabetes (T1D) and Islet Transplantation. (PubMed, J Diabetes Res) - P, P1/2, P2, P2/3, P3, P4 | "FDA-approved teplizumab for Stage 2 T1D is discussed along with other immunomodulators that have been tested in Phase 3 clinical trials or higher, including otelixizumab (another anti-CD3 monoclonal antibody), daclizumab (an anti-CD25 monoclonal antibody), ladarixin (CXCR1/2 inhibitor), and antithymocyte globulin (ATG)...Several immunomodulators involved in Phase 3 clinical studies of islet transplantation are also discussed, including alemtuzumab, basiliximab, etanercept, and reparixin, some already FDA-approved for other uses...This review provides background, mechanism of action, results of completed trials, and adverse effects as well as details regarding ongoing clinical trials for each of these immunomodulators. Trial Registration: ClinicalTrials.gov identifier: NCT03875729, NCT01030861, NCT00129259, NCT00385697, NCT01280682; NCT03929601, NCT04598893, NCT05757713, NCT00678886, NCT01123083, NCT00064714, NCT00468117, NCT04628481,..."

Journal • Review • Diabetes • Immunology • Metabolic Disorders • Transplantation • Type 1 Diabetes Mellitus • CXCR1

Enzymatic characterization of five thioredoxins and a thioredoxin reductase from Myxococcus xanthus. (PubMed, FEMS Microbiol Lett) - "Trxs typically have a CGPC active-site motif; however, M. xanthus Trxs have slightly different active-site sequences, with the exception of Trx4...TrxR reduced oxidized Trx1 as the best substrate, with a kcat/Km value of 0.253 min-1 μM-1, which was 10-28-fold higher than that of the other Trxs. These results suggest that all Trxs possess reducing activity and that Trx1 may be the most functional in M. xanthus because TrxR most efficiently reduces oxidized Trx1."

Journal

Effect of Immunotherapy on C-peptide Levels in Patients With Type I Diabetes Mellitus: A Systematic Review of Randomized Controlled Trials. (PubMed, Cureus) - "Teplizumab, rituximab, otelixizumab, and abatacept show potential for preserving beta cell function by reducing C-peptide loss in patients with type I diabetes mellitus. However, careful monitoring of adverse reactions, particularly viral infections and cytokine release syndrome, is necessary for the safe implementation of these therapies."

IO biomarker • Journal • Review • Cytomegalovirus Infection • Diabetes • Immunology • Infectious Disease • Inflammation • Metabolic Disorders • Nephrology • Type 1 Diabetes Mellitus

Trx4, a novel thioredoxin protein, is important for Toxoplasma gondii fitness. (PubMed, Parasit Vectors) - "Trx4 plays an important role in T. gondii invasion and virulence in Type I RH strain and Type II Pru strain. Combining the TurboID system with CRISPR-Cas9 technique revealed many PV-localized proximity proteins associated with Trx4. These findings suggest a versatile role of Trx4 in mediating the processes that occur in this distinctive intracellular membrane-bound vacuolar compartment."

Journal

Baseline plasma proinsulin response to glucose for predicting therapeutic response to otelixizumab in recent-onset type 1 diabetes. (PubMed, Diabetes Res Clin Pract) - P2 | "In recent-onset type 1 diabetes, elevated acutely glucose-stimulated proinsulin may complement or replace acutely or sustainedly stimulated C-peptide release for identifying good responders to anti-CD3, but not as outcome measure."

Journal • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

The Functional Relationship between NADPH Thioredoxin Reductase C, 2-Cys Peroxiredoxins, and m-Type Thioredoxins in the Regulation of Calvin-Benson Cycle and Malate-Valve Enzymes in Arabidopsis. (PubMed, Antioxidants (Basel)) - "The single trxm1 and trxm4 mutants showed a wild-type phenotype, growth retardation being noticed only in the trxm1m4 double mutant...These effects were suppressed by the decreased contents of 2-Cys Prx, since the quadruple ntrc-trxm1m4-2cpb mutant displayed a wild-type-like phenotype. These results show that the activity of m-type Trxs in the light-dependent regulation of biosynthetic enzymes and malate valve is controlled by the NTRC-2-Cys-Prx system."

Journal

Anti-CD3 monoclonal antibodies for the prevention and treatment of type 1 diabetes: A literature review. (PubMed, Am J Health Syst Pharm) - "Anti-CD3 mAbs are promising disease-modifying treatments for T1D. Their role in T1D may introduce short-term and long-term benefits with the potential to mitigate the significant disease burden; however, more evidence is required for an accurate assessment."

Journal • Review • Diabetes • Immunology • Metabolic Disorders • Type 1 Diabetes Mellitus

Investigational therapies targeting CD3 for prevention and treatment of type 1 diabetes. (PubMed, Expert Opin Investig Drugs) - "We discuss pre-clinical studies, phase II/III clinical trials, testing the anti-CD3 mAb teplizumab in subjects at T1D high risk, and testing teplizumab and otelixizumab in T1D recent onset patients. Recent phase II clinical trials with teplizumab in recent-onset T1D seem encouraging, but benefits associated with the use of anti-CD3 mAb in recent-onset T1D are still controversial. A better patient selection, based on immunological profiles and specific biomarkers, is crucial to improve clinical outcomes in T1D immunotherapies."

IO biomarker • Journal • Diabetes • Immunology • Metabolic Disorders • Type 1 Diabetes Mellitus

[VIRTUAL] Functional characterization of CD3specific DNA aptamers (ESGCT 2021) - "A number of therapeutic strategies that modulate T cell immunity by targeting CD3 protein, the signaling component of the Tcell receptor, has been used in clinics to develop immunosuppressive agents in transplantation (OKT3), autoimmune type I diabetes and psoriasis (teplizumab and otelixizumab). More recently, bispecific therapies retargeting the cytotoxic activity of effector T cells by binding to CD3 to tumors expressing tumorassociated antigen have demonstrated striking activity in patients across different cancers (blinatumomab and catumaxomab)...Accordingly, these aptamers did not induce any activation of primary human T lymphocytes nor the internalization of CD3 receptors upon binding, which is of particular interest for the development of inert targeting agents without any immunomodulating properties. All together these lead CD3 aptamers exhibit unique properties and qualify for further preclinical and clinical development of CD3targeting therapeutics."

Dermatology • Diabetes • Immune Modulation • Immunology • Inflammation • Metabolic Disorders • Oncology • Psoriasis • Transplantation • Type 1 Diabetes Mellitus

[VIRTUAL] Functional Characterization of CD3-Specific DNA Aptamers (ASGCT 2021) - "A number of therapeutic strategies that modulate T cell immunity by targeting CD3, the signaling component of the T-cell receptor, are widely used in clinics as immunosuppressive agents in transplantation (OKT3), autoimmune type I diabetes and psoriasis (teplizumab and otelixizumab). More recently, bispecific therapies retargeting the cytotoxic activity of effector T cells by binding to CD3 to tumors expressing tumor-associated antigen have demonstrated striking activity in patients across different cancers (blinatumomab)...Preliminary in vivo biodistribution data will also be presented. All together these lead CD3 aptamers exhibit unique properties and qualify for further preclinical and clinical development of CD3-targeting therapeutics."

Dermatology • Diabetes • Immune Modulation • Immunology • Inflammation • Metabolic Disorders • Oncology • Psoriasis • Transplantation • Type 1 Diabetes Mellitus

A randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal antibody otelixizumab in new-onset type 1 diabetes. (PubMed, Diabetologia) - P1/2 | "A metabolic response was observed with otelixizumab 9 mg, while doses higher than 18 mg increased the risk of unwanted clinical EBV reactivation. Although otelixizumab can temporarily compromise immunocompetence, allowing EBV to reactivate, the effect is dose dependent and transient, as evidenced by a rapid emergence of EBV-specific T cells preceding long-term control over EBV reactivation."

Clinical • Journal • Diabetes • Epstein-Barr Virus Infection • Immunology • Metabolic Disorders • Type 1 Diabetes Mellitus

Targeting T cells in inflammatory bowel disease. (PubMed, Pharmacol Res) - "Amongst anti-CD3 antibodies, visilizumab and foralumab did not show clinical efficacy in ulcerative colitis (UC) and Crohn's disease (CD) patients, respectively, whereas otelixizumab has been tested in vitro only. The anti-CD4 BF-5 and cM-T412, and the anti-CD25 basiliximab and daclizumab were not effective in CD and UC patients, respectively...Apart from ustekinumab, all the other drugs targeting T cell-derived cytokines failed. The reinduction of lamina propria T cell apoptosis is a mechanism to modulate T cell survival exploited by cyclosporin A, azathioprine and anti-tumor necrosis factor-α agents, such as infliximab, adalimumab and golimumab. In this article, we review the drugs targeting T cells via surface receptors, via T cell-derived cytokines, via CRAC channels or by inducing apoptosis."

Journal • Review • Crohn's disease • Gastroenterology • Immune Modulation • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • CD40LG • NKG2D • TNFA

Physiological and proteomic responses of reactive oxygen species metabolism and antioxidant machinery in mulberry (Morus alba L.) seedling leaves to NaCl and NaHCO stress. (PubMed, Ecotoxicol Environ Saf) - "Under NaHCO stress, the expression of the electron donor of ferredoxin-thioredoxin reductase (FTR), together with Trx-related proteins, such as thioredoxin M (TrxM), thioredoxin M4 (TrxM4), thioredoxin X (TrxX), TrxF, and Trx CSDP32 were significantly decreased, suggesting that the thioredoxin-peroxiredoxin (Trx-Prx) pathway's function of scavenging HO of in mulberry seedling leaves was inhibited. Taken together, under NaCl stress, excessive production of O· mulberry seedlings leaves was inhibited, and HO was effectively scavenged by CAT, AsA-GSH cycle and Trx-Prx pathway. Under NaHCO stress, despite the enhanced functions of POD and AsA-GSH cycle, the scavenging of O· by SOD was not effective, and that of HO by CAT and Trx-Prx pathway were inhibited; and in turn, the oxidative damage to mulberry seedling leaves could not be reduced."

Journal

Trial of otelixizumab for adults with newly diagnosed type 1 diabetes mellitus (Autoimmune): DEFEND-1 (clinicaltrials.gov) - P3, N=272, N=240 -> 272; Active, not recruiting -> Completed

Enrollment • Trial completion • Diabetes

UK Small/Mid Cap Research: Morning Meeting Note - 1st call – alert - Previously announced pipeline discontinuations include Oncogel, otelixizumab and CM3, which reduces analysts’ EmV by 9p, or 3%.

Financial analyst: Clinical; Commercial • Diabetes

Investigation of Otelixizumab in New-Onset, Autoimmune Type 1 Diabetes Mellitus Patients (clinicaltrials.gov) - P2; N=40; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: Jul 2020 ->Jan 2021

Trial completion date • Biosimilar • Diabetes • Immunology

Tolerx and GlaxoSmithKline Announce Phase 3 Defend-1 Study of Otelixizumab in Type 1 Diabetes Did Not Meet Its Primary Endpoint (PRNewswire) -

Tolerx & GSK announced that P3 DEFEND-1 study of otelixizumab, did not meet the primary efficacy endpoint of change in C-peptide at month 12 in patients with new-onset autoimmune type 1 diabetes; GSK will continue to explore additional dosing regimens to inform decisions about the future clinical development programme for otelixizumab;  New recruitment and dosing in the DEFEND-2 study, the ongoing confirmatory P 3 study has been suspended pending review of the DEFEND-1 results

P3 data • Diabetes

Target engagement and cellular fate of otelixizumab; a repeat dose escalation study of an anti-CD3ε mAb in New-Onset Type 1 Diabetes Mellitus Patients. (PubMed, Br J Clin Pharmacol) - "Data from this study revealed maximum target engagement and CD3 /TCR modulation is achieved at doses of 18, 27mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3 mAbs."

Clinical • Journal

Identification and characterisation of the dose response of otelixizumab in new onset type 1 diabetes patients (EASD 2019) - P1/2; "Maximum tolerated dose was identified at 18mg based on predefined EBV reactivation stopping criteria. EBV clinical manifestations and increased EBV viral load were found to be dose-dependent and transient, a phenomenon associated with the rapid advent of EBV-specific T-cell responses. Evidence of β-cell preservation measured by MMTT was observed at the dose of 9 mg up to 18 months but not at 18 mg and 27 mg."

Clinical

Elevated T cell levels in peripheral blood predict poor clinical response following rituximab treatment in new-onset type 1 diabetes. (PubMed, Genes Immun) - "Biologic treatment of type 1 diabetes (T1D) with agents including anti-CD3 (otelixizumab and teplizumab), anti-CD20 (rituximab), LFA3Ig (alafacept), and CTLA4Ig (abatacept) results in transient stabilization of insulin C-peptide, a surrogate for endogenous insulin secretion. Our findings illustrate complexity in hematopoietic remodeling that accompanies B cell depletion by rituximab, which impacts and predicts therapeutic efficacy in T1D. Our data also suggest that a combination of rituximab with therapy targeting CD4 + T cells may be beneficial for T1D subjects."

Clinical • Journal

Anti-CD3 and p38 inhibition as a potential novel combination therapy acting to boost CD8 regulatory T cells whilst minimising inflammatory cytokine release in rheumatoid arthritis (BSR 2019) - "...We have been investigating the potential for the anti-CD3 antibody otelixizumab (OTX) as a therapy in RA in combination with the p38 inhibitor losmapimod measuring their effects on CD8 Treg and cytokine release from PBMC from patients with RA. PBMC from RA patients treated with conventional disease modifying anti-rheumatic drugs (cDMARDs), adalimumab or etanercept were stimulated with OTX in the presence of absence of losmapimod for 24 hours and 5 days... These data suggest that the addition of a p38 inhibitor to anti-CD3 therapy could boost CD8 Treg induction whilst reducing the side effects associated with inflammatory cytokine release. Our data further suggest that the administration of this combination to patients with RA treated with anti-TNF could yield additional therapeutic benefits through enhanced Treg numbers and suppressor function. Anti-CD3 together with a p38 inhibitor could potentially be used as a novel therapy for patients with RA, possibly on a..."

Combination therapy

Proteomic Analyses of Thioredoxins f and m Arabidopsis thaliana Mutants Indicate Specific Functions for These Proteins in Plants. (PubMed, Antioxidants (Basel)) - "...Interestingly, 68% of the differentially expressed proteins in trxf1 and trxf2 mutants were downregulated, whilst 75% were upregulated in trxm1, trxm2, trxm3 and trxm4 lines...Notably, a significant set of proteins related to the answer to stress situations and hormone signalling were affected. Despite some studies being necessary to find specific target proteins, these results show signs that are suggest that the f and m type plastidial TRXs most likely have some additional specific functions."

Journal