Immunoglobulin G1 Monoclonal Antibody Research Articles

Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer’s disease

BackgroundVariants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer’s disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy.MethodsPreclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers.ResultsIn cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks.ConclusionsThese findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD.Trial registrationClinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.clinicaltrials.gov/study/NCT03635047.

Anti-MET Antibody Therapies in Non-Small-Cell Lung Cancer: Current Progress and Future Directions.

Background/Objectives: Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer mortality globally, though advances in targeted therapies have improved treatment outcomes. The mesenchymal-epithelial transition (MET) gene plays a significant role in NSCLC, often through protein overexpression, exon 14 skipping mutations, and gene amplification, many of which arise as resistance mechanisms to other oncogenic drivers like epidermal growth factor receptor (EGFR) mutations. This review examines the development and clinical efficacy of anti-MET antibody therapies. Methods: A comprehensive literature search was conducted using major medical databases looking at key relevant studies on anti-MET antibody studies. Both authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Amivantamab, a bispecific EGFR/MET antibody was approved to treat EGFR exon 20 insertion and now has recently been extended to target classical EGFR mutations with progression on osimertinib. Other important anti-MET targeted therapies in development include antibody drug conjugates such as telisotuzumab vedotin, REGN5093-M114, and AZD9592 and emibetuzumab, which is a humanized immunoglobulin G4 monoclonal bivalent MET antibody. Conclusions: MET plays a significant role in NSCLC and amivantamab along with other anti-MET targeted therapies play a role in directly targeting MET and addressing acquired resistance to oncogenic drivers. Future research should focus on developing novel MET antibody drugs and exploring new therapeutic combinations to enhance treatment efficacy and overcome resistance in NSCLC. Refining biomarker-driven approaches to ensure precise patient selection is also critical to optimizing treatment outcomes.

Cutting-edge approaches to B-cell depletion in autoimmune diseases.

B-cell depletion therapy (BCDT) has been employed to treat autoimmune disease for ~20 years. Immunoglobulin G1 (IgG1) monoclonal antibodies targeting CD20 and utilizing effector function (eg, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis) to eliminate B cells have historically been the predominant therapeutic approaches. More recently, diverse BCDT approaches targeting a variety of B-cell surface antigens have been developed for use in hematologic malignancies, including effector-function-enhanced monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) treatment, and bispecific T-cell engagers (TCEs). The latter category of antibodies employs CD3 engagement to augment the killing of target cells. Given the improvement in B-cell depletion observed with CAR-T and TCEs compared with conventional monospecific antibodies for treatment of hematologic malignancies and the recent case reports demonstrating therapeutic benefit of CAR-T in autoimmune disease, there is potential for these mechanisms to be effective for B-cell-mediated autoimmune disease. In this review, we discuss the various BCDTs that are being developed in autoimmune diseases, describing the molecule designs, depletion mechanisms, and potential advantages and disadvantages of each approach as they pertain to safety, efficacy, and patient experience. Additionally, recent advances and strategies with TCEs are presented to help broaden understanding of the potential for bispecific antibodies to safely and effectively engage T cells for deep B-cell depletion in autoimmune diseases.

Efficacy and safety of two fixed doses of ibalizumab plus optimized background regimen in treatment-experienced HIV-positive individuals.

Sustained viral suppression in patients with multidrug-resistant (MDR) human immunodeficiency virus (HIV) infection remains difficult; accordingly, agents targeting different steps in the HIV life cycle are needed. Ibalizumab, a humanized immunoglobulin G4 monoclonal antibody, is a cluster of differentiation (CD4)-directed post-attachment inhibitor. In this Phase IIb study, 113 individuals with MDR HIV-1 and limited treatment options were assigned an optimized background regimen (OBR) and randomized to either 800 mg ibalizumab every two weeks (q2wk; n=59) or 2,000 mg ibalizumab every four weeks (q4wk; n=54) up to Week 24. Viral loads (VL) below the detection limit were achieved in 44% and 28% of patients in the 800 mg q2wk and 2,000 mg q4wk groups, respectively, at Week 24. Mean (standard deviation) VL (log10 copies/mL) decreased from Baseline (4.6(0.8), 800 mg q2wk; 4.7(0.7), 2,000 mg q4wk) to Week 2, with the reduction maintained through Week 24 (2.9(1.5), 800 mg q2wk; 3.2(1.4), 2,000 mg q4wk). Baseline CD4+ counts were 80.5 and 54.0 cells/μL in the 800 mg q2wk and 2,000 mg q4wk groups, respectively. Mean CD4+ T-cell count was increased at Week 24 in both groups. No serious adverse events were related to ibalizumab. In heavily treatment-experienced patients with HIV (PWH) at a more advanced baseline disease severity, clinically significant response rates at Week 24 were achieved with ibalizumab plus OBR. Ibalizumab's unique mechanism of action and lack of cross-resistance to other antiretroviral agents make it an important component of combination treatment regimens for PWH with limited treatment options.

Long-Term Safety of Gantenerumab in Participants with Alzheimer's Disease: A Phase III, Double-Blind, and Open-Label Extension Study (Marguerite RoAD).

Gantenerumab is an anti-amyloid-β immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in Marguerite RoAD (MR; NCT02051608), a Phase III, double-blind (DB), placebo-controlled study in participants with mild Alzheimer's disease (AD) dementia. Following a preplanned futility analysis of the SCarlet RoAD study (NCT01224106), MR was converted into an open-label extension (OLE). The DB study aimed to assess the efficacy of gantenerumab compared with placebo from baseline to Week 104 in participants with mild AD dementia. Following conversion to an OLE, this objective became exploratory, as the OLE assessed the long-term safety and tolerability of SC gantenerumab at doses of up to 1,200 mg every 4 weeks (Q4W) in OLE participants. Eligible DB study participants were offered the opportunity to receive gantenerumab up-titrated to 1,200 mg Q4W. Safety and tolerability were assessed using magnetic resonance imaging (MRI), physical and neurologic examinations, and adverse event monitoring. Overall, 225 participants were rolled over from the DB part of MR and received ≥1 gantenerumab dose in the OLE. The median treatment duration was 123 weeks. Fifty-nine (26.2%) and 41 (18.2%) participants had amyloid-related imaging abnormality (ARIA)-edema and ARIA-hemorrhage MRI findings, respectively. ARIA findings were manageable with MRI monitoring and dose intervention; most were asymptomatic. There were no unexpected safety findings. SC gantenerumab at doses of up to 1,200 mg Q4W were well tolerated in participants with mild AD dementia.

Pharmacokinetics and Pharmacodynamics of Nipocalimab, a Neonatal Fc Receptor Blocker, in Healthy Japanese Volunteers.

Nipocalimab is a high-affinity, fully human, effectorless immunoglobulin G1 monoclonal antibody targeting the neonatal Fc receptor and is currently under evaluation for the treatment of rare and prevalent immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases. This phase I, randomized, double-blind, placebo-controlled, single-dose escalation study in healthy Japanese volunteers (N = 24) assessed the safety, pharmacokinetics, and effect on the serum immunoglobulin G level of single doses of nipocalimab. Volunteers were grouped into three cohorts and received intravenous nipocalimab at 10, 30, or 60 mg/kg or placebo. To complement the study, genetic variation in the Fcγ receptor and transporter subunit of the neonatal Fc receptor was analyzed in Japanese and diverse populations. Nipocalimab was generally safe and well tolerated at all dose levels, with three (12.5% [3/24]) volunteers experiencing treatment-emergent adverse events across all nipocalimab doses. Mean serum immunoglobulin G levels decreased in a dose-dependent manner from baseline with nipocalimab treatment compared with placebo. Maximum serum nipocalimab concentrations demonstrated proportional increases with dose, while the area under theconcentration-time curve was dose dependent and demonstrated non-linear increases with dose. Mean observed half-life was longer as the dose increased. Analysis of genetic variation in Fcγ receptor and transporter identified no unique Japanese variants or variants that alter amino acid sequences in or near the neonatal Fc receptor immunoglobulin G binding site targeted by nipocalimab. The comparable pharmacokinetic/pharmacodynamic profiles and highly conserved neonatal Fc receptor structure among diverse populations further support the clinical development of nipocalimab for the treatment of various immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases across global sites and populations, including the Japanese population.

Evaluating the Efficacy of Infliximab in Inflammatory Bowel Disease: A Systematic Review of the Literature.

The introduction of steroid therapy in 1955 markedly decreased the mortality rate of severe ulcerative colitis (UC) from 24% in the placebo group to 7%, and it is currently less than 1% in specialist centers. Despite this advancement, the response of severe UC to steroids has stagnated over the past 50 years, with a high rate of colectomy persisting for severe to moderately severe cases. Infliximab (IFX) (Remicade, CentocorInc., Malvern, PA, United States), an intravenously administered chimeric monoclonal immunoglobulin G1 antibody targeting tumor necrosis factor-alpha (TNF-α), has shown efficacy in numerous randomized controlled trials for treating moderate to severe and fistulizing Crohn's disease, particularly in patients unresponsive to conventional therapies. This led to its approval by the US Food and Drug Administration in 1998 for treating active and fistulizing Crohn's disease. Most clinical research on IFX has focused on Crohn's disease, which is characterized as a Th1-type condition driven by pro-inflammatory cytokines like TNF-α. Conversely, UC has traditionally been viewed as a Th2-type condition where TNF-α plays a lesser role. However, recent studies indicate that TNF-α might also contribute to the pathogenesis of UC. These findings highlight the necessity for larger randomized controlled trials to further investigate the benefits of therapies like IFX, with the ultimate goal of improving treatment outcomes and quality of life for patients with inflammatory bowel disease.

Nonclinical and clinical characterization of MAU868, a novel human-derived monoclonal neutralizing antibody targeting BK polyomavirus VP1

Reactivation of BK polyomavirus (BKPyV) can cause significant kidney and bladder disease in immunocompromised patients. There are currently no effective, BKPyV-specific therapies. MAU868 is a novel, human immunoglobulin (Ig) G1 monoclonal antibody that binds the major capsid protein, VP1, of BKPyV with picomolar affinity, neutralizes infection by the 4 major BKPyV genotypes (EC50 ranging from 0.009-0.093 μg/mL; EC90 ranging from 0.102-4.160 μg/mL), and has comparable activity against variants with highly prevalent VP1 polymorphisms. No resistance-associated variants were identified in long-term selection studies, indicating a high in vitro barrier-to-resistance. The high-resolution crystal structure of MAU868 in complex with VP1 pentamer identified 3 key contact residues in VP1 (Y169, R170, and K172). A first-in-human study was conducted to assess the safety, tolerability, and pharmacokinetics of MAU868 following intravenous and subcutaneous administration to healthy adults in a randomized, placebo-controlled, double-blinded, single ascending dose design. MAU868 was safe and well-tolerated. All adverse events were grade 1 and resolved. The pharmacokinetics of MAU868 was typical of a human IgG, with dose-proportional systemic exposure and an elimination half-life ranging between 23 and 30 days. These results demonstrate the potential of MAU868 as a first-in-class therapeutic agent for the treatment or prevention of BKPyV disease.

Demonstration of Physicochemical and Functional Similarity of the Biosimilar BAT1806/BIIB800 to Reference Tocilizumab.

Tocilizumab is an immunoglobulin G1 monoclonal antibody targeting the interleukin-6 receptor (IL-6R). BAT1806/BIIB800 (tocilizumab-bavi) has been developed as a biosimilar to the reference product tocilizumab (TCZ). The objective of this study was to demonstrate physicochemical and functional similarity between BAT1806/BIIB800 and TCZ in a comprehensive comparability exercise. A comprehensive panel of over 20 methods was used to generate datasets comparing critical and non-critical product quality attributes for 10 BAT1806/BIIB800 lots and 44 TCZ lots (16 sourced from China, 16 from the EU, and 12 from the US). Primary structure, higher-order structure, and physicochemical properties were assessed using liquid chromatography, mass spectrometry, various spectroscopy techniques/methods, capillary electrophoresis, and thermoanalytical techniques. Fragment antigen-binding (Fab)- and fragment crystallizable (Fc)-mediated biological properties were assessed using cell-based assays, immunoassays, flow cytometry, and kinetic binding assays. BAT1806/BIIB800 and TCZ (irrespective of source) were shown to be similar in terms of structural and functional properties. No differences were observed in terms of the most critical quality attributes, that is, soluble-IL-6R binding and inhibition of IL-6-mediated cell proliferation. BAT1806/BIIB800 and TCZ demonstrated similarity in terms of Fab- and Fc-mediated binding and biological activity. Minor differences were observed in glycosylation (afucosylation and sialylation), glycation, aggregation, and charge variants, which were demonstrated to be not clinically relevant. BAT1806/BIIB800 and TCZ were highly similar for all critical quality attributes. Where differences were observed in less critical quality attributes, additional analytical assessments and clinical study results determined these to be not clinically meaningful.

Teprotumumab for the treatment of Thyroid eye disease.

Thyroid eye disease (TED) is the most common extra thyroidal manifestation of Graves' disease (GD). It may also present in those who are hypothyroid or euthyroid. The characteristic clinical manifestations of TED: chemosis, lid swelling, proptosis and diplopia are driven by a combination of inflammation and extracellular matrix modification. It has recently emerged that one of the major drivers of this molecular signature is the over-expression of the insulin like growth factor-1 receptor (IGF-1R) on key effector cells in TED pathogenesis. The overexpression of the IGF-1R is coupled with a dysregulation of the IGF-1R axis, which links other pathways that modulate inflammation, such as fibrosis and extracellular matrix organization, in patients with TED. This overexpression is also found to persist from the acute stage into the chronic phase. Teprotumumab, a fully human immunoglobulin (Ig) G1 monoclonal antibody that inhibits the IGF-1R, recently gained approval in the US for the treatment of TED. In phase 2 and phase 3 clinical studies, teprotumumab showed efficacy in reducing inflammation, proptosis, diplopia and burden on quality of life, in patients who were treated. Post introduction studies have confirmed the results of the phase 2 and phase 3 studies. Since 2020, over 5, 800 patients have been treated with teprotumumab and it appears to be well tolerated. The American Thyroid Association and the European Thyroid Association have recommended it as first line therapy for patients with moderate to severe TED, who display features of proptosis and diplopia.

A phase 1 study of REGN6569, a GITR mAb, in combination with cemiplimab in patients (pts) with advanced solid tumor malignancies: Initial dose-escalation results.

2650 Background: REGN6569 is a fully human immunoglobulin G1 monoclonal antibody (mAb) that is highly specific for glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR). GITR is expressed on several immune cell subtypes, notably regulatory T cells (Tregs), and activated natural killer (NK) cells. REGN6569 demonstrated greater in vitro antibody-dependent cell-mediated cytotoxicity against GITR-expressing Tregs, as compared to GITR-expressing CD8+ T cells. Mouse studies showed that REGN6569 + cemiplimab (anti-PD-1) combination treatment achieved longer-term tumor responses compared with either drug alone. Methods: This is a first-in-human study (NCT04465487) evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of REGN6569 administered intravenously (IV) every 3 weeks (Q3W) + cemiplimab 350 mg IV Q3W, in pts with advanced solid tumors for which immune checkpoint inhibitor therapies have not been approved or are not available. The study includes a dose-escalation part with 5 dose levels (DL1-DL5) for REGN6569 (“4+3” design), with an initial dose of REGN6569 monotherapy given as a safety lead-in followed by REGN6569 + cemiplimab in subsequent doses. Results: As of the data cutoff date Oct 20, 2023, the dose-escalation part has been completed. 29 pts (median age 58.0 years, 62.1% male) were treated with REGN6569 + cemiplimab, up to the 1200 mg dose level (DL5), across many solid tumor types. The most common tumor type was colorectal cancer (34.5%). One pt (40 mg DL2) experienced a dose-limiting toxicity (Grade 3 hepatic failure); maximum tolerated dose was not reached. Twelve pts (41.4%) had a Grade ≥3 treatment-emergent adverse event (TEAE) and 16 pts (55.2%) had a treatment-related TEAE (any grade). The most frequent TEAEs (any grade) were arthralgia (24.1%), infusion-related reactions, and abdominal pain (20.7% each). There were no treatment-related deaths; 19 (65.5%) pts had disease progression leading to death. Two pts achieved ongoing partial responses by investigator assessment with REGN6569 + cemiplimab treatment: 1 pt with mucoepidermoid tumor of the parotid gland treated with 120 mg (DL3) REGN6569 and 1 pt with B3 thymoma treated with 400 mg (DL4) REGN6569, with duration of responses, 5.6 and 10.4 months, respectively. Full receptor occupancy on circulating Tregs was observed in all dose cohorts following REGN6569 treatment. Increased frequency (~10–50%) of proliferating NK cells in peripheral blood was observed post REGN6569 treatment across all dose cohorts. Conclusions: In this dose-escalation study, REGN6569 was administered up to 1200 mg (DL5) in combination with cemiplimab with one dose-limiting toxicity. The study has progressed to dose-expansion cohorts in anti–PD-1-resistant head and neck cancer, with pts treated with REGN6569 (DL5) + cemiplimab. Clinical trial information: NCT04465487 .

Sugemalimab in locally advanced and advanced Chinese NSCLC: A real-world retrospective study.

e20575 Background: Lung cancer is a major cause of cancer deaths in China. Immunotherapy has emerged as a promising treatment approach for advanced NSCLC without sensitive mutations. Sugemalimab, a fully human immunoglobulin G4 monoclonal antibody, retains its Fc function, inducing antibody-dependent cellular phagocytosis. This study aims to evaluate the real-world effectiveness and safety of Sugemalimab in various treatment patterns, particularly with radiotherapy, in Chinese NSCLC patients with locally advanced or metastatic disease. Methods: We retrospectively evaluated locally advanced (LA-) and metastatic (m-) NSCLC patients (pts) treated with Sugemalimab in Cancer Hospital, Chinese Academy of Medical Sciences from Feb. 2022 to Sep. 2023. Demographic characteristics, clinical features, genetic landscape and therapy patterns were collected. We employed descriptive statistics to determine the Objective Response Rate (ORR) and Disease Control Rate (DCR), and used the Kaplan-Meier method for estimating Progression-Free Survival (PFS) and Overall Survival (OS). Safety profiles, including adverse events and immune-related pneumonitis, were similarly analyzed. Results: 76 pts with LA-NSCLC and mNSCLC were enrolled. Majority were male (92.1%) and smokers (84.2%) and ECOG PS 0-1 (78.9%). Median age was 66. Squamous-cell carcinoma was found in 44 pts (57.9%). The main metastatic sites were bone, brain, liver, lung and lymph node for mNSCLC pts. Genetic profiling in 39 pts revealed TP53 mutations in 19 (48.7%) and KRAS mutations in 10 (25.6%). A total of 38 pts (51.3%) received 1L Sugemalimab therapy, while 21 pts (27.6%) receiving 2L. Main treatment pattern was Sugemalimab plus platinum-based chemo. Radiotherapy (RT) was main local therapy approach, concurrent with Sugemalimab in 18 pts. Majority of pts received either volumetric modulated arc therapy or intensity-modulated radiation therapy to thoracic lesions. Tomotherapy was administered to brain metastases in 2 pts. The median follow-up time was 9.18m at this cut-off date. 16 pts receiving Sugemalimab plus chemo achieved objective response (ORR 44.4%) and DCR was 91.5% in 1L therapy. Median PFS (mPFS) has not been reached. PFS rate at 6m, 12m was 75.6%, 62.1% respectively. 1L OS was immature. For pts receiving additional thoracic RT concurrent with 1L systematic therapy, mPFS was still not mature. PFS rate was 82.4% at 6m and 74.9% at 12 m. Common RT-related side effects were radiation pneumonitis, radiation esophagitis and skin injury. None immune-related pneumonitis was found in this population. Only one case of immune-related pneumonitis was observed in a pts without RT. Conclusions: Our study demonstrated Sugemalimab-based therapy provide clinical benefits to LA-NSCLC and mNSCLC with good safety in real-world setting. The combination treatment of Sugemalimab with radiotherapy illustrates low pulmonary toxicity and superior tolerability.

Denosumab: A Useful Addition to the Armamentarium for the Management of Male Osteoporosis.

Bone is a dynamic tissue. It remodels, preserving serum calcium, repairing microdamage, and maintaining strength. Osteoporosis is caused by a decrease in bone strength, which manifests clinically as low-energy vertebral and non-vertebral fractures. Osteoporosis poses a significant public health challenge. While it's often portrayed as primarily impacting postmenopausal women, there's been growing recognition among researchers and clinicians regarding its prevalence in men. Major fracture in men has higher mortality rates than in women. Denosumab is a fully human monoclonal immunoglobulin G2 (IgG2) antibody that binds to RANKL, the principal regulator of osteoclastic bone resorption. Multiple studies suggest that denosumab is both effective and safe, exhibiting higher adherence rates and greater patient satisfaction. In this narrative review, we highlighted the effects of denosumab in men with osteoporosis, subsequent changes in bone mineral density, and bone turnover markers outlining the literature and guideline support.

#2267 IL-33 Inhibition with tozorakimab for diabetic kidney disease: a randomized, placebo-controlled phase 2b study

Abstract Background and Aims In patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), persistent, low-grade inflammation is a significant risk factor for adverse kidney outcomes. Previously, we identified interleukin-33 (IL-33) as an over-expressed inflammatory cytokine in kidney biopsies from patients with CKD and showed a significant benefit of inhibiting IL-33 signaling in a rodent model of diabetic kidney disease (DKD). Here, we investigate the therapeutic potential of tozorakimab, a high-affinity IL-33-neutralizing immunoglobulin G1 monoclonal antibody, in patients with DKD. Method FRONTIER-1 (NCT04170543) was a phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of tozorakimab in patients with DKD; defined as T2D with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m2, a urinary albumin-to-creatinine ratio (UACR) of 100-3,000 mg/g, and on angiotensin-converting-enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) for > 6 weeks before the treatment period. Participants were randomly assigned to four different doses of tozorakimab or volume-matched placebo, administered subcutaneously every 28 days for 24 weeks. The randomization process was stratified based on region and the use of SGLT2 inhibitors (SGLT2i). All participants received 10 mg of dapagliflozin Days 85–168, discontinuing existing SGLT2i if applicable. The primary objective of the study was to evaluate the effect of tozorakimab on UACR. A sample size of 565 patients provided at least 80% power to detect a 30% reduction in the change from baseline to week 24 in UACR between each tozorakimab treatment group and placebo. Efficacy endpoints were evaluated in the Per Protocol Population (PPP; initiated dapagliflozin treatment), whereas safety and tolerability were assessed for all dosed participants. Results Between 11 December 2019 and 16 May 2023, we assessed 1,575 patients for eligibility in Argentina, Canada, Chile, Peru, South Korea, Japan, and the United States. 599 (38%) participants were assigned to tozorakimab or placebo. Owing to the COVID-19 pandemic, the study was temporarily halted between March and June 2020. This precautionary measure resulted in the discontinuation of 26 participants. Upon resuming, the study incorporated significant modifications to adapt to the pandemic environment. 573 participants (Full Analysis Population) were randomized after the study was restarted: 29.7% were female; their mean age (±SD) was 67 years (±10); mean eGFR was 48 mL/min/1.73 m2 (±15); and the geometric mean UACR was 460 mg/g (coefficient of variation = 151%). Most participants were taking an ACEi (30%) or ARB (65%), and 28% an SGLT2i. 139 participants received placebo, while 96, 91, 95, and 152 participants received 30, 60, 120, and 300 mg tozorakimab, respectively. The baseline characteristics were balanced across treatment groups, and significant target engagement was observed in all dose arms. Tozorakimab was generally well tolerated and the incidences of adverse events (Aes), serious Aes, discontinuations, and death were similar to placebo. Initial evaluation identified 476 participants in the PPP with 109, 81, 80, 72, and 134 on placebo, 30, 60, 120, and 300 mg tozorakimab, respectively. The primary efficacy analysis demonstrated an inhibition of IL-33 signaling but failed to establish a statistically significant difference in UACR reduction between placebo and treatment groups. The median %-change from baseline was –22% (–46%, 24%) in the placebo group and ranged from –23% to –25% in the tozorakimab groups at week 24. Similarly, no significant effect on eGFR was observed. Following study completion, Good Clinical Practice concerns arose at one clinical trial site with 15 participants. The investigation of these issues is ongoing, but significant alterations to the study results are not anticipated. Conclusion This study did not demonstrate a clinically meaningful reduction in UACR with tozorakimab treatment in patients with T2D and CKD. Further investigation is warranted to clarify the role of IL-33 in DKD.

#425 Felzartamab (anti-CD38) in patients with IgA Nephropathy—interim results from the IGNAZ study

Abstract Background and Aims Most patients with IgA nephropathy (IgAN) will progress to kidney failure within 10-15 years of diagnosis. Sustained proteinuria is the best predictor of adverse long-term kidney outcomes and is a surrogate marker for efficacy. CD38+ plasma cells are likely the main source of pathogenic Gd-IgA1, and the related autoantibodies in IgAN. Felzartamab (felza; HIB202) is a recombinant purified human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to CD38 on plasma cells and is being studied across immune-mediated kidney diseases such as IgAN, Primary Membranous Nephropathy, Lupus Nephritis, and Antibody Mediated Rejection. The primary aims of the IGNAZ study were to assess: 1) efficacy of felza compared to placebo on urine protein:creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) change from baseline, and 2) the relationship between exposure, safety, and efficacy in each of 3 dose groups vs. placebo. Interim results with 15 months of follow-up from this 24-month trial are presented. Method In Part 1, 48 IgAN subjects were randomized in a 1:1:1:1 ratio across a placebo and 3 active arms in this multicenter, double-blind placebo-controlled, phase IIa trial. The M1, M2, and M3 active arms received 2 doses in 15 days, 5 doses in 2 months, and 9 doses in 5 months, respectively. In Part 2, 6 Japanese subjects received the M3 regimen, open-label, and have been followed for 9 months. Key inclusion criteria included ages 18-80 years, biopsy confirmed diagnosis of IgAN within the past 8 years, proteinuria at screening ≥1.0 g/d, eGFR ≥30 ml/min/1.73 m2 (by CKD-EPI), and background stable and maximally tolerated renin angiotensin system inhibitors. Results 48 randomized subjects were enrolled at 28 sites in the US and in 14 different countries in Europe and in Asia, of which 46 completed the treatment phase. Mean (SD) baseline characteristics (Parts 1 and 2 combined): age 41.6 (12.3) yrs, UPCR 1.67 (1.0) g/g, eGFR 74.6 (30.3) ml/min/1.73 m2. 67% of subjects were male. Intention-to-treat with felza demonstrated rapid, clinically meaningful reductions in UPCR with the maximal treatment effect being observed in the M3 9-dose regimen. In Part 1, percentage change from baseline in UPCR was −14% for placebo and −25% for M3 9-dose arm at month 3, and +9% for placebo and −35% for M3 at month 6 (Fig. A). Reductions in proteinuria observed at month 6 persisted until Month 15, 10 months after the last dose: +6% and −38% mean UPCR change from baseline for placebo and the M3 9-dose arm, respectively (Fig. B). Relatively stable eGFR values were observed for the felza arms compared to loss of eGFR in the placebo arm. Rapid, durable reductions in IgA and Gd-IgA1 levels were seen across the dosing arms, with reductions lasting 10 months after the last dose (Fig. C). IgG recovery occurred faster off-treatment than IgA. Results in the Part 2 subjects were similar to the Part 1 M3 cohort through 9 months. There were no apparent dose-dependent adverse events and no exposure-safety relationship. Treatment-emergent adverse events (TEAEs) were generally of mild or moderate intensity or toxicity grade. The most common TEAE assessed as related by study investigator was infusion related reactions (IRR), most of which occurred on the first infusion. There was one treatment-related serious AE due to an IRR. Five subjects discontinued treatment due to IRRs or drug hypersensitivity; for four of the five subjects, the infusion rate was higher than protocol-specified or had an error in pre-medication. TEAE infections were comparable between placebo and felza arms: Placebo (33.3%), M1 (33.3%), M2 (36.4%), M3 (38.5%), Part 2 (50.0%); all were Grades 1 or 2, and non-serious. Conclusion This proof-of-concept study highlights the potential for disease modification in IgAN with the anti-CD38 mAb felza and supports continued research as a potential treatment for high-risk IgAN patients. Felza treatment resulted in clinically meaningful, prolonged UPCR reductions and eGFR stabilization sustained ≥10 months after dosing was completed. Felza was generally well tolerated with rapid recovery of IgG with durable reductions in IgA and pathogenic Gd-IgA1 levels.

Safety and efficacy of narsoplimab in pediatric and adult patients with transplant-associated thrombotic microangiopathy: a real-world experience

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication following hematopoietic stem cell transplantation (HSCT). No approved treatments are currently available. This study presents real-world data obtained with narsoplimab, a human immunoglobulin G4 monoclonal antibody that inhibits MASP-2, the effector enzyme of the lectin pathway of the complement system. Between January 2018 and August 2023, 20 (13 adult and 7 pediatric) patients diagnosed with TA-TMA received narsoplimab under an ongoing compassionate use program. The diagnosis was based on internationally defined criteria for pediatric and adult patients. Fifteen patients fulfilled the criteria recently established by an international consensus on TA-TMA. Nineteen patients exhibited high-risk characteristics. Thirteen patients (65%) responded to narsoplimab, achieving transfusion independence and significant clinical improvement. The one-hundred-day Overall Survival (OS) post-TA-TMA diagnosis was 70%, and 100% for responders. Narsoplimab proved to be effective and safe in the treatment of high-risk TA-TMA, with no increased infectious complications or other safety signals of concern across all age groups. The high response rates and the encouraging survival outcomes underscore the potential of narsoplimab as a valuable therapeutic option, particularly for high-risk cases.

Bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer via modulating HAT1 and increasing IL-9.

Bevacizumab is a recombinant humanized monoclonal immunoglobulin (Ig) G1 antibody of VEGF, and inhibits angiogenesis and tumor growth in hepatocellular carcinoma (HCC). Ferroptosis, a new form of regulated cell death function independently of the apoptotic machinery, has been accepted as an attractive target for pharmacological intervention; the ferroptosis pathway can enhance cell immune activity of anti-PD1 immunotherapy in HCC. In this study we investigated whether and how bevacizumab regulated ferroptosis and immune activity in liver cancer. Firstly, we performed RNA-sequencing in bevacizumab-treated human liver cancer cell line HepG2 cells, and found that bevacizumab significantly altered the expression of a number of genes including VEGF, PI3K, HAT1, SLC7A11 and IL-9 in liver cancer, bevacizumab upregulated 37 ferroptosis-related drivers, and downregulated 17 ferroptosis-related suppressors in particular. We demonstrated that bevacizumab triggered ferroptosis in liver cancer cells by driving VEGF/PI3K/HAT1/SLC7A11 axis. Clinical data confirmed that the expression levels of VEGF were positively associated with those of PI3K, HAT1 and SLC7A11 in HCC tissues. Meanwhile, we found that bevacizumab enhanced immune cell activity in tumor immune-microenvironment. We identified that HAT1 up-regulated miR-143 targeting IL-9 mRNA 3'UTR in liver cancer cells; bevacizumab treatment resulted in the increase of IL-9 levels and its secretion via VEGF/PI3K/HAT1/miR-143/IL-9 axis, which led to the inhibition of tumor growth in vivo through increasing the release of IL-2 and Granzyme B from activated CD8+ T cells. We conclude that in addition to inhibiting angiogenesis, bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer. This study provides new insight into the mechanisms by which bevacizumab synergistically modulates ferroptosis and CD8+ T cell immune activity in liver cancer.

Garadacimab for hereditary angioedema attack prevention: long-term efficacy, quality of life, and safety data from a phase 2, randomised, open-label extension study

Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long-term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema. This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double-blind, placebo-controlled) and a treatment period 2 (TP2: ≥44-week open-label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open-label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long-term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed. Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open-label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 39·0 years (IQR 27·0-53·0), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 87·9 weeks (IQR 50·0-106·6) in the garadacimab 200 mg group and 44·1 weeks (24·1-56·1) in the garadacimab 600 mg group. Median monthly attack rates were 0·0 (IQR 0·0-0·1) in the garadacimab 200 mg group and 0·1 (0·0-0·4) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run-in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths. Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long-term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema. CSL Behring.

The Role of Rituximab in the Management of Heart Failure

Rituximab is a chimeric monoclonal antibody mice/humans that bind the transmembrane antigen, CD20 specifically. The mechanism of heart failure is mediated by neurohormonal pathways: the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and the natriuretic peptide system, thereby triggering activation of the immune system. This literature review will discuss the role of B cell targeted therapy, in this case rituximab in the management of heart failure. Modulation of the immune response holds great promise in the 30% of cases of myocarditis where inflammation does not resolve and progression to chronic inflammatory dilated cardiomyopathy occurs. Pharmacologically, rituximab is a monoclonal immunoglobulin G1 antibody drug that is given intravenously. Rituximab targets the CD20 antigen expressed on the surface of mature B lymphocytes, including memory B cells but not on stem cells or plasma cells. In conclusion, rituximab causes a selective and temporary decrease in the CD20+ B cell subpopulation and represents a more specific and targeted approach to B cell-induced disorders including heart failure.

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers.

Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50mg, 150mg, 240mg) or subcutaneously (SC; 240mg, 675mg, 1200mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. The study enrolled 49 HVs, with a median age of 39 (range 18-73)years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-timecurve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50mg IV) tested positive for ADAs at a single time point (day15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition. RO7303509 was well tolerated at single SC doses up to 1200mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. ISRCTN13175485.