Human IgG1 Monoclonal Antibody Research Articles

Fc gamma receptors promote antibody-induced LILRB4 internalization and immune regulation of monocytic AML.

The immune checkpoint leukocyte immunoglobulin-like receptor B4 (LILRB4) is found specifically on the cell surface of acute monocytic leukemia (monocytic AML), an aggressive and common subtype of AML. We have developed a humanized monoclonal IgG1 LILRB4-blocking antibody (h128-3), which improved immune regulation but reduced cell surface expression of LILRB4 in monocytic AML models by 40-60%. Interestingly, most of this effect was neutralized by mutation of the Fc region of the antibody (h128-3/N297A), which prevents interaction with Fc gamma receptors (FcγRs). This suggested that there is FcγR-dependent antigenic modulation underlying h128-3's effects, a mechanism known to alter the function of antibodies targeting B-cell malignancies. We disrupted the Fc-FcγR interaction pharmacologically and with stable CRISPR-Cas9-mediated genetic knockout of FcγRs in monocytic AML cell lines to investigate the role of FcγR-dependent antigenic modulation in the regulation of LILRB4 by h128-3. When FcγRI is inhibited or removed from the surface of monocytic AML cells, h128-3 cannot optimally perform its blocking function, resulting in activation of the LILRB4 inhibitory receptor and leading to a 15-25% decrease in T-cell-mediated cytotoxicity in vitro. In the absence of FcγRI, scaffolding by FcγRIIa allows h128-3 to maintain LILRB4-blocking function. Here we define a FcγR-dependent antigenic modulation mechanism underlying the function of an immunoreceptor blocking antibody for the first time in myeloid malignancy. This research will facilitate the development of safe, precision-targeted antibody therapeutics in myeloid malignancies with greater potency and efficacy.

Preliminary Results of a Phase 1, First-in-Human Study of INA03, an Anti-CD71 Antibody-Drug Conjugate in Patients with Relapsed or Refractory (R/R) Acute Leukemias

Background: Relapsed or refractory (R/R) acute leukemias (AL) represent major therapeutic challenges. Several reports have highlighted the deregulation of iron metabolism in various proliferative tumor models (and notably AL) which includes the over-expression of the transferrin receptor (TfR1/CD71). Our strategy is thus to harness CD71 overexpression to specifically target cytotoxic agents to leukemic cells. INA03 is an antibody drug conjugate (ADC) constituted of a humanized monoclonal IgG 4 against CD71 and MMAE. We herein report the preliminary safety and efficacy data of a phase 1 trial INA03 (NCT03957915) evaluating INA03 in R/R AL. Methods: INA03 is given as 30 minutes IV infusion on days 1 (Loading dose,LD) followed by maintenance injections on D15 for cycle 1 and on D1 and D15 of cycle 2 and beyond. Eligibility criteria are age >18y, ECOG<2, R/R AL after at least one line of treatment with high dose chemotherapy and/or Vidaza and Venetoclax (VEN), LVEF>50%, Creatinine Clearance >30ml/min, normal liver function. The study design is based on a continuous reassessment method and includes 2 parts: a Loading Dose (LD) Titration study (Part 1, completed), followed by a Dose Escalation Part 2. During Part 1, sequential cohorts of 2 pts were included to receive ascending LD of INA03 followed by repeated fixed doses of INA03 to deal with a potential sink effect related to the high expression of CD71 in normal erythroblasts. During Part 2, sequential cohorts of 3 pts received escalating doses of INA03 Q2 weeks in 28-day cycles. The objectives were to establish the maximal tolerated dose (MTD) for subsequent administration and both safety/tolerability and anti-leukemic activity. Results: With a cutoff date of July 05, 2023, 27 patients (pts) across 10 cohorts were included in the study. The median age was 73 (range: 39 - 83), 25 (93%) pts had AML and two (7%) had ALL. Four (14.8%) pts had a prior allogeneic stem cell transplantation and 18 (66.6%) had prior VEN exposure. Pts received escalating doses of INA03 of 0.02 mg/kg to 3 mg/kg. Two patients in the 3 mg/kg loading dose cohort presented a dose limiting toxicity (DLT), one with grade 3 toxic erythema, grade 3 hepatitis and grade 3 mucositis and one with grade 4 colonic perforation. Up to the 2.5 mg/kg dose, no grade 2-4 treatment emerging adverse events (TEAE) were observed among the 19 evaluable pts and only one related grade 1 TEAE (hyperkalemia/phosphatemia) was reported. Transient decrease of reticulocyte count and erythroblasts percentage were observed at 0.5 mg/kg and above. Blasts reductions were seen in 6/20 (30%) evaluable pts at dose > 1 mg/kg including two partial responses according to ELN 2022 classification. MMAE pharmacokinetics (PK) appears dose-proportional with a small accumulation after repeated IV, while INA03 PK exhibits target-mediated drug disposition without accumulation. Conclusions: The preliminary results of this phase 1 study indicate that INA03 is well tolerated for doses up to 2.5 mg/kg. Induction of transient erythroblastopenia indicates effective targeting of CD71 in vivo and early signs of antileukemic efficacy have been observed in patients with refractory AL. Inclusion in the trial are continuing and additional data will be presented.

Phase I/Ib, open-label, multicenter, dose-escalation study of the anti-TGF-β monoclonal antibody, NIS793, in combination with spartalizumab in adult patients with advanced tumors

BackgroundNIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-β). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors.MethodsPatients received...

Current and Emerging Therapies for Atopic Dermatitis in the Elderly.

Atopic dermatitis (AD) in the elderly has recently emerged as a distinct subgroup of AD, garnering widespread concern due to its increasing global incidence rate. Epidermal barrier dysfunction, inflammatory response, and chronic pruritus interact with each other, contributing to the pathogenesis andpathophysiology of AD in the elderly. Although fundamental medications are essential for managing AD in the elderly, older adults often struggle with regular usage of moisturizing emollients, topical medications, and avoidance of environmental triggers, leading to recurrent or even exacerbated disease progression. Therefore, a systematic medication approach is necessary to control pruritus and skin lesions. Traditional systemic treatments may not adequately meet the treatment needs of moderate and severe AD in the elderly and may even pose certain safety risks. Biologics and Janus kinase (JAK) inhibitors, exhibiting excellent clinical efficacy, have made significant breakthroughs in AD treatment. Existing evidence suggests that dupilumab, a human monoclonal IgG4 antibody, has been confirmed as an effective and safe first-line systematic treatment for moderate to severe AD in the elderly, with no notable differences between adults and the elderly. However, the limited inclusion of elderly patients in related clinical studies hinders the generalizability of these findings. As older patients face a higher risk of adverse events with JAK inhibitors, JAK inhibitors are recommended when no other suitable treatment options are available. Obtaining population-specific data is crucial for making evidence-based treatment choices when managing AD in older adults with JAK inhibitors.

Sintilimab Injection Combination with Concurrent Chemoradiotherapy (cCRT) in Patients with Localized Esophageal Squamous Cell Carcinoma: A Prospective, Multi-Center, Single-Arm Trial in Progress

Esophageal cancer had accounted for the sixth highest incidence and the fourth highest death rate in China. The predominant histological subtype is esophageal squamous cell carcinoma (ESCC). At initial diagnosis, more than half of patients with ESCC are unfit for surgery. An accepted alternative to surgery is concurrent chemoradiotherapy (cCRT); however, many patients experience local recurrence or distant metastasis after cCRT. Therefore, innovative therapies are needed. Sintilimab is a fully human IgG4 monoclonal antibody, exhibiting the highest affinity for human PD-1 and a lower off-rate, the PD-1 receptor occupancy of sintilimab on circulating T cells is superior. In previous studies, sintilimab, alone and in combination with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced ESCC. This prospective, single-arm study (NCT04602013) is designed to explore the efficacy of Sintilimab in combination with cCRT. Eligible patients have histologically confirmed localized ESCC for whom cCRT is suitable and surgery is unsuitable/ declined; patients couldn't have received prior chemoradiotherapy. Approximately 53 Chinese patients from 5 centers will be to receive sintilimab (body weight <60kg: 3mg/kg IV Q3W; body weight ≥60kg: 200mg IV Q3W) in combination with cisplatin (25 mg/m2 IV on Days 1-3 of each 3-week cycle) plus paclitaxel for injection (albumin bound) (180 mg/m2). and radiotherapy at a total dose of 60Gy. Duration of treatment will be up to 12 months for sintilimab, including two cycles for concurrent administration of chemotherapy and radiotherapy. Progression-free survival (PFS), assessed by a Blinded Independent Review Committee per RECIST v1.1, is the primary endpoint of the study. Secondary efficacy endpoints include overall response rate, duration of response, and overall survival. Incidence and severity of adverse events (CTCAE V5.0) and patient-reported outcomes of health-related quality of life are additional secondary endpoints. A total of 17 patients have completed sintilimab injection combination with concurrent chemoradiotherapy,17/53 (32%). Objective response rate (ORR) 62.5% and a median progression free survival (mPFS) 17 months. 1-year overall survival (OS) 88.2%. The most common AEs included granulocytopenia (43.7%), thrombo -cytopenia (56.2%), radiation esophagitis (50%), nausea and vomiting (50%), and immune pneumonia (18.7%). Of these AEs greater than grade 3 granulocytopenia (25.0%), thrombocytopenia (35.0%), radiation esophagitis (12.5%), and nausea and vomiting (31.3%), and one patient developed grade 3 immune pneumonia (6.2%), which recovered with treatment. The treatment of sintilimab with CCRT is safe and effective for localized ESCC patients, even with high-dose radiotherapy (60Gy). This study may help to address the unmet need for new therapeutic options for patients with localized ESCC.

Lecanemab Clarity AD: Quality-of-Life Results from a Randomized, Double-Blind Phase 3 Trial in Early Alzheimer’s Disease

BackgroundLecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to amyloid-beta protein protofibrils. In phase 3 development, lecanemab has been shown to reduce markers of amyloid in early Alzheimer’s disease and reduce decline on clinical endpoints of cognition and function at 18 months.ObjectivesTo describe the health-related quality-of-life (HRQoL) results from Clarity AD which were exploratory outcomes in this trial.DesignClarity AD was an 18-month, multi-center, doubleblind, phase 3 trial.SettingEarly Alzheimer’s disease.ParticipantsIndividuals 50–90 years of age with a diagnosis of mild cognitive impairment or mild dementia due to Alzheimer’s disease and positron emission tomography or cerebrospinal fluid evidence of cerebral amyloid accumulation.InterventionPlacebo or lecanemab 10-mg/kg IV biweekly.MeasurementsHRQoL was measured at baseline and every 6 months using the European Quality of Life–5 Dimensions (EQ-5D-5L; by subject) and Quality of Life in AD (QOL-AD; by subject and proxy). Study partner burden was measured using the Zarit Burden Interview (ZBI).ResultsA total of 1795 participants were enrolled (lecanemab:898; placebo:897). At month 18, adjusted mean change from baseline in EQ-5D-5L and QOL-AD by subject showed 49% and 56% less decline, respectively. QOL-AD rated by study partner as proxy resulted in 23% less decline. ZBI adjusted mean change from baseline at 18 months resulted in 38% less increase of care partner burden. Individual HRQoL test items and dimensions also showed lecanemab benefit.ConclusionsLecanemab was associated with a relative preservation of HRQoL and less increase in caregiver burden, with consistent benefits seen across different quality of life scales and within scale subdomains. These benefits provide valuable patient reported outcomes which, together with previously reported benefits of lecanemab across multiple measures of cognition, function, disease progression, and biomarkers, demonstrate that lecanemab treatment may offer meaningful benefits to patients, care partners, and society.

Sintilimab treatment for chronic active Epstein–Barr virus infection and Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in children

BackgroundChronic active Epstein–Barr virus infection (CAEBV) and Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) are rare but life-threatening progressive diseases triggered by EBV infection. Glucocorticoid/immunosuppressants treatment is temporarily effective; however, most patients relapse and/or progress. Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy; however, there are risks of transplantation-associated complications. Currently there is no standard treatment for CAEBV and EBV-HLH. Programmed death protein 1 (PD-1) inhibitors have achieved a high response in many EBV-related diseases. Sintilimab (a recombinant human IgG4 monoclonal antibody against PD-1) disrupts the interaction between PD-1 and its ligand, leading to T cell reinvigoration.MethodsA retrospective analysis was performed on three children with CAEBV or EBV-HLH in the Children’s Hospital of Soochow University between 12 December 2020 and 28 November 2022. The efficacy of sintilimab was evaluated.ResultsThree patients, including two males and one female, were analyzed. Among them, two children were diagnosed with CAEBV with intermittent fever for more than four years, and one child was diagnosed with EBV-HLH. After sintilimab treatment and a mean follow-up of 17.1 months (range 10.0–23.3 months), patients 1 and 3 achieved a complete clinical response and patient 2 achieved a partial clinical response. All three children showed a > 50% decrease in EBV-DNA load in both blood and plasma. EBV-DNA copies in sorted T, B, and NK cells were also markedly decreased after sintilimab treatment.ConclusionOur data supported the efficacy of PD-1 targeted therapy in certain patients with CAEBV and EBV-HLH, and suggested that sintilimab could provide a cure for these diseases, without HSCT. More prospective studies and longer follow-up are needed to confirm these conclusions.

Generation and Characterization of Mirikizumab, a Humanized Monoclonal Antibody Targeting the p19 Subunit of IL-23.

Interleukin (IL)-23 exists as a heterodimer consisting of p19 and p40 and is a key cytokine for promoting inflammatory responses in a variety of target organs. IL-23 plays a key role in the differentiation and maintenance of T helper 17 cells, and deregulation of IL-23 can result in autoimmune pathologies of the skin, lungs, and gut. This study describes the generation and characterization of mirikizumab (miri), a humanized IgG4 monoclonal antibody directed against the p19 subunit of IL-23. Miri binds human and cynomolgus monkey IL-23 with high affinity and binds rabbit IL-23 weakly but does not bind to rodent IL-23 or the other IL-23 family members IL-12, IL-27, or IL-35. Miri effectively inhibits the interaction of IL-23 with its receptor, and potently blocks IL-23-induced IL-17 production in cell-based assays while preserving the function of IL-12. In both local and systemic in vivo mouse models, miri blocked IL-23-induced keratin mRNA or IL-17 production, respectively. These data provide a comprehensive preclinical characterization of miri, for which efficacy and safety have been demonstrated in human clinical trials for psoriasis, ulcerative colitis, and Crohn's disease. SIGNIFICANCE STATEMENT: This article describes the generation and characterization of mirikizumab, a high affinity, neutralizing IgG4 variant monoclonal antibody that is under development for the treatment of ulcerative colitis and Crohn's disease. Neutralization of interleukin (IL)-23 is achieved by preventing the binding of IL-23 p19 subunit to the IL-23 receptor and does not affect the IL-12 pathway.

Role of Anti-CD38 Monoclonal Antibodies in the Treatment of Adult Immune Hematological Diseases.

Daratumumab is a first-in-class human anti-CD38 IgG1 monoclonal antibody approved for treating newly diagnosed and relapsed refractory multiple myeloma. Pre-clinical data supported daratumumab's ability to deplete autoantibodies producing plasma cells, B-cells, and NK cells. Those reports showed promising results on using daratumumab in autoimmune disorders that are refractory to multiple lines of therapies, which encouraged using daratumumab in various autoimmune conditions that are refractory to standard therapies. This review aims to summarize the literature reporting experience using anti-CD38 antibodies in hematological autoimmune diseases, focusing on the most common autoimmune hematological diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, post-transplant cytopenia, and pure red blood cell aplasia.

TROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer.

Despite recent treatment advances, the prognosis for patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) remains poor. The antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) is composed of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable, cleavable linker. The phase III TROPION-Breast02 trial in patients previously untreated for locally recurrent inoperable or metastatic TNBC, who are not candidates for PD-1/PD-L1 inhibitors is evaluating efficacy and safety of Dato-DXd versus investigator's choice of chemotherapy (ICC). Approximately 600 patients will be randomized 1:1 to Dato-DXd 6mg/kg iv. every 3weeks or ICC (paclitaxel, nab-paclitaxel, carboplatin, capecitabine or eribulin mesylate). Dual primary end points are progression-free survival by blinded independent central review and overall survival.

Brodalumab in the Treatment of Plaque Psoriasis Localized in Difficult-to-Treat Areas: A Narrative Review.

Psoriasis is a common chronic, immune-mediated, inflammatory skin disease that in certain localization results difficult to treat. Psoriatic lesions in difficult-to-treat areas might be hardly managed as no standardized therapeutic approach and the application of topical treatments might have great limitations. Systemic agents, including biologic therapies, have been proven effective in treating this subgroup of patients. In particular, current evidence has shown beneficial effects with the use of brodalumab, a fully human IgG2 monoclonal antibody antagonizing the IL-17 receptor A subunit (IL-17RA). The aim of this narrative review was to collect published data about efficacy and safety of brodalumab in the treatment of psoriasis occurring in difficult-to-treat areas. Data on brodalumab effectiveness and safety deriving from both trials and real-world setting that had been published in the last 15 years were collected for this review, together with clinical findings issued during international meetings. In phase 3 trials, brodalumab demonstrated to be effective in promoting a rapid response in scalp psoriasis as well as in generalized pustular psoriasis and erythrodermic psoriasis. Nail psoriasis demonstrated marked clinical improvement after treatment with brodalumab. Amelioration of palmoplantar psoriasis was also described in brodalumab-treated patients. Various retrospective real-world studies reported a complete clearance of psoriatic lesions in difficult-to-treat areas, including genitalia, through short-term brodalumab treatment. Brodalumab, combining rapid and sustained efficacy with a favorable safety profile, may be a valid therapeutic option for severe variants of psoriasis as well as for psoriasis localized in difficult-to-treat areas.

Characterization of a Musculoskeletal Syndrome of Enthesitis and Arthritis in Patients With Atopic Dermatitis Treated With Dupilumab, an Interleukin-4/13 Inhibitor.

To characterize the presentation and outcomes of patients with atopic dermatitis (AD) who developed musculoskeletal symptoms after treatment with dupilumab, a human IgG4 monoclonal antibody that blocks the functions of interleukin-4 (IL-4) and IL-13, key pathologic pathways in AD. This article reports an observational cohort of patients receiving dupilumab who developed new-onset musculoskeletal symptoms after dupilumab therapy at our center. All patients had a comprehensive rheumatologic history and examination, with imaging by ultrasonography (US) or magnetic resonance imaging (MRI) in most patients. Between October 2018 and February 2021, we recorded 470 patients with AD commencing dupilumab treatment from routine clinical care records. Of 36 patients referred for rheumatologic assessment, we identified 26 patients (14 male, 12 female) with a musculoskeletal syndrome of inflammatory enthesitis, arthritis, and/or tenosynovitis. Clinical findings were confirmed by US and MRI. All patients had very good response to dupilumab treatment, and no specific predictors of musculoskeletal syndrome were noted. Symptoms were mild in 16 patients, moderate in 6 patients, and severe in 4 patients. Receipt of nonsteroidal antiinflammatory drugs or cyclooxygenase 2 inhibitors, reduction of dupilumab dose/frequency, and cessation of dupilumab therapy led to improvement, but moderate or severe symptoms persisted for many months. We report a new musculoskeletal syndrome of inflammatory enthesitis/arthritis/tenosynovitis in some patients receiving the IL-4 receptor antagonist dupilumab. This response to a cytokine-targeting therapy provides key insights into the pathogenesis of enthesitis.

Mirikizumab for the treatment of moderate to severe ulcerative colitis.

Despite a growing number of available therapeutic options for ulcerative colitis (UC), up to 50% of patients do not respond to initial treatment or lose response over time, highlighting the need for novel therapies. The IL-23 pathway has emerged as an important therapeutic target for UC. Mirikizumab is a humanized IgG4 monoclonal antibody against the p19 subunit of IL-23, dosed intravenously during induction and subcutaneously during maintenance. It is effective for the induction and maintenance of remission in moderately to severely active UC, including patients with prior failure of biological or tofacitinib therapy. Like other IL-23 antagonists, mirikizumab has a favorable safety profile. It is the first agent of its class to receive regulatory approval for moderately to severely active UC in Europe.

Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab

BackgroundEmicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating patients with hemophilia A (HA) with or without FVIII inhibitors. However, emicizumab only partially mimics FVIII activity; it prevents but does not treat acute bleeds. Emergency management is particularly complicated in patients with FVIII inhibitors receiving emicizumab prophylaxis in whom exogenous FVIII is inefficient. We have shown recently that Imlifidase (IdeS), a bacterial IgG-degrading enzyme, efficiently eliminates human anti-FVIII IgG in a mouse model of severe HA with inhibitors and opens a therapeutic window for the administration of exogenous FVIII. ObjectivesTo investigate the impact of IdeS treatment in inhibitor-positive HA mice injected with emicizumab. MethodsIdeS was injected to HA mice reconstituted with human neutralizing anti-FVIII IgG and treated with emicizumab. ResultsIdeS hydrolyzed emicizumab in vitro and in vivo, albeit, at slower rates than another recombinant human monoclonal IgG4. While F(ab’)2 fragments were rapidly cleared from the circulation, thus leading to a rapid loss of emicizumab procoagulant activity, low amounts of single-cleaved intermediate IgG persisted for several days. Moreover, the IdeS-mediated elimination of the neutralizing anti-FVIII IgG and restoration of the hemostatic efficacy of exogenous FVIII were not impaired by the presence of emicizumab and polyclonal human IgG in inhibitor-positive HA mice. ConclusionOur results suggest that IdeS could be administered to inhibitor-positive patients with HA receiving emicizumab prophylaxis to improve and ease the management of breakthrough bleeds or programmed major surgeries.

Utilizing PK and PD Biomarkers to Guide the First-in-Human Starting Dose Selection of MTBT1466A: A Novel Humanized Monoclonal Anti-TGFβ3 Antibody for the Treatment of Fibrotic Diseases

MTBT1466A is a high-affinity TGFβ3-specific humanized IgG1 monoclonal antibody with reduced Fc effector function, currently under investigation in clinical trials as a potential anti-fibrotic therapy. Here, we characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of MTBT1466A in mice and monkeys and predicted the PK/PD of MTBT1466A in humans to guide the selection of the first-in-human (FIH) starting dose. MTBT1466A demonstrated a typical IgG1-like biphasic PK profile in monkeys, and the predicted human clearance of 2.69 mL/day/kg and t1/2 of 20.4 days are consistent with those expected for a human IgG1 antibody. In a mouse model of bleomycin-induced lung fibrosis, changes in expression of TGFβ3-related genes, serpine1, fibronectin-1, and collagen 1A1 were used as PD biomarkers to determine the minimum pharmacologically active dose of 1 mg/kg. Unlike in the fibrosis mouse model, evidence of target engagement in healthy monkeys was only observed at higher doses. Using a PKPD-guided approach, the recommended FIH dose of 50 mg, IV, provided exposures that were shown to be safe and well tolerated in healthy volunteers. MTBT1466A PK in healthy volunteers was predicted reasonably well using a PK model with allometric scaling of PK parameters from monkey data. Taken together, this work provides insights into the PK/PD behavior of MTBT1466A in preclinical species, and supports the translatability of the preclinical data into the clinic.

An overview of the preclinical discovery and development of tezepelumab for the treatment of asthma

ABSTRACT Introduction Tezepelumab is a human IgG2 monoclonal antibody (mAb) that binds to human thymic stromal lymphopoietin (TSLP), preventing its interaction with the receptor and inhibiting multiple downstream inflammatory pathways. TSLP is an alarmin relevant to the pathogenesis of asthma. Areas covered This article focuses on the significance of TSLP in developing asthma and how tezepelumab can target it, thus playing a potentially relevant role in the treatment of asthma. Expert opinion An extensive clinical development program has shown that tezepelumab can improve all key primary and secondary endpoints in patients with severe asthma, compared to placebo, when added to standard therapy. Of particular importance is the favorable impact of this biological drug on exacerbation rates and lung function in patients with uncontrolled severe asthma regardless of the type 2 endotype. Therefore, tezepelumab is likely the first biologic to treat asthma exacerbations in patients with low eosinophil levels successfully. Furthermore, it appears to be a safe drug and can be ‘self-administered’ using a pre-filled, disposable pen. Tezepelumab should be preferred over other currently available biologics because blocking upstream mediators may have a broader therapeutic impact than those that inhibit downstream cytokines and/or block their receptors.

TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer.

Improving the prognosis for patients with metastatic HR+/HER2- breast cancer remains an unmet need. Patients with tumors that have progressed on endocrine therapy and/or are not eligible for endocrine therapy had limited treatment options beyond chemotherapy. Antibody-drug conjugates are a novel and promising treatment class in this setting. Datopotamab deruxtecan (Dato-DXd) consists of a TROP2-directed humanized IgG1 monoclonal antibody attached via a serum-stable cleavable linker to a topoisomerase I inhibitor payload. TROPION-Breast01 is an ongoing phase III study that is evaluating the efficacy and safety of Dato-DXd compared with investigator's choice of standard-of-care chemotherapy in patients with inoperable or metastatic HR+/HER2- breast cancer who have received one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting. Clinical Trial Registration: NCT05104866 (ClinicalTrials.gov).

Aducanumab: an uprising hope with vague horizons

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Amyloid-beta (Aβ) deposition, is one of the processes involved in the pathophysiology of AD, has inspired interest in targeted therapies, including monoclonal antibodies. Aducanumab acts as a fully human IgG1 monoclonal antibody against Aβ by binding to amyloid plaques and was approved by the Food and Drug Administration (FDA) as the first disease-modifying drug for mild cognitive impairment and mild stages of AD. This accelerated approval, albeit the termination of the two phase III clinical trials of aducanumab due to results of futility analysis, has provoked controversy among the key opinion leaders in the field of cognitive neurology. Aducanumab poses significant financial constraints on patients and healthcare systems. Furthermore, the precise diagnosis of AD stages for appropriate aducanumab initiation remains a formidable challenge. The drug’s administration necessitates specialized infrastructure and medical equipment, and it may induce amyloid-related imaging abnormalities (ARIA), potentially resulting in cerebral edema or hemorrhage. These disadvantages might outweigh the potential benefits of the medication, especially considering the uncertainties regarding its efficacy. This commentary is intended to briefly evaluate the application of aducanumab in developing countries, considering the associated diagnostic challenges, clinical efficacy, cost, and potential adverse effects.

Dupilumab for Chronic Prurigo: Case Series on Effectiveness, Safety, and Quality of Life

Background: Chronic prurigo (CPG) is a pruritic skin disease, characterized by an itch-scratch cycle and scarring. It reduces patients’ quality of life (QoL). Dupilumab is a monoclonal human IgG antibody that inhibits signaling of the interleukin 4 (IL-4) and interleukin 13 (IL-13) pathways through blockade of the IL-4 receptor. Patients with CPG who receive dupilumab often report great improvement in itch and overall QoL. We therefore reviewed our experience in order to follow up on QoL, safety, and treatment response in patients with CPG who received dupilumab. Methods: We conducted a real-world retrospective single-center case series. Outcomes were assessed by phone interviews and photographs using validated questionnaires and scores. Demographic data were obtained from the hospital files. Follow-up was up to 2 years. We assessed QoL with the Dermatology Life Quality Index (DLQI) and the Itchy quality of life questionnaire (ItchyQoL). Numerical Rating Scale (NRS) was used to assess itch. Prurigo lesions were documented with the Prurigo activity and severity score (PAS). Results: Ten patients were included in this study. Results were reported up to 2 years after treatment with dupilumab. The response variables for DLQI, ItchyQoL, NRS, and PAS analyses showed a statistically significant decrease over time (DLQI: p ≤ 0.0001 [−0.84; −1.27], ItchyQoL: p ≤ 0.0001 [−9.89; −18.69], NRS maximum and average: p ≤ 0.0001 [−0.52; −0.86] and p ≤ 0.0001 [−0.55; −0.94], and PAS number of lesions: p = 0.0005 [−1.70; −5.28]). The percent decrease after 1 year of treatment (this estimate is based on model estimates) ranges from −42% to −82%. Four (40%) patients reported mild side effects. No serious side effects were reported. Conclusion: Dupilumab treatment of CGP for up to 2 years is associated with improved QoL and less itching.

418 A global, observational, cohort study of patients with atopic dermatitis to evaluate tralokinumab real-world clinical use (TRACE): baseline characteristics from the first 100 patients in Germany

Abstract Tralokinumab is a high-affinity, fully human IgG4 monoclonal antibody that specifically inhibits interleukin-13 (IL-13), a key driver of atopic dermatitis (AD) disease progression. Clinical trials have shown that tralokinumab is efficacious in patients with moderate-to-severe AD and has a favorable safety profile, including a low frequency of adverse events (AEs) such as conjunctivitis. However, management of patients in routine clinical practice differ from those enrolled in clinical trials due to strict inclusion/exclusion criteria, and there is currently a lack of clinical data on tralokinumab use in the real-world setting. TRACE is an observational cohort study of patients with AD, which aims to better understand the effectiveness, safety and clinical use of tralokinumab in the real-world setting. This study aims to describe baseline characteristics and initial insights from the first 100 patients enrolled into TRACE in Germany. TRACE is a longitudinal, prospective, new user, noncomparative, observational, single-cohort study, with primary data collection of adult patients with AD who are treated with tralokinumab, according to national approved labels. The study is taking place across countries in Europe, North America and the Middle East. The primary objective is to assess changes in clinical signs and symptoms of AD in tralokinumab-treated patients. Secondary objectives are to investigate safety, quality of life, patient-reported outcomes and adherence, among others. This analysis includes the first 100 patients enrolled from 39 sites across Germany. Of the first 100 patients in TRACE initiated on tralokinumab in Germany, the majority were males. Most patients had moderate-to-severe disease as indicated by their mean Investigator’s Global Assessment score and mean Eczema Area and Severity Index. Patients reported heavy symptomatic burden of disease, as demonstrated by their mean eczema-related sleep numerical rating scale (NRS) and mean worst daily pruritus NRS. Patients also reported a substantial impact on quality of life, as demonstrated by mean Dermatology Life Quality Index. Overall, approximately 4/5 of the patients were biologic-naïve. All biologic-experienced patients were previously treated with dupilumab, of whom most experienced one or more treatment failures. Reasons for switching from dupilumab included lack or loss of efficacy, and AEs, which included mainly conjunctivitis. Initial findings from the first 100 patients from TRACE in Germany showed that the majority of adult patients with moderate-to-severe AD treated with tralokinumab were biologic-naïve, indicating that tralokinumab is prescribed as first-line systemic treatment in the real world, in line with European Dermatology Forum guidelines. Of patients who switched from dupilumab, the main reasons for switching were lack or loss of efficacy, and conjunctivitis, indicating the need for an alternative biologic treatment such as tralokinumab.