Human Immunoglobulin G1 Monoclonal Antibody Research Articles

Abstract 9318: The Safety, Pharmacokinetics, Pharmacodynamics and Immunogenicity of Ebronucimab in Healthy Volunteers: Result From a Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Dose-Escalation Study

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated to be effective therapeutic agents for lowing low-density lipoprotein cholesterol (LDL-C). Ebronucimab (AK102) is a novel fully human immunoglobulin G1 (IgG1) monoclonal antibody against PCSK9. The objective of this study is to investigate the safety and tolerability of ebronucimab in healthy subjects. Methods: A total of 32 healthy adult subjects were planned to be enrolled and treated in a dose escalation manner. In each cohort, 8 subjects were randomized in a 3:1 ratio to receive a single dose of ebronucimab (75, 150, 300 or 500 mg) or matching placebo via subcutaneous injection (Figure 1). Blood was drawn at pre-selected timepoints to evaluate the pharmacokinetic parameters, free PCSK9 concentration and anti-drug antibody (ADA). Safety assessment was carried out up to day 85 ± 3 or early termination visit. Results: Safety Among the 32 subjects recruited, 87.5% (21/24) subjects administrated ebronucimab and 75% (6/8) subjects treated with placebo reported treatment emergent adverse events (TEAEs). The majority of adverse events were mild and moderate in severity. No relationship was identified between the dose of ebronucimab and the incidence of TEAEs. No TEAEs leading to study discontinuation and death were reported. Pharmacokinetics (PK)/Pharmacodynamics (PD) Following a single subcutaneous injection of 75 mg to 500 mg ebronucimab in healthy subjects, the median of T max ranged from 2.0 to 6.0 days and t 1/2 was within 4.11 to 5.01 days across cohorts. C max, AUC 0-t , and AUC 0-∞ increased approximately in a dose-proportional manner, see Table 1 and Figure 2. Serum free PCSK9 was almost completely inhibited after ebronucimab injection. The lowest level of free PCSK9 was observed around 2 days post administration and maintained at a low level 14-22 days post injection, see Figure 3. Immunogenicity A total of 3 subjects were tested ADA positive at least once during the study (75 mg, 1 subject; 500 mg, 2 subjects). The incidence of ADAs in subjects treated with ebronucimab was 12.5 % (3/24). Conclusions: Ebronucimab was well tolerated in healthy subjects and no special safety signal was identified during the study.

Abstract 10451: Efficacy and Safety of Ebronucimab, a Monoclonal Antibody Against Pcsk9, in Patients With Hyperlipidemia: Result From a Phase 2, Randomized, Double-Blind, Placebo-Controlled Study

Introduction Elevated low-density lipoprotein cholesterol (LDL-C) is a well-recognized risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to Low-density lipoprotein receptors (LDL-R) and triggers their degradation. Inhibiting PCSK9 activity results in lowering LDL-C levels and further reduceing the risk of cardiovascular events. Ebronucimab (AK102) is a novel fully human immunoglobulin G1 (IgG1) monoclonal antibody against PCSK9. Objectives To evaluate the safety, efficacy of ebronucimab and further identify the optimal dosing scheme in patients with hyperlipidemia. Methods A total of 260 Chinese patients with hyperlipidemia (≧18 years, male or female) were planned to be enrolled, and randomized to receive ebronucimab 450 mg every 4 weeks (q4w), 300 mg q4w, 150 mg q2w, 75 mg q2w or matching placebo via subcutaneous injection. The patients were treated up to 12 weeks (day 85). Serum samples were collected at preselected timepoints to analyze the lipid profiles. Results Efficacy Ebronucimab showed significant and dose-dependent LDL-C reductions from baseline. At week 12, the mean reductions in LDL-C were 65.48 %, 48.14%, 63.69% and 37.39% for 450 mg q4w, 300 mg q4w, 150 mg q2w and 75 mg q2w dose groups, respectively. Patients in the 450 mg q4w and 150 mg q2w groups achieved higher and more sustained LDL-C reduction compared with other dose groups. Similar trend was observed in serum levels of total cholesterol (TC), apolipoprotein B (ApoB), lipoprotien (a) (LP[a]). Safety A total of 49.6% (130/262) patients experienced at least 1 treatment-emergent adverse event (TEAE), 109 patients (109/210 [51.9%]) in ebronucimab groups and 21 patients (21/52 [40.4%]) in the placebo group. Most TEAEs were mild and moderate. No adverse events were apparently dose dependent with ebronucimab. The overall incidence of serious adverse events (SAEs) was 3.4 % (9/262). Conclusions Ebronucimab was generally safe and well tolerated in Chinese patients with hyperlipidemia. Patients treated with ebronucimab achieved a significant reduction in serum levels of LDL-C and other lipids, especially in 450 mg q4w and 150 mg q2w treatment groups.

Population pharmacokinetic-pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease.

Lecanemab is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregate species, while demonstrating low affinity for Aβ monomer. This article describes the population pharmacokinetic (PK) and PK/pharmacodynamic (PD) analyses for amyloid plaques, as measured using positron emission tomography (PET), and biomarkers of amyloid pathology as evidenced by Aβ42/40 ratio and plasma p-tau181 following i.v. administration of lecanemab in subjects with early Alzheimer's disease. Lecanemab PKs were well-characterized with a two-compartment model with first-order elimination. Final PK model contained covariate effects of anti-drug antibody positive status, sex, body weight, and albumin on clearance. The time course of amyloid PET standard uptake ratio (SUVr), plasma Aβ42/40 ratio, and p-tau181 were described using indirect response models with lecanemab exposure as a maximum effect function stimulating the reduction of SUVr, and as a linear function increasing Aβ42/40 ratio and decreasing p-tau181 formation rates. PK/PD simulations show that 10mg/kg biweekly dosing results in larger and faster decrease in SUVr and p-tau181 and increase in Aβ42/40 ratio as compared to 10mg/kg monthly dose. Furthermore, the PK/PD simulations showed that after treatment discontinuation the brain amyloid re-accumulation to baseline levels is slow with a recovery half-life of ~4 years, whereas plasma Aβ42/40 ratio and p-tau181 return to baseline levels faster than amyloid. Given the relationship between changes in amyloid PET SUVr and soluble biomarkers, the developed PK/PD models can be used to inform lecanemab dose regimens in future clinical studies.

33270 Long-term efficacy and safety of risankizumab (RZB) for the treatment of moderate to-severe plaque psoriasis: Interim analysis of results from the LIMMitless open-label extension trial beyond 4 years of follow-up

RZB is a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits IL-23 by binding to its p19 subunit. In the ongoing LIMMitless open-label extension study (NCT03047395), patients initially randomized to receive RZB 150 mg for the treatment of moderate-to-severe plaque psoriasis in 5 double-blind phase 3 trials (UltIMMa-1/NCT02684370, UltIMMa-2/NCT02684357, SustaIMM/NCT03000075, NCT03255382, IMMvent/NCT02694523) were eligible to continue open-label RZB 150 mg every 12 weeks. This interim analysis evaluated efficacy through 232 weeks of continuous RZB treatment and safety up to the data cutoff (March 26, 2021); data beyond 4.5 years will be presented.

BMS-986012, an Anti–Fucosyl-GM1 Monoclonal Antibody as Monotherapy or in Combination With Nivolumab in Relapsed/Refractory SCLC: Results From a First-in-Human Phase 1/2 Study

IntroductionFucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1. MethodsCA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival. ResultsPatients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 [90%]). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval [CI]) was higher with BMS-986012 plus nivolumab (38% [20.7%–57.7%]) than with monotherapy (4% [0.8%–11.0%]). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4–not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%–20.7%) and 39.3% (21.7%–56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0–7.3) and 18.7 (8.2–37.3) months, respectively. ConclusionsBMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880).

Abstract 2479: Preclinical assessment of imaging agents for identification of fucosyl-GM1 expression in vivo

Abstract Background: Fucosyl-GM1 (FucGM1) is a monosialoganglioside highly expressed in 50%-70% of small cell lung cancer (SCLC) cells, supporting it as a potential biomarker. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to FucGM1 with high affinity and specificity. Understanding how FucGM1+ tumor expression correlates with response to BMS-986012 may improve patient selection and therapeutic efficacy. Objective: Evaluate ability of imaging agents built on BMS-986012 to detect tumor FucGM1 expression. Methods: BMS-986012 was labeled with a near-infrared fluorophore. Binding to human H520 (FucGM1−) and DMS79 (FucGM1+) xenografts was assessed in vivo via optical imaging. BMS-986012 was labeled with deferoxamine and radiolabeled to produce 89Zr-BMS-986279, which was evaluated in vitro with H520 and DMS79 cells. Tracer distribution and tumor accumulation was assessed by positron emission tomography (PET) imaging in mice bearing bilateral H520 and DMS79 xenografts and analyzed with ex vivo autoradiography (ARG). Results: Optical imaging with fluorescent BMS-986012 showed statistically significant accumulation in DMS79 vs H520 tumors at all time points (P<.05), beginning 6 hours post administration and reaching a 3:1 maximum uptake ratio. Maximum tumor to background signal was measured at 96 hours (final imaging time point). Total radiolabeled 89Zr-BMS-986279 binding to intact DMS79 cells was ≈15-fold higher than to H520 control cells in vitro and was almost completely blocked by coincubation with a 1000-fold excess of BMS-986012. In vivo, longitudinal PET imaging of 89Zr-BMS-986279 showed significantly higher tracer accumulation in FucGM1+ DMS79 xenografts vs H520 tumors (P<.001). The difference in tracer uptake between tumor models increased with time and was highest (≈2-fold) approximately 8 days post injection. PET signal decreased over time in both FucGM1− H520 xenografts and background muscle tissues, consistent with slow accumulation of specific binding and clearance from background common with antibody-based tracers. Ex vivo ARG studies confirmed in vivo PET results and indicated that 89Zr-BMS-986279 can be used to assess FucGM1 expression throughout the tumor volume, with signal found in the periphery and interior of tumor samples. Conclusions: In vitro cell binding, in vivo fluorescence and PET imaging, and ex vivo ARG studies demonstrated that 89Zr-BMS-986279 was sensitive and specific for detecting FucGM1 expression in tumor cells. Specificity to the intended target in animal disease models coupled with kinetics typical of antibody-based tracers further support the utility of 89Zr-BMS-986279 as a potential FucGM1 imaging agent. A phase 2 study is evaluating safety and efficacy of BMS-986012 combined with carboplatin, etoposide, or nivolumab in patients with newly diagnosed extensive-stage SCLC (NCT04702880). Citation Format: R. Adam Smith, Erin L. Cole, Andrea Olga Shorts, Thomas Petrone, Joonyoung Kim, Daniel Cohen, Paul Morin, Samuel J. Bonacorsi, Patrick L. Chow. Preclinical assessment of imaging agents for identification of fucosyl-GM1 expression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2479.

Pregnancy outcomes following periconceptional or gestational exposure to ustekinumab: Review of cases reported to the manufacturer's global safety database.

Ustekinumab, a human immunoglobulin G1 monoclonal antibody that binds to and inhibits interleukin (IL)-12/IL-23, is indicated for multiple immune-mediated diseases. Ustekinumab is actively transported across the placenta and theoretically could impact pregnancy outcomes. Limited data on pregnancy outcomes with ustekinumab exposure are available. To assess pregnancy outcomes in patients exposed to ustekinumab during pregnancy METHODS: Cumulative data on medically confirmed ustekinumab-exposed pregnancies from the manufacturer's Global Safety Database were summarised. Descriptive data for pregnancy outcomes were presented overall and by patient subgroups. As of 31 August 2020, 408 medically confirmed, prospective, maternal ustekinumab-exposed pregnancies with reported outcomes were identified. The mean maternal age was 31 years. Of the 420 pregnancy outcomes (including 4 sets of twins),a , b 340 (81%) were live births, 51 (12.1%) spontaneous abortions, 25 (6%) elective/induced abortions, 3 (0.7%) stillbirths and 1 (0.2%) ongoing pregnancy with foetal congenital anomaly (CA). Among 340 live births, 33 (9.7%) were born pre-term. The rate of major CAs was similar by indication (Crohn's disease vs psoriasis), ustekinumab dose (45 mg vs 90 mg) and timing and duration of maternal exposure to ustekinumab. Prospective outcomes of pregnancies with paternal periconceptional ustekinumab exposure (n= 87) included 92% live births (1.2% major CA), 5.7% spontaneous abortions and 2.3% elective/induced abortions. Rates of adverse pregnancy outcomes or CAs with ustekinumab exposure were consistent with rates reported for the US general population and do not suggest a higher risk associated with maternal or paternal exposure to ustekinumab.

Risankizumab treatment in psoriasis patients who failed anti-IL17: A 52-week real-life study.

Recent knowledge on the key role of interleukin (IL) 23/17 axis in psoriasis pathogenesis, led to development of new biologic drugs. Risankizumab is a humanized immunoglobulin G1 monoclonal antibody specifically targeting IL23. Its efficacy and safety were showed by both clinical trials and real‐life experiences. However, real‐life data on effectiveness and safety of risankizumab in patients who previously failed anti‐IL17 are scant. To assess the efficacy and safety of risankizumab in patients who previously failed anti‐IL17. A 52‐week real‐life retrospective study was performed to assess the long‐term efficacy and safety of risankizumab in patients who previously failed anti‐IL17. A total of 39 patients (26 male, 66.7%; mean age 50.5 ± 13.7 years) were enrolled. A statistically significant reduction of psoriasis area severity index (PASI) and body surface area (BSA) was assessed at each follow‐up (PASI at baseline vs. week 52: 13.7 ± 5.8 vs. 0.9 ± 0.8, p < 0.0001; BSA 21.9 ± 14.6 vs. 1.9 ± 1.7, p < 0.0001). Nail psoriasis severity index improved as well, being statistically significative only at week 16 and thereafter [9.3 ± 4.7 at baseline, 4.1 ± 2.4 (p < 0.01) at week 16, 1.4 ± 0.8 (p < 0.0001) at week 52]. Treatment was discontinued for primary and secondary inefficacy in 1(2.6%) and 3(7.7%) patients, respectively. No cases of serious adverse events were assessed. Our real‐life study confirmed the efficacy and safety of risankizumab, suggesting it as a valuable therapeutic weapon among the armamentarium of biologics, also in psoriasis patients who previously failed anti‐IL17 treatments.

The Changing Landscape of Systemic Treatment for Cervical Cancer: Rationale for Inhibition of the TGF-β and PD-L1 Pathways.

Cervical cancer is one of the most common and lethal cancers among women worldwide. Treatment options are limited in patients with persistent, recurrent, or metastatic cervical cancer, with <20% of women living >5 years. Persistent human papillomavirus (HPV) infection has been implicated in almost all cases of cervical cancer. HPV infection not only causes normal cervical cells to transform into cancer cells, but also creates an immunosuppressive environment for cancer cells to evade the immune system. Recent clinical trials of drugs targeting the PD-(L)1 pathway have demonstrated improvement in overall survival in patients with cervical cancer, but only 20% to 30% of patients show overall survival benefit beyond 2 years, and resistance to these treatments remains common. Therefore, novel treatment strategies targeting HPV infection–associated factors are currently being evaluated in clinical trials. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human immunoglobulin G1 monoclonal antibody that blocks PD-L1. Early clinical trials of bintrafusp alfa have shown promising results in patients with advanced cervical cancer.

Population Pharmacokinetics and Exposure-Response Relationships of Astegolimab in Patients With Severe Asthma.

Astegolimab is a fully human immunoglobulin G2 monoclonal antibody that binds to the ST2 receptor and blocks the interleukin‐33 signaling. It was evaluated in patients with uncontrolled severe asthma in the phase 2b study (Zenyatta) at doses of 70, 210, and 490 mg subcutaneously every 4 weeks for 52 weeks. This work aimed to characterize astegolimab pharmacokinetics, identify influential covariates contributing to its interindividual variability, and make a descriptive assessment of the exposure‐response relationships. A population pharmacokinetic model was developed using data from 368 patients in the Zenyatta study. Predicted average steady‐state concentration was used in the subsequent exposure‐response analyses, which evaluated efficacy (asthma exacerbation rate) and biomarker end points including forced expiratory volume in 1 second, fraction exhaled nitric oxide, blood eosinophils, and soluble ST2. A 2‐compartment disposition model with first‐order elimination and first‐order absorption best described the astegolimab pharmacokinetics. The relative bioavailability for the 70‐mg dose was 15.3% lower. Baseline body weight, estimated glomerular filtration rate, and eosinophils were statistically correlated with pharmacokinetic parameters, but only body weight had a clinically meaningful influence on the steady‐state exposure (ratios exceeding 0.8‐1.25). The exposure‐response of efficacy and biomarkers were generally flat with a weak trend in favor of the highest dose/exposure. This study characterized astegolimab pharmacokinetics in patients with asthma and showed typical pharmacokinetic behavior as a monoclonal antibody–based drug. The exposure‐response analyses suggested the highest dose tested in the Zenyatta study (490 mg every 4 weeks) performed close to the maximum effect, and no additional response may be expected above it.

Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment.

Transforming growth factor‐β (TGF‐β) and programmed death ligand 1 (PD‐L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF‐β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial‐to‐mesenchymal transition, and angiogenesis. Meanwhile, PD‐L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti‐PD‐L1 therapies have been approved for the treatment of various cancers, but TGF‐β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF‐β and PD‐L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual‐targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual‐targeting agent is bintrafusp alfa. This drug is a first‐in‐class bifunctional fusion protein that consists of the extracellular domain of the TGF‐βRII receptor (a TGF‐β ‘trap’) fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD‐L1. Given the immunosuppressive effects of the TGF‐β and PD‐L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.

Post-authorisation safety study of burosumab use in paediatric, adolescent and adult patients with X-linked hypophosphataemia: rationale and description.

Background:X-linked hypophosphataemia (XLH) is a rare, inherited, phosphate-wasting disorder that elevates fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D (1,25(OH)2D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH)2D supplements. However, these treatments do not correct the primary pathogenic mechanism or treat all symptoms and can be associated with adverse effects. Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody against FGF23, approved for treating XLH in several geographical regions, including Europe and Israel. Burosumab restores normal serum phosphate levels, minimising the clinical consequences of XLH. Safety data on long-term treatment with burosumab are lacking owing to the rarity of XLH. This post-authorisation safety study (PASS) aims to evaluate the safety outcomes in patients aged >1 year.Methods:The PASS is a 10-year retrospective and prospective cohort study utilising data from the International XLH Registry (NCT03193476), which includes standard diagnostic and monitoring practice data at participating centres. The PASS aims to evaluate frequency and severity of safety outcomes, frequency and outcomes of pregnancies in female patients, and safety outcomes in patients with mild to moderate kidney disease at baseline, in children, adolescents and adults treated with burosumab for XLH. It is expected that there will be at least 400 patients who will be administered burosumab.Results:Data collection started on 24 April 2019. The expected date of the final study report is 31 December 2028, with two interim reports.Conclusion:This PASS will provide data on the long-term safety of burosumab treatment for XLH patients and describe safety outcomes for patients receiving burosumab contrasted with those patients receiving other XLH treatments, to help inform the future management of XLH patients. The PASS will be the largest real-world safety study of burosumab.Registry identification:The International XLH Registry is registered with clinicaltrials.gov as NCT03193476 (https://clinicaltrials.gov/ct2/show/NCT03193476), and the PASS is registered with the European Union electronic Register of Post-Authorisation Studies as EUPAS32190 (http://www.encepp.eu/encepp/viewResource.htm?id=32191).

Cytokine-release hypersensitivity reaction after the first dose of benralizumab for severe eosinophilic asthma

Benralizumab is a humanized immunoglobulin G1 monoclonal antibody that specifically binds to the alpha interleukin (IL)-5 receptor, blocking the signaling pathway that activates eosinophils. Furthermore, through its constant Fc region, it has the capability to bind to the FCγRIII receptor of natural killer cells and other immune cells, leading to the apoptosis of eosinophils through degranulation of these immune cells. 1 Pelaia C Vatrella A Bruni A Terracciano R Pelaia G Benralizumab in the treatment of severe asthma: design, development and potential place in therapy. Drug Des Dev Ther. 2018; 12: 619-628 Crossref PubMed Scopus (33) Google Scholar Here, we present a case of cytokine-release hypersensitivity reaction (CRHR) induced by benralizumab therapy in a patient with severe eosinophilic asthma.

Mogamulizumab Monotherapy in the Treatment of Relapsed/Refractory Peripheral T-Cell Lymphoma or Cutaneous T-Cell Lymphoma Patients in Single-Institution Experience

Objectives; T-cell lymphomas generally have a poor outcome with shorter long-term survival compared with B-cell lymphomas. CC chemokine receptor 4 (CCR4) is highly expressed by aggressive peripheral T-cell lymphoma, not otherwise specified (PTCLs), particularly adult T-cell leukemia/lymphoma (ATL) and cutaneous T-cell lymphomas (CTCLs). Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody that targets CCR4. In phase II study, Mogamulizumab has been shown to high clinical efficacy and low toxicity. However, its efficacy has not been well evaluated in the clinical setting. We retrospectively analyzed the efficacy and safety of Mogamulizumab of against relapsed/refractory non- ATL T-cell lymphomas.Methods; Fourteen patients with relapsed/ refractory CCR4 positive PTCLs or CTCL were treated with weekly Mogamulizumab (1.0 mg/kg) alone at Iwate Prefectural Central Hospital between January 2015 and June 2017. CCR4 expression was determined by immunohistochemistry by a central laboratory center (SRL, Tokyo, Japan). In the first line, most patients receive commonly anthracycline-containing induction chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). The patients had received a median of one previous chemotherapy regime (range 1-3).We retrospectively evaluated (1) the best overall response, (2) progression-free survival (PFS), (3) overall survival (OS), (4) the best response according to disease site(peripheral blood; PB, lymph nodes; LN and skin) and (5) safety. Response assessments were performed after eighth mogamulizumab infusions according to the 1999 IWG criteria guidelines for response assessments for NHL (IWG-NHL). Treatment efficacy in patients with CTCL was evaluated by using a Global Response Score. Treatment was discontinued if progressive disease (PD) was evident.For safety evaluations, adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs, version 4.0.Results; The median age was 69 years old (range 48-85). Eight patients are male. The diagnosis comprised PTCLs (n=12) and CTCL (n=2). The median follow up periods and median number of Mogamulizumab infusion were 293 days (range 49- 681) and 8 courses (range 2- 9). (1) Complete remission (CR) was achieved in two patients (16.7%) and partial remission in one patients (8.3%), stable disease (SD) in two patients (16.7%), respectively. And (2) median PFS was 88 days and (3) median OS was 475 days. Peripheral blood, lymph node and skin lesion were affected in two, ten, and six patients, respectively. (4) In PB, complete response (CR) was obtained in all two patients (100%) and two patients were achieved CR in skin lesion (33.3%). In LN, only one of ten patient manifested CR(10.0%). This patient's tumor burden is low. (5) With regard to safety issues, hematological AEs were frequently observed, and lymphocytopenia occurred in 62.5% of patients. However, the AEs were controllable and tolerated. Non-hematological AEs, including fever, infusion reactions and skin trouble , were frequently observed (37.5%, 25.0%, and 37.5%, respectively). Grade 3/4 non-hematological AEs were scarcely observed.Conclusions; Although Mogamulizumab monotherapy is effective with highly safety, the patients who had swollen lymph node may need combination chemotherapy with mogamulizumab. The number of patients was small in this retrospective analysis, further investigation are required. DisclosuresNo relevant conflicts of interest to declare.

Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study

An immune component of inflammatory bowel disease is up-regulated tumor necrosis factor-like ligand 1A (TL1A). Anti-TL1A antibodies such as PF-06480605, a fully human immunoglobulin G1 monoclonal antibody, may have therapeutic potential. This Phase 2a, multicenter, single-arm, open-label study (TUSCANY) evaluated safety, tolerability, efficacy, pharmacokinetics, and immunogenicity in PF-06480605-treated participants with moderate to severe ulcerative colitis (UC). Participants received 500 mg intravenous PF-06480605 every 2 weeks, 7 doses total, with a 3-month follow-up period. Primary safety and efficacy endpoints were the incidence of adverse events (AEs) and week 14 endoscopic improvement (EI) (Mayo endoscopic subscore= 0 or 1), respectively. Secondary endpoints included total soluble TL1A (free/drug-bound) (sTL1A), incidence of anti-drug and neutralizing antibodies, PF-06480605 concentrations, and changes in fecal calprotectin and high-sensitivity C-reactive protein. Histology was assessed at week14. The study enrolled 50 participants; 42 completed. Of 109 treatment-emergent AEs, 18 were treatment-related. The most common AEs were UC disease exacerbation and arthralgia (6 participants each). Four serious AEs, no deaths, and no malignancies were reported. Week 14 EI was observed in a statistically significant proportion of participants (38.2% [uniformly minimum-variance unbiased estimator, per protocol population]). Minimal histologic disease was observed after treatment (Robarts Histopathology Index ≤5: 33.3%; Geboes Index ≤3.2: 47.6%). sTL1A increase over time from baseline indicated sustained target engagement. Forty-one participants (82%) tested positive for anti-drug antibodies and 5 (10%) for neutralizing antibodies. PF-06480605 demonstrated an acceptable safety profile and statistically significant EI in participants with moderate to severe UC, warranting further study in a larger participant cohort. Tissue histopathology analyses support this conclusion. https://clinicaltrials.gov/NCT02840721.

OP26 Risankizumab induces early clinical remission and response in patients with Moderate-to-Severe Crohn’s Disease: Results from the phase 3 ADVANCE and MOTIVATE studies

Abstract Background Present therapies leave an unmet need for early and effective treatment for patients with Crohn’s disease (CD). Risankizumab (RZB), a humanized immunoglobulin G1 monoclonal antibody against the p19 subunit of interleukin-23, was evaluated as an induction therapy to induce early clinical remission and response in patients with moderate-to-severe CD in two double-blind, randomized, placebo (PBO)-controlled studies (ADVANCE [NCT03104413] and MOTIVATE [NCT03105128]). Methods Patients with moderate-to-severe CD (CD Activity Index [CDAI] of 220–450, Simple Endoscopic Score for CD [SES-CD] ≥ 6 [≥ 4 for isolated ileal disease] excluding the narrowing component, and average daily [liquid/very soft] stool frequency [SF] ≥ 4 and/or average daily abdominal pain [AP] score ≥ 2) who had inadequate response or intolerance to conventional and/or biologic treatment (ADVANCE), or biologic treatment only (MOTIVATE) were randomised 2:2:1 (ADVANCE) or 1:1:1 (MOTIVATE) to receive intravenous RZB 600 mg, RZB 1200 mg, or PBO as induction therapy at weeks 0, 4, and 8. Clinical remission (per either CDAI or a composite of SF and AP criteria), clinical response (per CDAI criterion), and enhanced clinical response (per a composite of SF and AP criteria) were evaluated at weeks 4, 8, and 12 (endpoints defined in Figure 1 footnotes). Safety was assessed throughout the studies. Results A total of 1419 patients from ADVANCE (N = 850) and MOTIVATE (N = 569) respectively, were randomised and included in the intention-to-treat population. In both studies, starting at week 4 (the first prespecified measurement), greater proportions of RZB 600 mg or RZB 1200 mg- vs PBO-treated patients achieved clinical remission per either CDAI (P = .01/P &amp;lt; .05) or SF/AP criteria (P &amp;lt; .01/P &amp;lt; .01), clinical response per CDAI criterion (P = .001/P &amp;lt; .01), and enhanced clinical response per SF/AP criteria (P &amp;lt; .01/P = .14) (Figure 1). For both RZB 600 mg and RZB 1200 mg, the efficacy and treatment effect increased through week 12 (P ≤ .001/P ≤ .001) (Figure 1). Treatment with RZB 600 mg or 1200 mg was well tolerated, and no new safety risks were identified.1,2 Conclusion Induction therapy with both RZB 600 mg and 1200 mg intravenous resulted in significantly greater clinical remission and response vs PBO as early as week 4 and sustained through week 12 in patients with moderate-to-severe CD who had inadequate response or intolerance to conventional and/or biologic treatment. References

OP36 Risankizumab therapy induces improvements in endoscopic endpoints in patients with Moderate-to-Severe Crohn’s Disease: Results from the phase 3 ADVANCE and MOTIVATE studies

Abstract Background Endoscopic healing has become a critical treatment target in Crohn’s disease (CD). Risankizumab (RZB), a humanized immunoglobulin G1 monoclonal antibody against the p19 subunit of interleukin 23, is being investigated as a treatment for moderate-to-severe CD. This analysis assessed different endoscopic endpoints in patients treated with RZB induction therapy in two double-blind, randomised, placebo (PBO)-controlled studies (ADVANCE [NCT03104413] and MOTIVATE [NCT03105128]). Methods Patients with moderate-to-severe CD (CD Activity Index [CDAI] of 220–450, Simple Endoscopic Score for CD [SES-CD] ≥ 6 [≥ 4 for isolated ileal disease] excluding the narrowing component, and average daily [liquid/very soft] stool frequency [SF] ≥ 4 and/or average daily abdominal pain [AP] score ≥ 2) who had demonstrated prior inadequate response or intolerance to conventional and/or biologic treatment (ADVANCE) or to biologic treatment (MOTIVATE) were randomised 2:2:1 (ADVANCE) or 1:1:1 (MOTIVATE) to receive intravenous (IV) RZB 600 mg, RZB 1200 mg, or PBO at weeks 0, 4, and 8. This analysis evaluated the proportion of patients who achieved endoscopic remission ulcer-free endoscopy (ie, absence of ulcers), and composite endpoints of CDAI clinical response and endoscopic response, and enhanced clinical response and endoscopic response at week 12 (endpoints defined in Figure 1 footnotes). All endoscopies were centrally read by a blinded reviewer. Safety was assessed throughout the studies. Results In ADVANCE and MOTIVATE, 850 and 569 patients, respectively, were randomised and included in the intent-to-treat population for this analysis. At week 12 greater proportions of RZB- vs PBO-treated patients in both studies achieved endoscopic remission (P ≤ .001), ulcer-free endoscopy (P ≤ .01), CDAI clinical response and endoscopic response (P ≤ .001), and enhanced clinical response and endoscopic response (P ≤ .001; Figure 1). Treatment with RZB 600 mg or 1200 mg was well tolerated, and no new safety risks were identified.1,2 Conclusion Induction therapy with IV RZB 600 mg or 1200 mg resulted in improved outcomes at week 12 compared with PBO as assessed by endoscopy and by composite endoscopic-clinical endpoints in patients with moderate-to-severe CD. References

AB0559 EFFICACY AND SAFETY OF RISANKIZUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AFTER INADEQUATE RESPONSE OR INTOLERANCE TO DMARDs: 24-WEEK RESULTS FROM THE PHASE 3, RANDOMIZED, DOUBLE-BLIND KEEPsAKE 1 TRIAL

AB0559 EFFICACY AND SAFETY OF RISANKIZUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AFTER INADEQUATE RESPONSE OR INTOLERANCE TO DMARDs: 24-WEEK RESULTS FROM THE PHASE 3, RANDOMIZED, DOUBLE-BLIND KEEPsAKE 1 TRIAL

Teprotumumab: The Dawn of Therapies in Moderate-to-Severe Thyroid-Associated Ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is a potentially sight-threatening ocular disease. About 3-5% of patients with TAO have severe disease with intense pain, inflammation, and sight-threatening corneal ulceration or compressive optic neuropathy. The current treatments of TAO are often suboptimal, mainly because the existing therapies do not target the pathogenesis of the disease. TAO mechanism is unclear. Ocular fibrocytes express relatively high levels of the functional TSH receptor (TSHR), and many indirect evidences support its participation. Over expression of insulin-like growth factor-1 receptor (IGF-IR) in fibroblasts, leading to inappropriate expression of inflammatory factors, production of hyaluronic acid and cell activation in orbital fibroblasts are also possible mechanisms. IGF-1R and TSHR form a physical and functional signaling complex. Inhibition of IGF-IR activity leads to the attenuation of signaling initiated at either receptor. Teprotumumab (TMB) is a human immunoglobulin G1 monoclonal antibody, binding to IGF-IR. Recently two TMB clinical trials had been implemented in TAO patients, indicating dramatic reductions in disease activity and severity, which approved its use for the treatment of TAO in the US. This review summarizes the treatments of TAO, focusing on the pathogenesis of IGF-1R in TAO and its application prospects.

P80.01 A Multicenter, Randomized, Phase 3 Trial of Penpulimab in Combination With Anlotinib or Chemotherapy as First-Line Treatment in Advanced NSCLC

Penpulimab, a human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) directed against human programmed cell death-1 (PD-1), was engineered to optimize receptor occupancy by improving duration of drug binding, and to eliminate Fc-mediated effector function that compromises anti-tumor immune cell function. Anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor. Chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). A combination of the PD-1 checkpoint inhibitor and the antiangiogenic drug may improve clinical response in NSCLC by blocking the accumulation of immunosuppressive cells and promoting influx of effector T cells into tumors.