Receptor Monoclonal Antibody Research Articles

Treatment Protocols in the Efficacy and Safety of Anti-EGFR Medicines in Combination with Standard Therapy for Patients with Nasopharyngeal Cancer: A Meta-Analysis.

This study was conducted to compare the efficacy of standard therapy (radiotherapy/RT/CT) with that of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody (NPC) therapy in patients with advanced nasopharyngeal cancer. A meta-analysis was performed to meet the objective of this study. The English databases PubMed, Cochrane Library, and Web of Science were searched. The literature review compared anti-EGFR-targeted therapy with conventional therapy practices. The main outcome measure was overall survival (OS). Secondary goals were progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and adverse events (grade 3). The database search resulted in 11 studies, with a total of 4219 participants. It was found that combining an anti-EGFR regimen with conventional therapy did not enhance OS (hazard ratio [HR] = 1.18; 95%confidence interval [CI] = 0.51-2.40; p = 0.70) or PFS appreciably (HR = 0.95; 95%CI = 0.51-1.48; p = 0.88) in patients with nasopharyngeal carcinoma. While LRRFS increased considerably (HR = 0.70; 95%CI = 0.67-1.00; p = 0.01), the combined regimen did not improve DMFS (HR = 0.86; 95%CI = 0.61-1.12; p = 0.36). Treatment-related adverse events included haematological toxicity (RR = 0.2; 95%CI = 0.08-0.45; p = 0.01), cutaneous reactions (RR = 7.05; 95%CI = 2.15-23.09; p = 0.01), and mucositis (RR = 1.96; 95%CI = 1.58-2.09; p = 0.01). Individuals who have nasopharyngeal cancer do not have an increased chance of surviving until a local recurrence of their disease if they get normal therapy in addition to an anti-EGFR regimen. However, this combination does not enhance overall survival. On the other hand, this factor adds to an increase in the number of adverse effects.

Efficacy of Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Resectable Colon Cancer

Efficacy of Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Resectable Colon Cancer

Anti-GnRH Receptor Monoclonal Antibody, GHR106 is First-inClass GnRH Antagonist

During the last decade, a monoclonal antibody, GHR106 was generated and characterized extensively biologically and immunologically. This antibody targets specific human pan cancer marker and is being evaluated for potential therapeutic applications in cancer immunotherapy and fertility regulations. GHR106 was generated against N1-29 oligopeptide located in the extracellular domains of human GnRH receptor found either in the anterior pituitary or in most of cancer cells. In vitro culture of cancer cells revealed that this antibody can induce apoptosis of cancer cells following 24-48 hours incubations. Anti-tumor activities of GHR106 were evaluated by typical nude mouse experiments in which the effective volume reduction of implanted tumor was observed. Humanized forms of GHR106 were made available in CAR (chimeric antigen receptor) T-cell constructs. GHR106 was shown separately to induce cytotoxic killings of cancer cells in vitro by releasing cytokines following incubations of tumor cells with CAR-T cell constructs. In addition, GHR106 also acts as GnRH antagonist by a specific targeting to pituitary GnRH receptor for reversible suppressions of reproductive hormones. These were demonstrated in “Proof of Concept” rabbit experiments. A single subcutaneous injection with 1-3mg/kg of GHR106 to rabbits of either sex could result in 60 to 90% reductions of gonadotropins, estrogen and/or testosterone over a period of one to two weeks. Based on these preclinical assessments, it can be concluded that GHR106 is restricted in tissue expressions and suitable for cancer immunotherapy. It can also act as long-acting GnRH antagonist to target specifically on GnRH receptor in anterior pituitary for numerous gynecological diseases including ovulation inhibition in IVF/ART, endometriosis-premenstrual syndrome, precocious puberty, uterine fibroids and/or polycystic ovarian syndrome.

The Increased Interleukin-6 Levels Can Be an Early Diagnostic Marker for New-Onset Refractory Status Epilepticus

New-onset refractory status epilepticus (NORSE) is a condition defined as the occurrence of refractory status epilepticus in patients without active epilepsy and no other acute causes of seizure. Although there is evidence that immune-mediated pathogenesis has a pivotal role in the epileptogenesis of NORSE, the diagnosis of NORSE is usually made on the clinical observation because there is no established biological marker suggesting the diagnosis of NORSE. We recently encountered a NORSE patient who was successfully treated with immunotherapy including tocilizumab, an anti-interleukin-6 (IL-6) receptor monoclonal antibody, and the markedly increased levels of serum and cerebrospinal fluid IL-6 were the only laboratory abnormality during the early treatment of the patient.

Targeting Treatment Resistance in Head and Neck Cancer through Unravelling Molecular Mechanisms

Head and neck cancer is a common malignancy worldwide and carries a poor prognosis when it is diagnosed late. Treatment itself often carries significant morbidity and impairs quality of life. There have been few actionable targets for squamous cell carcinoma of the head and neck, notably anti-epidermal growth factor receptor monoclonal antibody cetuximab and antiPD1 immunotherapy that have reached clinical use. We studied a polymorphism in the extracellular semaphorin domain of C-MET in the context of SCC head/neck and lung, uncovering a novel mechanism conferring biological aggressiveness and potential for therapeutic intervention. TP53 mutations are the most common somatic mutations in SCCHN and we studied the gain of function mutation p53R158G in the S4 strand of the DNA binding domain, uncovering the mechanism of carcinogenicity. In South East Asia including Malaysia and Singapore, nasopharyngeal carcinoma is associated with EBV and is the commonest head and neck malignancy, with a propensity for recurrence and metastases. We have interest in development of anti-vascular endothelial growth factor therapy as a means to overcome treatment resistance, and some of this work will be described in this presentation.

Immunohistochemical localisation of aquaporin 2 and vasopressin type 2 receptor in the human endolymphatic sac.

This study aimed to determine the distribution and subcellular localisation of aquaporin 2 and vasopressin type 2 receptor in the human endolymphatic sac. Ten samples of human endolymphatic sac were collected during acoustic neurinoma removal using the translabyrinthine approach. Immunohistochemistry and immunofluorescence were performed using aquaporin 2 and vasopressin type 2 receptor monoclonal antibodies. Confocal microscopy demonstrated that vasopressin type 2 receptor labelling was expressed in both the apical and basolateral plasma membranes, and in the cytoplasm of the endolymphatic sac epithelium, whereas aquaporin 2 was strongly expressed at the basolateral site of the endolymphatic sac epithelium, in both the intraosseous and extraosseous parts of the endolymphatic sac. Both aquaporin 2 and vasopressin type 2 receptor were detected in the epithelial cells of the human endolymphatic sac, suggesting that this channel may be involved in inner-ear fluid homeostasis. However, strong basolateral expression of aquaporin 2 in endolymphatic sac epithelium suggested that the function of aquaporin 2 may differ between the endolymphatic sac and kidney.

Genetic findings in a patient with paradoxical pyoderma gangrenosum induced by brodalumab

We describe a patient with psoriasis who developed pyoderma gangrenosum while on treatment with brodalumab, an anti-interleukin (IL)-17 receptor monoclonal antibody. Genetic analyses revealed heterozygous polymorphisms within the promoter region of the IL-6 (promoter polymorphism –174 G/C) and IL-10 genes (promoter polymorphism –1082 A/G).

Nipocalimab’s Selective Targeting of FcRn and IgG Clearance Preserves Key Immune Functions

Objective To characterize the effect of nipocalimab, a fully human, effectorless IgG1 anti-neonatal Fc receptor (FcRn) monoclonal antibody on immune function. Background Nipocalimab binds to FcRn with high affinity which prevents IgG recycling, leading to reduced serum levels of total IgGs, including pathogenic IgG autoantibodies. Rapid, sustained lowering of IgG was observed in the phase 2 VIVACITY study in generalized myasthenia gravis (gMG) and in phase 1 healthy volunteers. In gMG patients, nipocalimab induced rapid and sustained lowering of anti-AChR autoantibodies and MG-ADL scores, but no serious adverse events including clinically significant infections. Design/Methods Nipocalimab was evaluated extensively in vitro and in nonhuman primate-based chronic toxicology studies to evaluate selectivity, tolerability, safety and immunopharmacology. Safety, tolerability and immune-focused assessments in clinical phase 1 and Phase 2 MG studies were also completed (NCT02828046, NCT03772587). Results Nipocalimab binds specifically in vitro to FcRn without activation of effector function or inhibition of antigen presentation. In nonhuman primates administered up to 300 mg/kg nipocalimab QW for up to 6 months, sustained lowering of IgG was observed without adverse effects. Immunotoxicology identified no effect on immune cell phenotypes; CD8 T cell, NK or innate cell functions; T-dependent neoantigen IgM responses. Neoantigen IgG production was observed, but with lowered peak IgG titers consistent with the anticipated increase in IgG clearance with nipocalimab. In clinical studies, nipocalimab demonstrated a reproducible selective decrease in total serum IgG, including all subclasses of IgG, with no effect on IgM, IgA, IgE, CH50, C3, C4, inflammatory cytokines or acute phase proteins including, C-reactive protein (CRP). Conclusions These data suggest that nipocalimab can selectively lower IgG and IgG autoantibodies while preserving cellular immunity, complete IgM response and IgG production after neoantigen challenge. Overall, nipocalimab's selective effect on IgG recycling provides a mechanistic rationale for potentially decreased infection risk despite substantial IgG lowering.

Comprehensive Analyses of the Intracellular and in Vivo Disposition of Fab- Small Interfering RNA Conjugate to Identify Key Issues to Improve Its in Vivo Activity.

Comprehensive analyses of intracellular disposition and in vivo pharmacokinetics were performed for small interfering RNA (siRNA) conjugated with the Fab fragment of panitumumab, a fully humanized monoclonal antibody against epidermal growth factor receptor (EGFR). The Fab-siRNA conjugate was internalized into EGFR-expressing cancer cells in an antigen-dependent manner. Intracellular disposition was quantitatively evaluated using fluorescent-labeled panitumumab and confocal microscopy. The majority of internalized panitumumab was suggested to be transferred into lysosomes. In vivo pharmacokinetics were evaluated in EGFR-expressing tumor-bearing mice. Intact Fab-siRNA was measured by immunoprecipitation using anti-Fab antibody followed by quantitative polymerase chain reaction. The Fab portion was measured by a ligand binding assay. Intact Fab-siRNA concentrations rapidly decreased in the plasma and tumor, although the Fab portion concentration remained high, suggesting extensive degradation in the linker-siRNA portion. After incubation of Fab-siRNA in mouse plasma, samples were digested with proteinase K, and extracted siRNA tagged with Fab-derived peptide was subjected to an ion-pair reversed-phase liquid chromatography with mass spectrometry analysis. Results suggested that hydrolysis from the 3' end of the antisense strand of siRNA is the major metabolizing pathway. Based on these findings, endosomal escape and stability in lysosomes, blood, and tumor are key factors to improve to achieve efficient target gene knockdown in tumors, and stabilizing the 3' end of the antisense strand was suggested to be most efficient. Our approaches clearly identified the key issues of Fab-siRNA from a pharmacokinetics aspect, which will be useful for improving the in vivo activity of siRNA conjugated with not only Fab but also other immunoproteins. SIGNIFICANCE STATEMENT: The intracellular and in vivo disposition of Fab-small interfering RNA (siRNA) conjugate was comprehensively investigated using various approaches, including newly developed analytical methods. This study clearly shows that improvements in siRNA stability in lysosomes, blood, and tumor are needed for target gene knockdown in tumors. The major metabolic pathway of Fab-siRNA is 3' exonuclease degradation, suggesting that optimization of the conjugation site to Fab might help improve stability.

Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab

BackgroundMigraine involves central and peripheral nervous system mechanisms. Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody with little central nervous system penetrance, is effective for migraine prevention. The objective of this study was to determine if response to erenumab is associated with alterations in brain functional connectivity and pain-induced brain activations.MethodsAdults with 6–25 migraine days per month during a 4-week headache diary run-in phase underwent pre-treatment brain functional MRI (fMRI) that included resting-state functional connectivity and BOLD measurements in response to moderately painful heat stimulation to the forearm. This was followed by two treatments with 140 mg erenumab, at baseline and 4 weeks later. Post-treatment fMRI was performed 2 weeks and 8 weeks following the first erenumab treatment. A longitudinal Sandwich estimator analysis was used to identify pre- to post-treatment changes in resting-state functional connectivity and brain activations in response to thermal pain. fMRI findings were compared between erenumab treatment-responders vs. erenumab non-responders.ResultsPre- and post-treatment longitudinal imaging data were available from 32 participants. Average age was 40.3 (+/− 13) years and 29 were female. Pre-treatment average migraine day frequency was 13.8 (+/− 4.7) / 28 days and average headache day frequency was 15.8 (+/− 4.4) / 28 days. Eighteen of 32 (56%) were erenumab responders. Compared to erenumab non-responders, erenumab responders had post-treatment differences in 1) network functional connectivity amongst pain-processing regions, including higher global efficiency, clustering coefficient, node degree, regional efficiency, and modularity, 2) region-to-region functional connectivity between several regions including temporal pole, supramarginal gyrus, and hypothalamus, and 3) pain-induced activations in the middle cingulate, posterior cingulate, and periaqueductal gray matter.ConclusionsReductions in migraine day frequency accompanying erenumab treatment are associated with changes in resting state functional connectivity and central processing of extracranial painful stimuli that differ from erenumab non-responders.Trial registrationclinicaltrials.gov(NCT03773562).

Assessment of the Pharmacokinetics and Safety of Spesolimab, a Humanised Anti-interleukin-36 Receptor Monoclonal Antibody, in Healthy Non-Japanese and Japanese Subjects: Results from Phase I Clinical Studies.

The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of spesolimab in healthy non-Japanese and Japanese subjects. Five phase I clinical studies (three placebo-controlled dose-escalation, two open-label) were conducted in healthy volunteers; single or multiple doses of spesolimab were administered by intravenous infusion or subcutaneous injection. Plasma samples were collected to investigate the pharmacokinetics of spesolimab and evaluate changes with respect to dose, frequency of dosing, formulation and injection site. Immunogenicity, safety and tolerability were also assessed. Intravenous spesolimab exhibited target-mediated drug disposition at low doses (0.01-0.3 mg/kg) and linear kinetics at doses ≥0.3mg/kg. Steady state was not attained after the fourth weekly dose because of the long half-life (3-5 weeks). Bioavailability of subcutaneous spesolimab increased with increasing dose over the range of 150-600mg and was higher when administered to the thigh than to the abdomen. The pharmacokinetic profile was consistent between Japanese and non-Japanese subjects. Positive anti-drug antibody responses occurred during the terminal phase of the spesolimab concentration-time profile in 26.7-33.3% and 16.7-37.5% of subjects receiving intravenous and subcutaneous spesolimab, respectively. The impact of anti-drug antibodies on spesolimab pharmacokinetics was low in healthy volunteers, with the impact on spesolimab plasma concentrations only observed in a few subjects at higher titres (≥11,400). No serious adverse events were reported; intravenous doses up to 1200 mg were well tolerated in healthy volunteers. The pharmacokinetic profile and safety data obtained from these phase I clinical studies have been used to guide spesolimab dosing in clinical studies of patients with interleukin-36-mediated diseases. For Studies 1-5, NCT02525679, NCT02852824, NCT03100903, NCT03123094, NCT03617835.

CD19 Expression by IHC Alone Is Not a Predictor of Response to Loncastuximab Tesirine: Results from the LOTIS-2 Clinical Trial and Quantitative Systems Pharmacology Modeling

Introduction: CD19 is a clinically-validated target for the treatment of B-cell malignancies, and several CD19-targeted therapies have received approval, including chimeric antigen receptor T-cell (CAR-T) therapy, antibody-drug conjugates (ADCs), monoclonal antibodies, and bispecific agents. However, the optimal sequencing of these treatments has not yet been clarified. Loncastuximab tesirine (loncastuximab tesirine-lypl; Lonca) is an ADC comprising an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin, indicated for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 systemic treatments. Prior CAR-T therapy does not preclude a response to Lonca, and responses were also observed in patients who received CAR-T therapy post-Lonca. The present analysis was performed to determine the contribution of CD19 expression to responses in patients treated with Lonca. Methods: CD19 expression determined by immunohistochemistry (IHC) was evaluated in a cohort of patients enrolled in the LOTIS-2 clinical trial (NCT03589469) with available tissue samples obtained after their last anti-cancer systemic therapy and prior to Lonca. IHC was performed using the LE-CD19 antibody (DAKO), and expression was analyzed using the BenchMark ULTRA platform (Ventana). CD19 expression was assessed by semiquantitative scoring of both the percentage of positive tumor cells and the H-Score (semiquantitative assessment of the percentage of CD19 positive cells and staining intensity). Quantitative Systems Pharmacology (QSP) modeling was used to predict response to Lonca and to test hypotheses regarding patient-specific covariates. Results: The cohort included patients with any prior systemic therapies (n = 59), including patients who received CAR-T as the last therapy prior to biopsy (n = 9). Responses to Lonca were seen in patients across all levels of CD19 expression, including patients with extremely low or no detectable CD19 expression at baseline and extremely low H-Scores. On the basis of the QSP modeling, patients are anticipated to achieve disease response to Lonca with CD19 tumor cell-surface densities as low as 1,000 molecules/cell (Figure 2). Conclusions: Response to Lonca was observed in R/R DLBCL patients with very low CD19 tumor expression as measured by IHC. QSP modeling predicts that CD19 expression level by IHC is not predictive of response to Lonca, whereas the addition of CD19 surface density improves the response prediction. Patients responded to Lonca with estimated tumor cell surface densities as low as 1,000 molecules/cell, normally below the level of IHC detection. Our findings indicate that Lonca is an effective treatment option for patients with R/R DLBCL following ≥ 2 lines of treatment, even in patients expected to have a low level of CD19 expression. These results serve as a basis for future studies addressing sequencing of CD19-targeted agents. Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Design of Effisayil™ 2: A Randomized, Double-Blind, Placebo-Controlled Study of Spesolimab in Preventing Flares in Patients with Generalized Pustular Psoriasis.

Generalized pustular psoriasis (GPP) is a rare autoinflammatory skin disease characterized by flares of widespread erythema with sterile pustules, and can be relapsing with recurrent flares, or persistent with intermittent flares. Spesolimab, a humanized anti-interleukin-36 (IL-36) receptor monoclonal antibody, targets the key IL-36 pathogenetic pathway in GPP. A previous study showed that spesolimab treatment led to rapid pustular and skin clearance in patients with GPP flares, which was sustained for up to 12weeks. This study investigates the long-term effects of spesolimab on GPP flares, for which no specific treatments are currently available. The Effisayil™ 2 study will assess whether maintenance treatment with subcutaneous spesolimab prevents the occurrence of GPP flares and determine the optimal dosing regimen to achieve this aim. Patients will have a documented history of GPP with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear) at screening and randomization. Patients will be randomized 1:1:1:1 to three groups receiving a 600-mg subcutaneous loading dose of spesolimab followed by a 300-mg maintenance dose administered every 4 or 12weeks, or a 300-mg loading dose followed by a 150-mg maintenance dose administered every 12weeks, and one group receiving placebo, for 48weeks. The primary endpoint is time to first GPP flare. If a patient experiences a GPP flare during the randomized maintenance treatment period, an open-label intravenous dose of 900-mg spesolimab will be administered, with an option for a second intravenous dose after 1week. Effisayil™ 2 is the first placebo-controlled study in patients with GPP to investigate whether maintenance treatment with spesolimab can prevent flares and provide sustained disease control. This study will provide valuable insights on the long-term management of patients with this potentially life-threatening skin disease. NCT04399837.

Identification of small molecules as potential inhibitors of interleukin 6: a multi-computational investigation.

IL(interleukin)-6 is a multifunctional cytokine crucial for immunological, hematopoiesis, inflammation, and bone metabolism. Strikingly, IL-6 has been shown to significantly contribute to the initiation of cytokine storm-an acute systemic inflammatory syndrome in Covid-19 patients. Recent study has showed that blocking the IL-6 signaling pathway with an anti-IL-6 receptor monoclonal antibody (mAb) can reduce the severity of COVID-19 symptoms and enhance patient survival. However, the mAb has several drawbacks, such as high cost, potential immunogenicity, and invasive administration due to the large-molecule protein product. Instead, these issues could be mitigated using small molecule IL-6 inhibitors, but none are currently available. This study aimed to discover IL-6 inhibitors based on the PPI with a novel camelid Fab fragment, namely 68F2, in a crystal protein complex structure (PDB ID: 4ZS7). The pharmacophore models and molecular docking were used to screen compounds from DrugBank databases. The oral bioavailability of the top 24 ligands from the screening was predicted by the SwissAMDE tool. Subsequently, the selected molecules from docking and MD simulation illustrated a promising binding affinity in the formation of stable complexes at the active binding pocket of IL-6. Binding energies using the MM-PBSA technique were applied to the top 4 hit compounds. The result indicated that DB08402 and DB12903 could form strong interactions and build stable protein-ligand complexes with IL-6. These potential compounds may serve as a basis for further developing small molecule IL-6 inhibitors in the future.

RF04 | PSUN135 Genetic Inactivation of Glutaminase Reduces Amino Acid Induced Alpha Cell Proliferation

Abstract Glucagon stimulates glycogenolysis and gluconeogenesis in liver resulting in increased hepatic glucose output. Thus, interrupting glucagon signaling in liver reduces blood glucose levels in animal models and individuals with diabetes. However, interrupting glucagon signaling also leads to hyperaminoacidemia and proliferation of glucagon secreting alpha cells, evidence of an endocrine liver-alpha cell axis. Among the high amino acids, we previously identified high glutamine levels are required for alpha cell proliferation. We recently found that glutaminase (GLS) is expressed in alpha cells at much higher levels than any other pancreatic endocrine cells. Additionally, mouse pancreatic islets cultured in high amino acid containing media and treated with the small molecule inhibitor of GLS (CB839) have reduced alpha cell proliferation (Vehicle: 7.6 ± 2.2%, 0.1µM CB839: 0.11 ± 0.05%**, 10µM: 0.02 ± 0.01%**; n=3-4, **p < 0.01). To further characterize the role of glutamine metabolism in glutamine-induced alpha cell proliferation, GLS activity was specifically knocked out in mouse alpha cells by breeding Gcg-CRE ERT2 with Glsflox mice (aGlsKO). Targeted deletion of Gls expression in most alpha cells was confirmed by staining for GLS and glucagon (aGlsWT: 95% GLS+, aGlsKO: 18% GLS+). Mice were treated with a glucagon receptor monoclonal antibody (GCGR mAb/mAb-4) for 10 days or with isotype control IgG. aGlsWT mice treated with GCGR mAb have robust alpha cell proliferation while aGlsKO mice treated with GCGR mAb for 10 days showed a 4.5-fold decrease in alpha cell proliferation and were similar to mice treated with the control IgG (aGlsWT Ab: 15.7 ± 3.6% alpha cell proliferation, aGlsWT IgG: 1.0 ± 0.4%***, aGlsKO Ab: 3.4 ± 0.6%**; n=4-6, ***p < 0.001). In addition, aGlsWT mice treated with GCGR mAb showed a robust activation of mTOR in alpha cells as measured by phospho-S6 expression while this was lost in aGlsKO mice treated with GCGR mAb. Induced expression of the mTOR-dependent glutamine transporter SLC38A5 was also lost (aGlsWT Ab: 25.0 ± 4.8% alpha cell SLC38A5 expression, aGlsWT IgG: 0.40 ± 0.27%***, aGlsKO Ab: 3.7 ± 3.5%***, n= 2-4, ***p < 0.001). Similar results on proliferation and mTOR activation in alpha cells were observed after 4 weeks of GCGR mAb treatment. Together these data suggest a critical role for glutamine metabolism via glutaminase in alpha cell proliferation. Presentation: Saturday, June 11, 2022 1:36 p.m. - 1:41 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Efficacy of a Recombinant Humanized Anti-IL-6 Receptor Monoclonal Antibody Compared to Hemoperfusion in Severe COVID-19 Pneumonia: Ambispective Cohort Study

Efficacy of a Recombinant Humanized Anti-IL-6 Receptor Monoclonal Antibody Compared to Hemoperfusion in Severe COVID-19 Pneumonia: Ambispective Cohort Study

Inpatient Constipation Among Migraine Patients Prescribed Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies and Standard of Care Antiepileptic Drugs: A Retrospective Cohort Study in a United States Electronic Health Record Database.

Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody (mAb), was approved by the US Food and Drug Administration in May 2018. Constipation with serious complications was added to the Warning and Precautions section in the erenumab Prescribing Information in October 2019 after events were observed during post-marketing surveillance. We aimed to assess and compare the risk of inpatient constipation, and, separately, inpatient constipation with serious complications, among patients with migraine treated with CGRP mAbs and standard of care antiepileptic drugs (AEDs). Within Optum's Electronic Health Record Research Database, patients with migraine who initiated erenumab, other CGRP mAbs, and AEDs were identified from May 2018 through March 2020. Erenumab initiators were propensity score-matched separately to initiators of other CGRP mAbs and AEDs. Incident inpatient constipation events, and serious complications, were identified using multiple risk windows for outcome assessment (30-, 60-, 90-day risk windows, and all available follow-up). Odds ratios (ORs) were calculated comparing inpatient constipation risk among matched erenumab initiators relative to comparators. We identified 17,902 erenumab, 13,404 other CGRP mAb, and 49,497 AED initiators who met study criteria. Among matched initiators, the risk of inpatient constipation was 0.46% (95% confidence interval (CI) 0.35-0.60) for erenumab and 0.44% (95%CI 0.33-0.58) for other CGRP mAbs within the 90-day risk window, with a corresponding OR of 1.06 (95%CI 0.72-1.55). Among matched erenumab and AED initiators, inpatient constipation risk was 0.53% (95%CI 0.42-0.66) and 0.76% (95%CI 0.62-0.92), respectively, and the OR was 0.69 (95%CI 0.51-0.94). Few serious complications were observed. Patients initiating erenumab had similar risk of inpatient constipation within 90days of treatment initiation versus patients initiating other CGRP mAbs, and lower risk versus patients initiating AEDs. These findings provide context to events observed during post-marketing surveillance.

Prevention and management of cetuximab-related hypomagnesemia.

321 Background: Cetuximab is an epidermal growth factor receptor monoclonal antibody indicated for the treatment of squamous cell carcinoma of the head and neck and RAS wild-type metastatic colorectal cancer. Hypomagnesemia is a reversible adverse event associated with cetuximab treatment. Here, we provide the key considerations in prevention and management of cetuximab-related hypomagnesemia events in clinical practice. Methods: A PubMed literature search was conducted for articles published between 18 March 2012 and 18 March 2022 using “cetuximab” and “hypomagnesemia” as keywords. Of the 75 articles retrieved, 20 were considered relevant and are included here.Articles were excluded if they focused on hypomagnesemia-associated clinical benefits. Data were summarized and grouped into the following categories: risk and risk factors; monitoring; prevention; and management. Results: The relative risk of grade 3/4 hypomagnesemia following cetuximab therapy appears to be approximately 1.5 times higher for colorectal cancer compared with head and neck cancer. Several risk factors have been identified including age, comorbidities, treatment duration, baseline electrolyte levels, concomitant platinum-based chemotherapy, and polypharmacy. Although the frequencies of hypomagnesemia events vary between the studies identified, data from the included meta-analyses suggest that the incidence of grade 3/4 hypomagnesemia is around 4% among patients receiving cetuximab therapy. Early and regular monitoring of magnesium levels is recommended ideally every 4 to 8 weeks, especially in patients at high risk of serious complications, and up to 8 weeks following treatment cessation. Proposed proactive prophylactic interventions include magnesium supplementation for patients with baseline magnesium levels < 1.8 mg/dL, to prevent severe hypomagnesemia. The management approach depends on the degree of hypomagnesemia, the symptoms and risk factors, and may include supplementation with oral magnesium salts and/or parenteral forms; intravenous forms may be preferred due to low bioavailability and gastrointestinal adverse events related to oral supplements. While recommendations for initiating magnesium replacement in grade 1 (> 1.2 mg/dL) and grade 2 (0.9–1.2 mg/dL) hypomagnesemia events vary, magnesium supplementation should be given to patients with grade 3 (0.7–0.9 mg/dL) or grade 4 (< 0.7 mg/dL) hypomagnesemia, due to high risk of serious adverse cardiac events. If magnesium levels do not improve or continue to decrease despite supplementation, a pause in cetuximab administration may be considered. Conclusions: Hypomagnesemia is a reversible and manageable cetuximab-related adverse event and should not interfere with treatment outcomes. A periodic check of magnesium levels during treatment with cetuximab is recommended.

γ-aminobutyric acid modulates α-cell hyperplasia but not β-cell regeneration induced by glucagon receptor antagonism in type 1 diabetic mice.

To investigate whether treatment with γ-aminobutyric acid (GABA) alone or in combination with glucagon receptor (GCGR) monoclonal antibody (mAb) exerted beneficial effects on β-cell mass and α-cell mass, and to explore the origins of the regenerated β-cells in mice with type 1 diabetes (T1D). Streptozotocin (STZ)-induced T1D mice were treated with intraperitoneal injection of GABA (250μg/kg per day) and/or REMD 2.59 (a GCGR mAb, 5mg/kg per week), or IgG dissolved in PBS for 8weeks. Plasma hormone levels and islet cell morphology were evaluated by ELISA and immunofluorescence, respectively. The origins of the regenerated β-cells were analyzed by double-immunostaining, α-cell lineage-tracing and BrdU-tracing studies. After the 8-week treatment, GABA or GCGR mAb alone or in combination ameliorated hyperglycemia in STZ-induced T1D mice. GCGR mAb upregulated plasma insulin level and increased β-cell mass, and GABA appeared to have similar effects in T1D mice. However, combination treatment did not reveal any additive or synergistic effect. Interestingly, the GCGR mAb-induced increment of plasma glucagon level and α-cell mass was attenuated by the combined treatment of GABA. In addition, duct-derived β-cell neogenesis and α-to-β cell conversion but not β-cell proliferation contributed to the increased β-cell mass in T1D mice. These results suggested that GABA attenuated α-cell hyperplasia but did not potentiates β-cell regeneration induced by GCGR mAb in T1D mice. Our findings provide novel insights into a combination treatment strategy for β-cell regeneration in T1D.

Expert consensus on the diagnosis and treatment of severe and critical coronavirus disease 2019.

Expert consensus on the diagnosis and treatment of severe and critical coronavirus disease 2019.