Cemiplimab: First Global Approval Markham, Anthony; Duggan, Sean
Drugs (New York, N.Y.),
11/2018, Letnik:
78, Številka:
17
Journal Article
Recenzirano
Cemiplimab (LIBTAYO
®
; cemiplimab-rwlc), a human programmed death receptor-1 (PD-1) monoclonal antibody that binds to PD-1 and blocks its interaction with programmed death ligands 1 (PD-L1) and 2 ...(PD-L2), is being developed by Regeneron Pharmaceuticals and Sanofi Genzyme. The drug is being investigated as a treatment for various cancers and in September 2018 received approval in the USA for the treatment of patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation. This article summarizes the milestones in the development of cemiplimab leading to this first global approval for the treatment of advanced cutaneous squamous cell carcinoma.
Galcanezumab-gnlm (Emgality™; Eli Lilly and Company), hereafter galcanezumab, is a humanized monoclonal antibody against the calcitonin gene-related peptide (CGRP) ligand. A potent vasodilator, CGRP ...is implicated in nociceptive transmission and migraine pathogenesis. In September 2018, the US FDA approved galcanezumab as a once-monthly subcutaneous injection for the preventive treatment of migraine in adults. In the same month, the EMA issued a positive opinion for galcanezumab for the prophylaxis of migraine in adults who have at least 4 migraine days per month. Galcanezumab is also undergoing phase III evaluation for the preventive treatment of cluster headache in North America and Europe. This article summarizes the milestones in the development of galcanezumab leading to its first approval for the preventive treatment of migraine in adults.
Antibody drugs with a high affinity and specificity are effective and safe for intractable diseases, such as cancers and autoimmune diseases. Furthermore, they have played a central role in drug ...discovery, currently accounting for eight of the top 20 pharmaceutical products worldwide by sales. Forty years ago, clinical trials on antibody drugs that were thought to be a magic bullet failed, partly due to the immunogenicity of monoclonal antibodies produced in mice. The recent breakthrough in antibody drugs is largely because of the contribution of phage display technology. Here, we reviewed the importance of phage display technology as a powerful platform for antibody drug discovery from various perspectives, such as the development of human monoclonal antibodies, affinity enhancement of monoclonal antibodies, and the identification of therapeutic targets for antibody drugs.
Summary
Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, ...dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long‐term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3‐year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time‐dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.
The treatment of cancer has largely relied on killing tumor cells with nonspecific cytotoxic therapies and radiotherapy. This approach, however, has limitations including severe systemic toxicities, ...bystander effects on normal cells, recurrence of drug-resistant tumor cells, and the inability to target micrometastases or subclinical disease. An increased understanding of the critical role of the immune system in cancer development and progression has led to new treatment strategies using various immunotherapies. It is now recognized that established tumors have numerous mechanisms of suppressing the antitumor immune response including production of inhibitory cytokines, recruitment of immunosuppressive immune cells, and upregulation of coinhibitory receptors known as immune checkpoints. This review focuses on the immune checkpoint inhibitors, a novel class of immunotherapy first approved in 2011. Our objective is to highlight similarities and differences among the three immune checkpoint inhibitors approved by the U.S. Food and Drug Administration-ipilimumab, pembrolizumab, and nivolumab-to facilitate therapeutic decision making. We conducted a review of the published literature and conference proceedings and present a critical appraisal of the clinical evidence supporting their use in the treatment of metastatic melanoma and advanced squamous non-small cell lung cancer (NSCLC). We also compare and contrast their current place in cancer therapy and patterns of immune-related toxicities, and discuss the role of dual immune checkpoint inhibition and strategies for the management of immune-related adverse events. The immune checkpoint inhibitors have demonstrated a dramatic improvement in overall survival in patients with advanced melanoma and squamous NSCLC, along with acceptable toxicity profiles. These agents have a clear role in the first-line treatment of advanced melanoma and in the second-line treatment of advanced squamous NSCLC.
Background & Aims The role of interleukin (IL)-5 in the pathogenesis of eosinophilic esophagitis (EoE) has been established in animal models; anti–IL-5 therapy has been reported to be effective in ...adults. We investigated whether IL-5 has a role in accumulation of esophageal eosinophils in children with EoE and whether therapy with mepolizumab, an antibody against IL-5, reduces the number of esophageal intraepithelial eosinophils in children with EoE. Methods We performed an international, multicenter, double-blind, randomized, prospective study of 59 children with EoE, defined as baseline peak count of esophageal intraepithelial eosinophils of ≥20 in at least 1 high-power field (hpf). Patients received an infusion every 4 weeks (a total of 3 infusions) of 0.55, 2.5, or 10 mg/kg mepolizumab. No placebo group was used. Results Baseline peak and mean esophageal intraepithelial eosinophil counts were (mean ± SE) 122.5 ± 8.78 and 39.1 ± 3.63 per hpf, respectively. Four weeks after the third infusion, peak eosinophil counts were <5 per hpf in 5 of 57 children (8.8%); we did not observe differences among groups given different doses of mepolizumab. Reduced peak and mean eosinophil counts, to <20 per hpf, were observed in 18 of 57 (31.6%) and 51 of 57 (89.5%) children, respectively. Peak and mean esophageal intraepithelial eosinophil counts decreased significantly to 40.2 ± 5.17 and 9.3 ± 1.25 per hpf, respectively ( P < .0001). An analysis to evaluate predictors of response associated a higher mean baseline esophageal intraepithelial eosinophil count with a greater reduction in mean count ( P < .0001). Conclusions IL-5 is involved in the pathogenesis of EoE in children. Mepolizumab, an antibody against IL-5, reduces esophageal eosinophilic inflammation in these patients.
We analyzed in B-chronic lymphocytic leukemia (B-CLL) whole blood assays the activity of therapeutic mAbs alemtuzumab, rituximab, and type II glycoengineered anti-CD20 mAb GA101. Whole blood samples ...were treated with Abs, and death of CD19(+) B-CLL was measured by flow cytometry. Alemtuzumab efficiently lysed B-CLL targets with maximal lysis at 1-4 h (62%). In contrast, rituximab induced a more limited cell death (21%) that was maximal only at 24 h. GA101 killed B-CLL targets to a similar extent but more rapidly than rituximab, with 19.2 and 23.5% cell death at 4 and 24 h, respectively, compared with 7.9 and 21.4% for rituximab. Lysis by both rituximab and GA101 correlated directly with CD20 expression levels (r(2) = 0.88 and 0.85, respectively). Interestingly, lysis by all three Abs at high concentrations was mostly complement dependent, because it was blocked by the anti-C5 Ab eculizumab by 90% in the case of alemtuzumab and rituximab and by 64% in the case of GA101. Although GA101 caused homotypic adhesion, it induced only limited (3%) direct cell death of purified B-CLL cells. Both rituximab and GA101 showed the same efficiency in phagocytosis assays, but phagocytosis was not significant in whole blood due to excess Igs. Finally, GA101 at 1-100 μg/ml induced 2- to 3-fold more efficient NK cell degranulation than rituximab in isolated B-CLL or normal PBMCs. GA101, but not rituximab, also mediated significant NK cell degranulation in whole blood samples. Thus, complement and Ab-dependent cellular cytotoxicity are believed to be the major effector mechanisms of GA101 in whole blood assays.
The COVID-19 pandemic urgently needs therapeutic and prophylactic interventions. Here, we report the rapid identification of SARS-CoV-2-neutralizing antibodies by high-throughput single-cell RNA and ...VDJ sequencing of antigen-enriched B cells from 60 convalescent patients. From 8,558 antigen-binding IgG1+ clonotypes, 14 potent neutralizing antibodies were identified, with the most potent one, BD-368-2, exhibiting an IC50 of 1.2 and 15 ng/mL against pseudotyped and authentic SARS-CoV-2, respectively. BD-368-2 also displayed strong therapeutic and prophylactic efficacy in SARS-CoV-2-infected hACE2-transgenic mice. Additionally, the 3.8 Å cryo-EM structure of a neutralizing antibody in complex with the spike-ectodomain trimer revealed the antibody’s epitope overlaps with the ACE2 binding site. Moreover, we demonstrated that SARS-CoV-2-neutralizing antibodies could be directly selected based on similarities of their predicted CDR3H structures to those of SARS-CoV-neutralizing antibodies. Altogether, we showed that human neutralizing antibodies could be efficiently discovered by high-throughput single B cell sequencing in response to pandemic infectious diseases.
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•8,558 IgG1+ antigen-binding clonotypes were identified by high-throughput scRNA/VDJ-seq•14 potent SARS-CoV-2 neutralizing antibodies were found from 60 convalescent patients•BD-368-2 showed high therapeutic and prophylactic efficacy in SARS-CoV-2-infected mice•Neutralizing antibodies can be directly selected based on predicted CDR3H structures
Neutralizing antibodies, which could effectively block virus entry into host cells, are urgently needed for intervention against COVID-19. Using high-throughput single-cell RNA sequencing, Cao et al. identified fourteen potent neutralizing antibodies from 60 convalescent patients’ B cells. The most potent antibody, BD-368-2, exhibits high therapeutic and prophylactic efficacy in SARS-CoV-2-infected mice.
In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) ...versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA.
Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization).
For STRIDE, durvalumab, and sorafenib, median 95% confidence interval (CI) follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified.
These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.
•This updated analysis of the phase III HIMALAYA study in uHCC showed sustained OS benefit with STRIDE vs sorafenib.•Four-year OS rates were 25.2% with STRIDE vs 15.1% with sorafenib.•STRIDE improved OS vs sorafenib across subgroups and further improved 3- and 4-year OS rates in those with disease control.•Subsequent anticancer systemic therapy was more common in the sorafenib vs STRIDE arm.•No new serious treatment-related AEs occurred after the primary analysis for STRIDE.
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