期刊,BioDrugs 2022年36卷3期_国家学术搜索

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Adis International

主办单位：Adis International

国际刊号：1173-8804

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Passive Immunotherapy Against SARS-CoV-2: From Plasma-Based Therapy to Single Potent Antibodies in the Race to Stay Ahead of the Variants

Strohl, William R.Ku, ZhiqiangAn, ZhiqiangCarroll, Stephen F....

93页

查看更多>>摘要：The COVID-19 pandemic is now approaching 2 years old, with more than 440 million people infected and nearly six million dead worldwide, making it the most significant pandemic since the 1918 influenza pandemic. The severity and significance of SARS-CoV-2 was recognized immediately upon discovery, leading to innumerable companies and institutes designing and generating vaccines and therapeutic antibodies literally as soon as recombinant SARS-CoV-2 spike protein sequence was available. Within months of the pandemic start, several antibodies had been generated, tested, and moved into clinical trials, including Eli Lilly's bamlanivimab and etesevimab, Regeneron's mixture of imdevimab and casirivimab, Vir's sotrovimab, Celltrion's regdanvimab, and Lilly's bebtelovimab. These antibodies all have now received at least Emergency Use Authorizations (EUAs) and some have received full approval in select countries. To date, more than three dozen antibodies or antibody combinations have been forwarded into clinical trials. These antibodies to SARS-CoV-2 all target the receptor-binding domain (RBD), with some blocking the ability of the RBD to bind human ACE2, while others bind core regions of the RBD to modulate spike stability or ability to fuse to host cell membranes. While these antibodies were being discovered and developed, new variants of SARS-CoV-2 have cropped up in real time, altering the antibody landscape on a moving basis. Over the past year, the search has widened to find antibodies capable of neutralizing the wide array of variants that have arisen, including Alpha, Beta, Gamma, Delta, and Omicron. The recent rise and dominance of the Omicron family of variants, including the rather disparate BA.1 and BA.2 variants, demonstrate the need to continue to find new approaches to neutralize the rapidly evolving SARS-CoV-2 virus. This review highlights both convalescent plasma- and polyclonal antibody-based approaches as well as the top approximately 50 antibodies to SARS-CoV-2, their epitopes, their ability to bind to SARS-CoV-2 variants, and how they are delivered. New approaches to antibody constructs, including single domain antibodies, bispecific antibodies, IgA- and IgM-based antibodies, and modified ACE2-Fc fusion proteins, are also described. Finally, antibodies being developed for palliative care of COVID-19 disease, including the ramifications of cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS), are described.

原文链接:

NSTL
Springer Nature

Dengue Vaccines: An Update

Torres-Flores, Jesus M.Reyes-Sandoval, ArturoSalazar, Ma Isabel

12页

查看更多>>摘要：Dengue is one of the most prevalent mosquito-borne diseases in the world, affecting an estimated 390 million people each year, according to models. For the last two decades, efforts to develop safe and effective vaccines to prevent dengue virus (DENV) infections have faced several challenges, mostly related to the complexity of conducting long-term studies to evaluate vaccine efficacy and safety to rule out the risk of vaccine-induced DHS/DSS, particularly in children. At least seven DENV vaccines have undergone different phases of clinical trials; however, only three of them (Dengvaxia (R), TV003, and TAK-003) have showed promising results, and are addressed in detail in this review in terms of their molecular design, efficacy, and immunogenicity. Safety-related challenges during DENV vaccine development are also discussed.

原文链接:

NSTL
Springer Nature

Novel Migraine Therapies May Reduce Public and Personal Disadvantages for People with Migraine

Bentivegna, EnricoMartelletti, PaoloAmbat, Fidel Dominique Festin

3页

查看更多>>摘要：The introduction of new drug classes for migraine, such as monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) or its receptor and small-molecule antagonists of CGRP, have opened a new scenario in a large population of individuals suffering from migraines. The provision of an effective and safe therapy can help overcome the high social and personal costs together with the burden of this disease by offering social, work and economic recovery to the people affected by migraine. Whether the satisfaction of personal and collective unmet needs will be achieved in the vast majority of migraine sufferers now depends only on the efficiency of the organizational care structures dedicated to this socially impactful disease. This path will offer personal benefits and significant psychosocial relief that will help to reduce the enormous current healthcare expenditure necessary for the management of the huge number of individuals suffering from migraines. The new pharmacological classes for prevention must be applied as an interdiction to the chronic phase to express their full rehabilitation potential.

原文链接:

NSTL
Springer Nature

Calcitonin Gene-Related Peptide (CGRP)-Targeted Monoclonal Antibodies and Antagonists in Migraine: Current Evidence and Rationale

Cohen, FredYuan, HsiangkuoSilberstein, Stephen D.

18页

查看更多>>摘要：Calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide found mostly in peptidergic sensory C-fibers, has been suggested to be implicated in the pathogenesis of migraine, which is one of the most common neurological disorders seen in medical practice, affecting almost 16% of the US population. While previously thought to be a vascular condition, migraine attacks are the result of neurogenic inflammation and peripheral/central sensitization through dysfunctional activation of the trigeminovascular system. To date, two classes of therapeutic agents have been developed to interrupt the function of CGRP: CGRP-targeted monoclonal antibodies (mAbs) and small-molecule antagonists (gepants). There are currently four CGRP-targeted mAbs and three gepants that are US Food and Drug Administration (FDA) approved for the treatment of migraine. Multiple phase II and III studies have established the efficacies and tolerability of these treatments. Previously, we reviewed the fundamental role of CGRP in migraine pathogenesis. Here, we discuss in depth the clinical evidence (randomized controlled trials and real-world studies), safety, and tolerability of CGRP-targeted mAbs and gepants for treating migraine.

原文链接:

NSTL
Springer Nature

Regulatory Evaluation of Biosimilars: Refinement of Principles Based on the Scientific Evidence and Clinical Experience

Kurki, PekkaKang, Hye-NaEkman, NiklasKnezevic, Ivana...

13页

查看更多>>摘要：The World Health Organization (WHO) guidelines on evaluation of similar biotherapeutic products (SBPs; also called biosimilars) were adopted by the WHO Expert Committee on Biological Standardization (ECBS) in 2009. In 2019, the ECBS considered that a more tailored and potentially reduced clinical data package may be acceptable in cases where this was clearly supported by the available scientific evidence. The goal of this publication is to review the current clinical experience and scientific evidence and to provide an expert perspective for updating the WHO guidelines to provide more flexibility and clarity. As the first step, the relevant guidelines by other regulatory bodies were reviewed in order to identify issues that might help with updating the WHO guidelines. Next, a literature search was conducted for information on the long-term efficacy, safety, and immunogenicity of biosimilars to identify possible long-term problems. Finally, a search for articles concerning the role of clinical studies in the benefit-risk evaluation of biosimilars was conducted. The analysis of other guidelines suggested that the WHO guidelines may need more emphasis on the importance of the state-of-the-art physicochemical and structural comparability exercise and in vitro functional testing. The use of "foreign" reference product will also need clarifications. The value of in vivo toxicological tests in the development of biosimilars is questionable, and the non-clinical part needs revisions accordingly. The concepts of "totality of evidence," "stepwise development," and "residual uncertainty" were applied in the evaluation of the clinical sections of the guideline. The review of long-term safety and efficacy demonstrated the robustness of the current biosimilar development concept. The analysis of the roles of different development phases suggested that the large efficacy, safety, and immunogenicity studies are, in most cases, redundant. The residual uncertainty of safety, immunogenicity, and efficacy of biosimilars that has shaped the current regulatory guidelines is now substantially reduced. This will allow the re-evaluation of the non-clinical and clinical requirements of the current WHO main guideline. The shift of the relative impact of the development phases towards physico-chemical and in vitro functional testing will provide a relief to the manufacturers and new challenges to the regulators.

原文链接:

NSTL
Springer Nature

Neoadjuvant Immune Checkpoint Inhibitor Therapy in Melanoma: Efficacy, Safety and Timing

van Akkooi, Alexander C. J.Zijlker, Lisanne P.Wouters, Michel W. J. M.

8页

查看更多>>摘要：The introduction of effective systemic therapies has significantly changed the treatment of stage III and IV melanoma. Both immune checkpoint inhibitors and targeted therapies have improved recurrence-free survival in the adjuvant setting. Recent interest has sparked for neoadjuvant systemic therapy with immune checkpoint inhibitors. The intended benefit of pre-operative treatment with immunotherapy is amongst others to enable tailoring of the surgery and adjuvant systemic therapy according to the treatment response. Most importantly, recurrence-free survival might be improved by neoadjuvant systemic therapy over the current standard of care of surgery followed by adjuvant systemic therapy. The first phase I and II trials investigating anti-PD1 inhibitors, both as a single agent and in combination with anti-CTLA-4 inhibitors or other therapeutic agents, have shown promising results. Pathological complete response on neoadjuvant systemic therapy seems a valid surrogate endpoint for relapse-free and overall survival. Pathological complete response rates in these trials vary between 30 and 70%. The optimal dose with respect to efficacy and toxicity and the interval between systemic and surgical treatment remain important issues to address. Accumulating follow-up data and ongoing phase III studies must prove if neoadjuvant systemic therapy is superior to surgery followed by standard-of-care adjuvant therapy.

原文链接:

NSTL
Springer Nature

Comparative Treatment Persistence with Bone-Targeting Agents Among Asian Patients with Bone Metastases from Solid Tumors: A Multinational Retrospective Cohort Study

Shen, Chin-YaoAu, Philip Chun-MingBaek, Yeon-HeeCheung, Ching-Lung...

12页

查看更多>>摘要：Background The efficacy of bone-targeting agents has been confirmed, but the generalizability of results to Asia is in question. Objective We aimed to evaluate and compare treatment persistence and re-initiation with different bone-targeting agents among patients with bone metastases from solid tumors. Methods This population-based cohort study included patients with bone metastasis with breast, lung, or prostate cancer who initiated bone-targeting agents, including denosumab, zoledronic acid, and pamidronate in Taiwan (2013-17), Hong Kong (2013-17), and Korea (2012-16). We described the patients' persistence with bone-targeting agents, by evaluating the interruption probability, and compared risks of treatment interruption. The rates of re-initiation with index bone-targeting agents were evaluated. Results We included 5127 patients (denosumab: 3440, zoledronic acid: 1210, pamidronate: 477) from Taiwan, 883 patients (denosumab: 458, zoledronic acid: 357, pamidronate: 68) from Hong Kong, and 4800 patients (zoledronic acid: 4068, pamidronate: 732) from Korea. Compared with zoledronic acid, denosumab had a lower risk of interruption in Taiwan (adjusted hazard ratio: 0.44; 95% confidence interval 0.40-0.48) and Hong Kong (0.36; 0.28-0.45). However, pamidronate was more likely to be interrupted than zoledronic acid in Taiwan (1.31; 1.11-1.54) and Korea (2.06; 1.83-2.32), but not in Hong Kong (1.13; 0.71-1.78). After discontinuation, original treatments with denosumab in Taiwan and zoledronic acid in Hong Kong were more likely to be resumed, while in Korea, the rates were similar among the bisphosphonates. Conclusions Denosumab was associated with a lower risk of interruption than bisphosphonates in patients with bone metastases in Taiwan and Hong Kong. Further investigations may be required to verify patients' actual reasons for discontinuation.

原文链接:

NSTL
Springer Nature

HLX11, a Proposed Pertuzumab Biosimilar: Pharmacokinetics, Immunogenicity, and Safety Profiles Compared to Three Reference Biologic Products (US-, EU-, and CN-Approved Pertuzumab) Administered to Healthy Male Subjects

Lin, LiliLong, QiheZhang, QianSun, Guilan...

17页

查看更多>>摘要：Background Pertuzumab is a humanized monoclonal antibody for the treatment of breast cancer. HLX11 is a biosimilar of pertuzumab developed by Shanghai Henlius Biotech, Inc. We conducted a bioequivalence study for HLX11 and pertuzumab (United States [US]-, European Union [EU]-, and China [CN]-approved products). Objectives This study compared the biosimilarity in pharmacokinetics (PK), safety, and immunogenicity between HLX11 and reference pertuzumab (approved in the US, the EU, and CN) in healthy Chinese male participants after a single infusion and further characterized the PK profile of HLX11. Methods Eligible individuals were randomized 1:1:1:1 to receive a single dose of 420 mg HLX11, US-, EU-, or CN-pertuzumab via intravenous infusion over 60 min. The primary endpoints were maximum serum drug concentration (C-max), area under the serum concentration-time curve (AUC) from time 0 to time of the last quantifiable concentration (AUC(0-t)), and AUC from time 0 to infinity (AUC(0-infinity)). PK bioequivalence was established if the 90% confidence intervals (CIs) of the geometric mean ratios of the primary endpoints were between 80.0 and 125.0%. Secondary endpoints included other PK parameters, safety, and immunogenicity. Results A total of 160 participants were enrolled and randomly assigned to each group (n = 40 per group). The 90% CIs of the geometric mean ratios of the primary endpoints were all within the prespecified equivalence margins (HLX11 vs. pertuzumab [US-, EU-, CN-approved products]: C-max 97.03-115.06%, 91.39-109.80%, 94.53-110.65%; AUC(0-t) 87.65-99.68%, 87.07-100.79%, 86.29-101.09%; AUC(0-infinity) 87.66-99.90%, 87.54-101.05%, 89.23-103.20%). The incidence of adverse drug reactions was comparable across the four groups. The presence of anti-drug antibodies or neutralizing antibodies had no obvious effect on PK. Conclusion The PK, safety, and immunogenicity of HLX11 were highly similar to those of reference pertuzumab (US-, EU-, CN-approved products). The established bioequivalence supports further clinical trials of HLX11 in cancer treatment.

原文链接:

NSTL
Springer Nature

Clinical Features and Drug Retention of TNF Inhibitors in Older Patients with Ankylosing Spondylitis: Results from the KOBIO Registry

Kim, Ji-WonLee, Eunyoung A.Kim, Hyoun-AhSuh, Chang-Hee...

9页

查看更多>>摘要：Objectives This study aimed to analyse the clinical features and outcomes of and reasons for discontinuing tumour necrosis factor (TNF) inhibitor therapy in older patients with ankylosing spondylitis (AS). Methods Data were extracted from the nationwide Korean College of Rheumatology Biologics registry. Clinical variables and outcomes were compared, and drug retention rate was evaluated. Results Among 1524 patients with AS treated with TNF inhibitors, 306 were aged >= 50 years ('older patients'). Fewer patients were male, the incidence of hypertension and diabetes was higher (all p < 0.001), and the proportion of peripheral arthritis (35.6 vs. 27.1%), Ankylosing Spondylitis Disease Activity Score-erythrocyte sedimentation rate (4.0 +/- 1.1 vs. 3.6 +/- 1.0), and Bath Ankylosing Spondylitis Functional Index (4.2 +/- 2.6 vs. 3.3 +/- 2.5) were all higher in older patients. Although the drug retention rate was lower (log-rank p = 0.018) and lack of efficacy and adverse events were more frequent in older patients (both p < 0.001), drug retention rates were not different after propensity score matching (log-rank p = 0.23). Improvements in disease activity and manifestations were comparable between groups, except for the incidence of peripheral arthritis, which decreased significantly less in older patients over 3 and 5 years. Conclusion Improvements in disease-related clinical factors and drug retention rates were not different between older and younger patients with AS receiving TNF inhibitors. However, the incidence of adverse events was higher in older patients.

原文链接:

NSTL
Springer Nature

Embracing Change: An International Survey Study on the Beliefs and Attitudes of Pediatric Rheumatologists Towards Biosimilars

Demirkan, Fatma GulSonmez, Hafize EmineLamot, LovroAkgun, Ozlem...

10页

查看更多>>摘要：Background Biosimilars have been adopted by clinicians more slowly than anticipated in the post-marketing phase. Objectives We aimed to reveal the perceptions and attitudes of pediatric rheumatologists towards biosimilars and the obstacles to biosimilar therapy. Methods A web-based survey designed to determine the knowledge, experience, and perceptions of pediatric rheumatologists about biosimilars was electronically mailed to the participants between April and August 2021. Responses were collected anonymously and subsequently analyzed. Results A total of 114 pediatric rheumatologists including fellows (32.4%), specialists (29.8%), and seniors (37.7%) responded to the questionnaire. According to the data, 75 (65.8%) physicians had already prescribed at least one biosimilar. The vast majority of participants were aware of the potential cost savings of biosimilars (84, 73.3%). Participants who felt insufficiently informed were 41.8%, 67.6%, and 83.7% among seniors, specialists, and fellows, respectively. In pediatric rheumatology, the scarcity of clinical trials and real-life data (64%) and inadequate information about tolerance to the biosimilars and related side effects in children (49.1%) were the most common barriers expressed by prescribers. Nearly half (45%) of the pediatric rheumatologists preferred to prescribe biosimilars in the treatment of biologic-naive cases. However, most (93%) were reluctant to switch a reference molecule to a biosimilar while the patient was doing well under the originator medicine. Conclusions This survey provided insights into the concerns about prescribing biosimilars among pediatric rheumatologists. In the field of pediatric rheumatology, further education about biosimilars and real-life experiences is required to better inform about treatment options in children.

原文链接:

NSTL
Springer Nature