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Newer Biologic and Small-Molecule Therapies for Inflammatory Bowel Disease.
Baumgart, DC, Le Berre, C
The New England journal of medicine. 2021;(14):1302-1315
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Site-selective modification strategies in antibody-drug conjugates.
Walsh, SJ, Bargh, JD, Dannheim, FM, Hanby, AR, Seki, H, Counsell, AJ, Ou, X, Fowler, E, Ashman, N, Takada, Y, et al
Chemical Society reviews. 2021;(2):1305-1353
Abstract
Antibody-drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. They have garnered widespread interest in drug discovery, particularly in oncology, as discrimination between healthy and malignant tissues or cells can be achieved. Nine ADCs have received approval from the US Food and Drug Administration and more than 80 others are currently undergoing clinical investigations for a range of solid tumours and haematological malignancies. Extensive research over the past decade has highlighted the critical nature of the linkage strategy adopted to attach the payload to the antibody. Whilst early generation ADCs were primarily synthesised as heterogeneous mixtures, these were found to have sub-optimal pharmacokinetics, stability, tolerability and/or efficacy. Efforts have now shifted towards generating homogeneous constructs with precise drug loading and predetermined, controlled sites of attachment. Homogeneous ADCs have repeatedly demonstrated superior overall pharmacological profiles compared to their heterogeneous counterparts. A wide range of methods have been developed in the pursuit of homogeneity, comprising chemical or enzymatic methods or a combination thereof to afford precise modification of specific amino acid or sugar residues. In this review, we discuss advances in chemical and enzymatic methods for site-specific antibody modification that result in the generation of homogeneous ADCs.
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Cell Surface GRP94 as a Novel Emerging Therapeutic Target for Monoclonal Antibody Cancer Therapy.
Kim, JW, Cho, YB, Lee, S
Cells. 2021;(3)
Abstract
Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER)-resident member of the heat shock protein 90 (HSP90) family. In physiological conditions, it plays a vital role in regulating biological functions, including chaperoning cellular proteins in the ER lumen, maintaining calcium homeostasis, and modulating immune system function. Recently, several reports have shown the functional role and clinical relevance of GRP94 overexpression in the progression and metastasis of several cancers. Therefore, the current review highlights GRP94's physiological and pathophysiological roles in normal and cancer cells. Additionally, the unmet medical needs of small chemical inhibitors and the current development status of monoclonal antibodies specifically targeting GRP94 will be discussed to emphasize the importance of cell surface GRP94 as an emerging therapeutic target in monoclonal antibody therapy for cancer.
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Antibody therapy for COVID-19.
Hammarström, L, Marcotte, H, Piralla, A, Baldanti, F, Pan-Hammarström, Q
Current opinion in allergy and clinical immunology. 2021;(6):553-558
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Abstract
PURPOSE OF REVIEW To provide an update of the current state of antibody therapy for Severe Acute Respiratory Syndrome Coronavirus 2 infection that has progressed immensely in a very short time period. RECENT FINDINGS Limited clinical effect of classical passive immunotherapy (plasma therapy, hyperimmune immunoglobulin [IgG] preparations) whereas monoclonal antibody therapy, if initiated early in the disease process, shows promising results. SUMMARY Although antibody therapy still remains to be fully explored in patients with COVID-19, a combination of IgG monoclonal antibodies against the receptor-binding domain of the spike protein currently appears to provide the best form of antibody therapy, Immunoglobulin A dimers and Immunoglobulin M pentamers also show promising preliminary therapeutic results.
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Time to dissect the autoimmune etiology of cancer antibody immunotherapy.
Dougan, M, Pietropaolo, M
The Journal of clinical investigation. 2020;(1):51-61
Abstract
Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory "checkpoint" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.
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Pharmacological treatments for eosinophilic esophagitis: current options and emerging therapies.
Lucendo, AJ
Expert review of clinical immunology. 2020;(1):63-77
Abstract
Introduction: The epidemiology of eosinophilic esophagitis (EoE) has increased rapidly to represent a common cause of chronic and recurrent esophageal symptoms. Current treatment options have limitations so the development of novel therapies is a matter of growing interest.Areas covered: This article provides an up-to-date discussion of current therapies and investigational options for EoE. Established anti-inflammatory treatments for EoE at present include dietary therapy, proton pump inhibitors and swallowed topic steroids, which should be combined with endoscopic dilation in case of strictures. Refractoriness, high recurrence rates, and need for long-term therapies have promoted the investigation of novel, esophageal-targeted formulas of topic corticosteroids, and monoclonal antibodies (including mepolizumab, reslizumab, QAX576, RPC4046, dupilumab, omalizumab, infliximab, and vedolizumab) for EoE, with some having been demonstrated as effective and safe in the short term. Several additional promising therapies are also discussed.Expert opinion: Several therapeutic targets have shown efficacy and will be approved to treat EoE, especially corticosteroid-sparing options and those for patients with multiple Th2-associated diseases. Personalized therapeutic strategies for initial and maintenance treatments of EoE must be rationally designed, to reduce the burden of disease and answer meaningfully the needs of all stakeholders involved in EoE.
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Approach to patients with hypophosphataemia.
Florenzano, P, Cipriani, C, Roszko, KL, Fukumoto, S, Collins, MT, Minisola, S, Pepe, J
The lancet. Diabetes & endocrinology. 2020;(2):163-174
Abstract
Phosphate metabolism is an evolving area of basic and clinical research. In the past 15 years, knowledge on disturbances of phosphate homoeostasis has expanded, as has the discovery of new targeted therapies. Hypophosphataemia might be the biochemical finding in several diseases, and its clinical evaluation should initially focus on the assessment of pathophysiological mechanisms leading to low serum phosphate concentrations. Clinical consequences of hypophosphataemia can involve multiple organ systems and vary depending on several factors, the most important being the underlying disorder. This Review focuses on the approach to patients with hypophosphataemia and how underlying pathophysiological mechanisms should be understood in the evaluation of differential diagnosis. We define an algorithm for the assessment of hypophosphataemia and review the most up-to-date literature on specific therapies. Continuous research in this area will result in a better understanding and management of patients with hypophosphataemia.
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Highlights of Studies in Cardiovascular Disease Prevention Presented at the 2020 American College of Cardiology Annual Scientific Session.
Jia, X, Al Rifai, M, Liu, J, Agarwala, A, Gulati, M, Virani, SS
Current atherosclerosis reports. 2020;(8):32
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Abstract
PURPOSE OF REVIEW The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the American College of Cardiology 2020 Virtual Scientific Session (ACC.20)/World Cardiology Congress (WCC). RECENT FINDINGS The studies reviewed include clinical trials on the efficacy and safety of alirocumab (Study in Participants with Homozygous Familial Hypercholesterolemia [ODYSSEY HoFH]) and evinacumab in the treatment of homozygous familial hypercholesterolemia (HoFH); Evaluating the Efficacy of E-cigarettes for Smoking Cessation (E3); the use of renal denervation in the treatment of hypertension (SPYRAL HTN-OFF MED PIVOTAL); and the assessment of vericiguat in the treatment of heart failure (A Study of Vericiguat in Participants with Heart Failure with Reduce Ejection Fraction [VICTORIA]). In addition, results from the pooled analysis of phase III trials on inclisiran and secondary analysis examining eicosapentaenoic acid levels and cardiovascular outcomes from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) were included. Finally, we discuss studies examining the use of polygenic risk score with low density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) on lifetime cardiovascular risk. The studies presented at the ACC.20/WCC represent notable contributions in the field of CVD prevention.
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Anti-IL-5 monoclonal antibodies for the treatment of asthma: an update.
Walsh, GM
Expert opinion on biological therapy. 2020;(10):1237-1244
Abstract
INTRODUCTION Asthma exhibits marked heterogeneity in symptoms with severe or refractory asthma representing a clear area of unmet medical need. These patients require more specifically targeted treatments with monoclonal antibody-based biologics targeted at inhibition of the type 2 cytokines IL-4, IL-5 and IL-13 having considerable potential as effective treatments for severe asthma. For the most part, anti-cytokine-based biologic therapies are more likely to give significant clinical benefit in carefully selected patient populations that take asthma phenotypes and endotypes into account. AREAS COVERED This review is based on recent English-language original articles in Pub Med or MedLine that reported significant clinical findings on the current status, therapeutic potential and safety of the anti-IL-5 biologics mepolizumab, reslizumab and benralizumab in the treatment of severe refractory asthma. EXPERT OPINION Anti-IL-5 treatment appears effective in patients with eosinophilic asthma through exacerbation prevention with accumulating evidence of glucocorticoid-sparing effects with an acceptable safety profile for these biologics.
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Panel Discussion: Some Aspects of the Management of Patients with X-Linked Hypophosphataemic Rickets.
Torregrosa, JV, Sánchez Del Pozo, J, Luiz Yanes, MI, Muñoz Torres, M
Advances in therapy. 2020;(Suppl 2):121-126
Abstract
X-linked hypophosphataemia (XLH) rickets is a rare disease frequently misdiagnosed and mismanaged. Despite having clinical guidelines that offers some therapeutic recommendations based on the clinical experience of experts, physicians still have questions about some important aspects of the diagnosis and treatment of XLH, such as when the disease should be suspected, who should be in charge of the diagnosis, what should be done once the disease is diagnosed, or what therapeutic options are currently available. The objective of this paper is to answer some of the more frequent questions related to the management of patients with XLH by a group of experts participating in a scientific conference on XLH held in Madrid.