Secukinumab, Pituitary Enlargement and Panhypopituitarism: Are They Related?

Pituitary adenomas represent the most common etiology of hypopituitarism associated with a pituitary enlargement, but other causes have been emerging, namely immune checkpoint inhibitors-induced hypophysitis (ipilimumab, nivolumab and pembrolizumab). Secukinumab is a recently approved human monoclonal antibody used for the treatment of psoriasis, with no know reported cases of hypophysitis. We describe a challenging case of panhypopituitarism in a patient with a pituitary incidentaloma and a timing relationship between secukinumab initiation and the manifestation of clinical features suggestive of hypopituitarism. In such intricate work-up, differential diagnosis should be carefully equated, taking into account the therapeutic and prognostic implications.

Isolation and comparative analysis of antibodies that broadly neutralize sarbecoviruses

The devastation caused by SARS-CoV-2 has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus, we identified a human monoclonal antibody, 10-40, that neutralized or bound all sarbecoviruses tested in vitro and protected against SARS-CoV-2 and SARS-CoV in vivo. Comparative studies with other receptor-binding domain (RBD)-directed antibodies showed 10-40 to have the greatest breadth against sarbecoviruses and thus its promise as an agent for pandemic preparedness. Moreover, structural analyses on 10-40 and similar antibodies not only defined an epitope cluster in the inner face of the RBD that is well conserved among sarbecoviruses, but also uncovered a new antibody class with a common CDRH3 motif. Our analyses also suggested that elicitation of this class of antibodies may not be overly difficult, an observation that bodes well for the development of a pan-sarbecovirus vaccine.

A Phase 2 randomized, double-blind, placebo-controlled trial of the monoclonal antibody MHAA4549A in patients with acute uncomplicated influenza A infection

Background MHAA4549A, a human monoclonal antibody targeting the influenza A hemagglutinin stalk, neutralizes influenza A virus in animal and human volunteer challenge studies. We investigated MHAA4549A safety and tolerability, efficacy, and pharmacokinetics in outpatients with acute, uncomplicated influenza A infection. Methods This was a Phase 2, randomized, double-blind, placebo-controlled trial of single intravenous (IV) doses of 3600 mg or 8400 mg MHAA4549A, or IV placebo in adult outpatients testing positive for influenza A. Patients were enrolled across 35 sites in 6 countries. Randomization and dosing occurred ≤ 72 hours of symptom onset; study duration was 14 weeks. The primary endpoint was the nature and frequency of adverse events (AEs). Secondary endpoints included median time to alleviation of all influenza symptoms, effects on nasopharyngeal viral load and duration of viral shedding, and MHAA4549A serum pharmacokinetics. Results Of 125 randomized patients, 124 received study treatment, with 99 confirmed positive for influenza A by central testing. Frequency of AEs between MHAA4549A and placebo groups was similar; nausea was most common (8 patients; 6.5%). MHAA4549A serum exposure was confirmed in all MHAA4549A-treated patients and was dose proportional. No hospitalizations or deaths occurred. Between MHAA4549A and placebo groups, no statistically significant differences occurred in median time to alleviation of all symptoms, nasopharyngeal viral load, or duration of viral shedding. Conclusions While MHAA4549A was safe and well-tolerated with confirmed exposure, the antibody did not improve clinical outcomes in patients with acute uncomplicated influenza A infection.

A human monoclonal antibody potently pan-neutralizes SARS-CoV-2 VOCs by targeting RBD invariant sites

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of novel corona virus disease (COVID-19). The neutralizing monoclonal antibodies (mAbs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are among the most promising strategies to prevent and treat COVID-19. However, SARS-CoV-2 variants of concern (VOCs) profoundly reduced the efficacies of most of mAbs and vaccines approved for clinical use. Herein, we demonstrated mAb 35B5 efficiently neutralizes both wild-type (WT) SARS-CoV-2 and VOCs, including B.1.617.2 (delta) variant, in vitro and in vivo. Cryo-electron microscopy (cryo-EM) revealed that 35B5 neutralizes SARS-CoV-2 by targeting a unique epitope that avoids the prevailing mutation sites on RBD identified in circulating VOCs, providing the molecular basis for its pan-neutralizing efficacy. The 35B5-binding epitope could also be exploited for the rational design of a universal SARS-CoV-2 vaccine.

PCSK9 Induces Tissue Factor Expression by Activation of TLR4/NFkB Signaling

Proprotein convertase subtilisin kexin 9 (PCSK9) increases LDL cholesterol (C) concentration by accelerating the hepatic degradation of the LDL receptor (R) thus promoting atherogenesis. The molecule, however, also exerts proinflammatory effects independent of circulating LDL-C by enhancing local cytokine production and activation of NFkB, a process that might involve Toll-like receptor 4 (TLR4), a crucial component of the innate immunity system. Tissue factor (TF), a glycoprotein which plays an essential role in coagulation and inflammation, is rapidly induced by circulating monocytes stimulated by proinflammatory agents through NFkB-dependent mechanisms. The aims of our study were (1) to assess whether PCSK9 may induce monocytic TF expression and (2) to evaluate whether the TLR4/NFkB signaling pathway may contribute to that effect. Experiments were carried out in peripheral blood mononuclear cells (PBMCs), THP-1 cells, and HEK293 cells transfected with plasmids encoding the human TLR4 complex. PCSK9 increased procoagulant activity (PCA), mRNA and TF protein expression in both PBMCs and THP-1 cultures. Pre-treatment with inhibitors of TLR4/NFkB signaling such as LPS-RS, CLI-095, and BAY 11-7082, downregulated PCSK9-induced TF expression. A similar effect was obtained by incubating cell cultures with anti-PCSK9 human monoclonal antibody. In TLR4-HEK293 cells, PCSK9 activated the TLR4/NFkB signaling pathway to an extent comparable to LPS, the specific agonist of TLR4s and quantitative confocal microscopy documented the colocalization of PCSK9 and TLR4s. In conclusion, PCSK9 induces TF expression through activation of TLR4/NFkB signaling.

Is Aducanumab for LMICs? Promises and Challenges

Aducanumab, a human monoclonal antibody, was approved in June of 2021 as the first disease-modifying treatment for Alzheimer’s disease by the United States Food and Drug Administration (U.S. FDA). A substantial proportion of patients with Alzheimer’s disease live in low- and middle-income countries (LMICs), and the debilitating effects of this disease exerts burdens on patients and caregivers in addition to the significant economic strains many nations bear. While the advantages of a disease-modifying therapy are clear in delaying the progression of disease to improve patient outcomes, aducanumab’s approval by the U.S. FDA was met with controversy for a plethora of reasons. This paper will provide precursory insights into aducanumab’s role, appropriateness, and cost-effectiveness in low- and middle-income countries. We extend some of the controversies associated with aducanumab, including the contradicting evidence from the two trials (EMERGE and ENGAGE) and the resources required to deliver the treatment safely and effectively to patients, among other key considerations.

How I Treat Frontline Transplant-eligible Multiple Myeloma

High dose Melphalan supported by autologous transplantation is the standard of care for eligible patients with newly diagnosed multiple myeloma for more than 25 years. Several randomized clinical trials have recently reaffirmed the strong position of transplant in the era of proteasome inhibitors and immunomodulatory drugs combinations, demonstrating a significant reduction of progression or death in comparison with strategies without transplant. Immunotherapy is currently changing the paradigm of multiple myeloma management and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved in the setting of newly diagnosed multiple myeloma. Quadruplets become the new standard in the transplantation programs, but outcomes remain heterogeneous with various response depth and duration. Otherwise, the development of sensitive and specific tools for disease prognostication allows to consider adaptive strategy to a dynamic risk. I discuss in this review the different available options for the treatment of transplant-eligible multiple myeloma patients in frontline setting.

IgA Nephropathy Secondary to Ipilimumab Use

Ipilimumab is a human monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4 approved for the treatment of non-small-cell lung cancer (NSCLC) and other malignancies. Despite a high prevalence of other immune-related adverse events (irAEs), checkpoint inhibitor (CPI)-related nephrotoxicity has been reported less frequently. In this clinical case report, we describe the evaluation of a 70-year-old female with stage IV NSCLC who presented with nephrotic range proteinuria 4 weeks after receiving her first cycle of ipilimumab. She underwent a renal biopsy and was found to have IgA nephropathy that was presumed to be secondary to ipilimumab use, given recent initiation of therapy and clinical history. Unfortunately, despite prompt initiation of corticosteroids, her acute kidney injury progressed and she required hemodialysis, later transitioning to hospice. To our knowledge, this is one of few reported cases of IgA nephropathy secondary to CPI use. With increasing use of CPIs, this case further emphasizes the need for continued surveillance for irAEs, which can occur at any point in a patient’s treatment course.