A new hope? Possibilities of therapeutic IgA antibodies in the treatment of inflammatory lung diseases.

Inflammatory lung diseases represent a persistent burden for patients and the global healthcare system. The combination of high morbidity, (partially) high mortality and limited innovations in the last decades, have resulted in a great demand for new therapeutics. Are therapeutic IgA antibodies possibly a new hope in the treatment of inflammatory lung diseases? Current research increasingly unravels the elementary functions of IgA as protector against infections and as modulator of overwhelming inflammation. With a focus on IgA, this review describes the pathological alterations in mucosal immunity and how they contribute to chronic inflammation in the most common inflammatory lung diseases. The current knowledge of IgA functions in the circulation, and particularly in the respiratory mucosa, are summarized. The interplay between neutrophils and IgA seems to be key in control of inflammation. In addition, the hurdles and benefits of therapeutic IgA antibodies, as well as the currently known clinically used IgA preparations are described. The data highlighted here, together with upcoming research strategies aiming at circumventing the current pitfalls in IgA research may pave the way for this promising antibody class in the application of inflammatory lung diseases.

Antibody therapy for COVID-19.

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.

A Case of Successful Management of Adult-Onset Linear IgA Bullous Disease With Sulfasalazine During the COVID-19 Pandemic.

Linear IgA bullous disease (LABD) is a rare, acquired, autoimmune, pruritic, and blistering skin condition. Dapsone is a first line treatment option, however, there are limited options if this fails, or if contraindicated. We present a case of successful management of LABD with sulfasalazine. A 46-year-old Caucasian female with LABD was commenced on high dose corticosteroids. She failed to wean, and dapsone was contraindicated due to a history of primary sclerosing cholangitis and risk of hepatitis. Following the failure of mycophenolate mofetil, sulfasalazine was trialed and successfully controlled both this patient’s LABD and ulcerative colitis. There is little literature on the use of sulfasalazine in dermatological conditions. We present sulfasalazine as an option for patients who are unable to use classically used treatments for LABD, or in those who have a dual diagnosis, as in this case, allowing for one agent to manage both conditions. Furthermore, The National Institute for Health and Care Excellence guidance mentions sulfasalazine as one of the few drugs that can be continued during the COVID-19 pandemic, and its use spared this patient from the significant immunosuppression associated with other treatment modalities.J Drugs Dermatol. 2022;21(12): doi:10.36849/JDD.6717.

Anti-SARS-CoV-2 IgG and IgA antibodies in COVID-19 convalescent plasma do not enhance viral infection.

The novel coronavirus, SARS-CoV-2 that causes COVID-19 has resulted in the death of nearly 4 million people within the last 18 months. While preventive vaccination, and monoclonal antibody therapies have been rapidly developed and deployed, early in the pandemic the use of COVID-19 convalescent plasma (CCP) was a common means of passive immunization with a theoretical risk of antibody-dependent enhancement (ADE) of viral infection. Though vaccines elicit a strong and protective immune response and transfusion of CCP with high titers of neutralization activity are correlated with better clinical outcomes, the question of whether antibodies in CCP can enhance infection of SARS-CoV-2 has not been directly addressed. In this study, we analyzed for and observed passive transfer of neutralization activity with CCP transfusion. Furthermore, to specifically understand if antibodies against the spike protein (S) enhance infection, we measured the anti-S IgG, IgA, and IgM responses and adapted retroviral-pseudotypes to measure virus neutralization with target cells expressing the ACE2 virus receptor and the Fc alpha receptor (FcαR) or Fc gamma receptor IIA (FcγRIIA). Whereas neutralizing activity of CCP correlated best with higher titers of anti-S IgG antibodies, the neutralizing titer was not affected when Fc receptors were present on target cells. These observations support the absence of antibody-dependent enhancement of infection (ADE) by IgG and IgA isotypes found in CCP. The results presented, therefore, not only supports the therapeutic use of currently available antibody-based treatment, including the continuation of CCP transfusion strategies, but also the use of various vaccine platforms in a prophylactic approach.

Therapeutic antibodies for COVID-19: is a new age of IgM, IgA and bispecific antibodies coming?

Early humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are dominated by IgM and IgA antibodies, which greatly contribute to virus neutralization at mucosal sites. Given the essential roles of IgM and IgA in the control and elimination of SARS-CoV-2 infection, the mucosal immunity could be exploited for therapeutic and prophylactic purposes. However, almost all neutralizing antibodies that are authorized for emergency use and under clinical development are IgG antibodies, and no vaccine has been developed to boost mucosal immunity for SARS-CoV-2 infection. In addition to IgM and IgA, bispecific antibodies (bsAbs) combine specificities of two antibodies in one molecule, representing an important alternative to monoclonal antibody cocktails. Here, we summarize the latest advances in studies on IgM, IgA and bsAbs against SARS-CoV-2. The current challenges and future directions in vaccine design and antibody-based therapeutics are also discussed.

Therapeutic immunoglobulin A antibody for dysbiosis-related diseases.

Dysbiosis is alterations in the microbial composition compared with a healthy microbiota and often features a reduction in gut microbial diversity and a change in microbial taxa. Dysbiosis, especially in the gut, has also been proposed to play a crucial role in the pathogenesis of a wide variety of diseases, including inflammatory bowel disease, colorectal cancer, cardiovascular disease, obesity, diabetes and multiple sclerosis. A body of evidence has shown that intestinal polymeric immunoglobulin A (IgA) antibodies are important to regulate the gut microbiota as well as to exclude pathogenic bacteria or viral infection such as influenza and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) at mucosal sites. Since the 1970s, trials for oral administration of therapeutic IgA or IgG have been performed mainly to treat infectious enteritis caused by pathogenic Escherichia coli or Clostridium difficile. However, few of them have been successfully developed for clinical application up to now. In addition to the protective function against intestinal pathogens, IgA is well known to modulate the gut commensal microbiota leading to symbiosis. Nevertheless, the development of therapeutic IgA drugs to treat dysbiosis is not progressing. In this review, the advantages of therapeutic IgA antibodies and the problems for their development will be discussed.

"Impact of pentaglobin in severe COVID 19 pneumonia- a prospective study."

BACKGROUND: The current COVID-19 pandemic has become a global public health crisis and presents a serious challenge in treatment of severe COVID pneumonia patients. With an imperative need for an effective treatment, we aimed to study the effectiveness of Pentaglobin, an intravenous immunoglobin in the treatment of severe Covid-19 pneumonia patients. METHODS: This is an open-label non-randomised controlled study. Patients in the study group (n = 17) received Pentaglobin in addition to standard therapy and the control group (n = 19) received only the standard of care treatment. Severity of illness were quantified by severity scores and inflammatory laboratory parameters were compared between the two groups. RESULTS: The average length of hospital stay in pentaglobin group were 12.35 ± 6.98 days compared to 10.94 ± 4.62 days in standard treatment group with mean difference of 1.4 days (p value = 0.4). Pentaglobin did not provide an added advantage in terms of reducing the duration of hospital stay. There was no significant difference between both the groups in terms of requirement of invasive ventilation (p = 0.56) and mortality (p = 0.86). CT Severity score (OR = 1.39 95% CI = 1.09-1.77, P = 0.01), APACHE II score (OR = 1.16 95% CI = 0.99-1.35, P = 0.05) and the SOFA score (OR = 2.11 95% CI = 1.13-3.93, P = 0.02) were independent predictors of mortality. CONCLUSION: The administration of pentaglobin in COVID -19 patients has no significant effect in reducing the risk of mechanical ventilation or death, in disease worsening or in reduction of inflammation.

Role of Immunoglobulin M and A Antibodies in the Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people globally. Virus infection requires the receptor-binding domain (RBD) of the spike protein. Although studies have demonstrated anti-spike and -RBD antibodies to be protective in animal models, and convalescent plasma as a promising therapeutic option, little is known about immunoglobulin isotypes capable of blocking infection. METHODS: We studied spike- and RBD-specific immunoglobulin isotypes in convalescent and acute plasma/serum samples using a multiplex bead assay. We also determined virus neutralization activities in plasma and serum samples, and purified immunoglobulin fractions using a vesicular stomatitis pseudovirus assay. RESULTS: Spike- and RBD-specific immunoglobulin (Ig) M, IgG1, and IgA1 were produced by all or nearly all subjects at variable levels and detected early after infection. All samples displayed neutralizing activity. Regression analyses revealed that IgM and IgG1 contributed most to neutralization, consistent with IgM and IgG fractions' neutralization potency. IgA also exhibited neutralizing activity, but with lower potency. CONCLUSION: IgG, IgM, and IgA are critical components of convalescent plasma used for treatment of coronavirus disease 2019 (COVID-19).

Hemophagocytic lymphohistiocytosis in COVID-19: Case reports of a stepwise approach.

RATIONALE: The immunologic syndrome induced by severe acute coronavirus disease 2019 (COVID-19) is yet not fully understood. Typical patterns of clinical and laboratory features match secondary hemophagocytic lymphohistiocytosis (sHLH). However, the optimal approach to COVID-19 patients testing positive for sHLH is still unclear. PATIENT CONCERNS: Three patients with COVID-19 are reviewed. All showed hyperinflammation and cytokine storm, necessitating intensive care treatment including mechanical ventilation. DIAGNOSIS: Secondary hemophagocytic lymphohistiocytosis due to severe COVID-19; diagnosed via HScore. INTERVENTIONS: A treatment regimen of methylprednisolone, pentaglobin, and anakinra was developed and administered. OUTCOMES: One patient survived the ICU stay. Two other patients, in whom sHLH was diagnosed too late, deceased. LESSONS: A routine screening of COVID-19 patients for secondary HLH by using the HScore is feasible; especially those patients deteriorating clinically with no sufficient response to shock management might be at particular high risk. A stepwise therapeutic approach comprising corticosteroids, immunoglobulins and anakinra, accompanied by immunoadsorption, may dampen cytokine storm effects, and potentially reduce mortality.

When Therapeutic IgA Antibodies Might Come of Age.

BACKGROUND: Extensive efforts have been made in optimizing monoclonal immunoglobulin (Ig)G antibodies for use in clinical practice. Accumulating evidence suggests that IgA or anti-FcαRI could also represent an exciting avenue toward novel therapeutic strategies. SUMMARY: Here, we underline that IgA is more effective in recruiting neutrophils for tumor cell killing and is potently active against several pathogens, including rotavirus, poliovirus, influenza virus, and SARS-CoV-2. IgA could also be used to modulate excessive immune responses in inflammatory diseases. Furthermore, secretory IgA is emerging as a major regulator of gut microbiota, which impacts intestinal homeostasis and global health as well. As such, IgA could be used to promote a healthy microbiota in a therapeutic setting. Key messages: IgA combines multifaceted functions that can be desirable for immunotherapy.