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Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is a subtype of non-Hodgkin lymphoma with a poor prognosis. Although first-line treatments for patients with localized ENKTL have been established, there is no gold standard treatment for patients with advanced ENKTL and refractory and/or relapsed disease. Anti-CD30 antibody-based therapy, including brentuximab vedotin (BV), has been shown to target malignant lymphomas with CD30 expression. In particular, this therapeutic agent has recently been suggested to be effective for Hodgkin lymphoma and mature T-cell lymphoma. However, the efficacy of BV toward ENKTL has not yet been established. Therefore, we investigated the expression of CD30 in a large cohort to evaluate BV as a potential treatment for ENKTL. In this study, 97 Japanese patients with newly diagnosed ENKTL between January 2007 and December 2015 were enrolled. Flow cytometry and immunohistochemistry were performed for the evaluation of CD30 expression. If the cut-off value of CD30 expression is 1% or more, there were 55 positive cases (56.5%). According to the localization of lesion, the frequency of CD30 expression was significantly higher in the non-nasal type than in the nasal type (P = .0394). No differences were observed in almost all clinical characteristics between CD30-positive cases and CD30-negative cases. In addition, the expression of CD30 was not a prognostic factor for either overall survival or progression-free survival. In conclusion, frequent expression of CD30 in ENKTL suggests anti-CD30 antibody-based therapy may be an effective treatment. [ABSTRACT FROM AUTHOR]

Abstract: Epidermal growth factor receptor (EGFR) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second‐site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M‐EGFR, but several mechanisms, including a third‐site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3×mAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M‐expressing tumors. We now report that 3×mAbs, including a triplet containing cetuximab and trastuzumab, inhibits C797S‐expressing tumors. Unlike osimertinib, which induces apoptosis, 3×mAbs promotes degradation of the three receptors and induces cellular senescence. Consistent with distinct mechanisms, treatments combining 3×mAbs plus sub‐inhibitory doses of osimertinib synergistically and persistently eliminated tumors. Thus, oligoclonal antibodies, either alone or in combination with kinase inhibitors, might preempt repeated cycles of treatment and rapid emergence of resistance. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancers (CRCs) expressing programmed death ligand 1 (PD-L1) have poor prognosis. In the multicohort KEYNOTE-028 trial, the anti–PD-1 antibody pembrolizumab was evaluated in 20 PD-L1–positive advanced solid tumors. Herein, we report results for the advanced CRC cohort. Methods: Patients with advanced, treatment-resistant PD-L1–positive carcinoma of the colon or rectum were enrolled, regardless of microsatellite instability (MSI) status. Pembrolizumab 10 mg/kg was administered every 2 weeks for up to 2 years or until disease progression/unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate by investigator review per Response Evaluation Criteria in Solid Tumors version 1.1. Data cutoff was June 20, 2016. Results: Of 137 patients with CRC and samples evaluable for PD-L1 expression, 33 (24%) had PD-L1–positive tumors, of which 23 were enrolled. Median follow-up was 5.3 months, and 8 patients (35%) reported treatment-related adverse events (AEs), most commonly fatigue (n = 3, 13%), stomatitis (n = 2, 9%), and asthenia (n = 2, 9%). One patient (4%) experienced grade 4 treatment-related increased blood bilirubin. No grade 3 AEs, discontinuations, or deaths were attributed to treatment. Most patients (n = 15, 65%) experienced progressive disease. One partial response occurred in a patient (4%) with MSI-high CRC. Conclusion: Pembrolizumab demonstrated a favorable safety profile in advanced PD-L1–positive CRC. Antitumor activity was observed in a single patient with MSI-high CRC, warranting further evaluation in this patient population. (Clinicaltrials.gov registration: NCT02054806) [ABSTRACT FROM AUTHOR]

Context: Monoclonal antibodies are being investigated for chronic pain to overcome the shortcomings of current treatment options. Objective: To provide a practical overview of monoclonal antibodies in clinical development for use in chronic pain conditions, with a focus on mechanisms of action and relevance to specific classes. Methods: Qualitative review using a systematic strategy to search for randomized controlled trials, systematic and nonsystematic (narrative) reviews, observational studies, nonclinical studies, and case reports for inclusion. Studies were identified via relevant search terms using an electronic search of MEDLINE via PubMed (1990 to June 2017) in addition to hand-searching reference lists of retrieved systematic and nonsystematic reviews. Results: Monoclonal antibodies targeting nerve growth factor, calcitonin gene-related peptide pathways, various ion channels, tumor necrosis factor-a, and epidermal growth factor receptor are in different stages of development. Mechanisms of action are dependent on specific signaling pathways, which commonly involve those related to peripheral neurogenic inflammation. In clinical studies, there has been a mixed response to different monoclonal antibodies in several chronic pain conditions, including migraine, neuropathic pain conditions (e.g., diabetic peripheral neuropathy), osteoarthritis, chronic back pain, ankylosing spondylitis, and cancer. Adverse events observed to date have generally been mild, although further studies are needed to ensure safety of monoclonal antibodies in early stages of development, especially where there is an overlap with non-pain-related pathways. High acquisition cost remains another treatment limitation. Conclusion: Monoclonal antibodies for chronic pain have the potential to overcome the limitations of current treatment options, but strategies to ensure their appropriate use need to be determined. [ABSTRACT FROM AUTHOR]

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers. [ABSTRACT FROM AUTHOR]

Fc receptors play important roles for a wide array of immune responses. In contrast to the well-defined Fcγ and Fce receptors, the molecular and functional characteristics of Fc receptors for IgA and IgM have remained incompletely understood for years. Recent progress has unveiled the characteristics of Fc receptors for IgA and IgM, including Fcα/μ receptor (Fcα/μR) (CD351), polymeric immunoglobulin receptor (poly-IgR), Fcα receptor (FcαRI) (CD89) and Fcμ receptor (FcμR). In this review, we summarize the molecular and functional characteristics of Fcα/μR in comparison with poly-IgR, FcμR and FcαRI, and focus particularly on the pro-inflammatory function of Fcα/μR expressed on marginal zone B cells in sepsis. [ABSTRACT FROM AUTHOR]

Survival periods of patients following surgical therapy of oral squamous cell carcinoma (OSCC) have previously been demonstrated to decrease over recent decades. Epidermal growth factor receptor (EGFR) and Cortactin are molecular markers that are important in tumour progression and development, and interact within the EGF pathway. Although EGFR antibody therapy exists, sufficient efforts for increased survival are still lacking due to the present limited response rates. The aim of the present study was to examine the association between EGFR and Cortactin expression on survival rates of OSCC patients and to determine whether EGFR and Cortactin expression levels are associated with advanced tumor sizes and lymphnode-metastases. In total, 222 OSCC patients were included in the study. EGFR and Cortactin expression in tumor tissue was evaluated by immunohistochemistry. Cox regression was used for survival analysis. Categories were tested for associations by using cross tabs (Chi-square test). Groups were compared by the non-parametric Mann Whitney U-test. Probabilities of less than 0.05 were considered significant and significant expression of Cortactin was observed in Advanced Union Internationale Contre le Cancer stage (P=0.032), including advanced tumour stage (P=0.021) and lymph node metastasis (P=0.049). High Cortactin expression was significantly associated with poorer survival rates (P=0.037). Further Cortactin expression was not associated with extracapsular spread, however EGFR exhibited a significant association (P=0.034). Neither EGFR nor Cortactin expression was correlated to grading. EGFR and Cortactin co-expression was demonstrated to be significantly associated with poorer survival rates in OSCC patients, suggesting that identification of predictive biomarkers for adjuvant therapies are of primary concern in OSCC. In particular, efficient dual-target therapy may act as an appropriate therapy to improve survival time for patients at advanced OSCC tumor stages. [ABSTRACT FROM AUTHOR]

Background: Engineering of the antibody’s fragment crystallizable (Fc) by modifying the amino acid sequence (Fc protein engineering) or the glycosylation pattern (Fc glyco-engineering) allows enhancing effector functions of tumor targeting antibodies. Here, we investigated whether complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of CD20 antibodies could be improved simultaneously by combining Fc protein engineering and glyco-engineering technologies. Methods and Results: Four variants of the CD20 antibody rituximab were generated: a native IgG1, a variant carrying the EFTAE modification (S267E/H268F/ S324T/G236A/I332E) for enhanced CDC as well as glycoengineered, non-fucosylated derivatives of both to boost ADCC. The antibodies bound CD20 specifically with similar affinity. Antibodies with EFTAE modification were more efficacious in mediating CDC, irrespective of fucosylation, than antibodies with wild-type sequences due to enhanced C1q binding. In contrast, non-fucosylated variants had an enhanced affinity to FcγRIIIA and improved ADCC activity. Importantly, the double-engineered antibody lacking fucose and carrying the EFTAE modification mediated both CDC and ADCC with higher efficacy than the native CD20 IgG1 antibody. Conclusion: Combining glyco-engineering and protein engineering technologies offers the opportunity to simultaneously enhance ADCC and CDC activities of therapeutic antibodies. This approach may represent an attractive strategy to further improve antibody therapy of cancer and deserves further evaluation. [ABSTRACT FROM AUTHOR]

Epithelial membrane protein 2 (EMP2) is a cell surface protein that has recently emerged as an object of neuro-oncological interest due to its potential to be utilized as a biomarker and target for antibody therapies. Preclinical studies have demonstrated that EMP2 is associated with disease prognosis in a number of human cancers, including glioblastoma. The four large extracellular domains of EMP2 and its association with the extracellular matrix makes it an attractive target for future cancer therapies. Translational research suggests that EMP2 may be targeted with antibodies to improve tumor control and survival in a variety of murine models and cancer types. However, in order to translate these preclinical findings into the clinic, future research will need to focus on elucidating the role EMP2 in the normal human body by better understanding its molecular and chemical interactions. The focus of this review is to provide a comprehensive insight into current research endeavors, discuss the potential for clinically translatable applications, and predict the future directions of such research. [ABSTRACT FROM AUTHOR]

To optimally utilize therapeutic monoclonal antibodies in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) understanding their mechanisms of action and the factors influencing these mechanisms is required. We show strong correlations between target antigen expression levels and sensitivity to complement-dependent cytotoxicity (CDC) induced by rituximab, ofatumumab, or alemtuzumab in a panel of cell lines derived from primary B-ALL cells and in primary B-ALL samples. Simultaneous loss of expression of membrane-bound complement regulatory proteins (mCRP) CD55 and CD59 due to glycophosphatidylinositol-anchor deficiency, significantly increased sensitivity to CDC. Accordingly, induced increase in CD55 or CD59 expression protected cells against CDC. The extent of protection co-depended on antigen expression and antibody concentration. In contrast, natural variation in mCRP expression could not be used as a single factor to predict sensitivity to CDC. In conclusion, sensitivity of B-ALL cells to CDC was predominantly determined by antibody concentration and target antigen expression. [ABSTRACT FROM AUTHOR]

Lung cancer is the most commonly diagnosed cancer among men and it is the third ranked in women. There are two major types of lung cancer, namely, small cell lung cancer (SCLC), which accounts for ~20% of the cases, and non-small cell lung cancer (NSCLC), which is the most common. Chemotherapy and chemoradiotherapy have been used as the first-line therapies but suffer from lack of efficacy and also of several toxic adverse effects. Immunotherapeutic approaches including tumor antigen vaccination, monoclonal antibodies targeting checkpoint pathways and also activated immune cells are being developed and have been shown to be effective in treating NSCLC. Despite their promise, efficacy of several immunotherapies has not been consistent. We undertook this meta-analysis study to analyze results from clinical trials that compared efficacy and safety of immunotherapies with placebo or chemotherapy/radiotherapy in improving overall survival (OS) and progression-free survival (PFS) of NSCLC patients. Various databases were searched to identify randomized clinical studies examining the efficacy and safety of antibody- and vaccine-based immunotherapies in NSCLC patients in comparison to chemotherapy or chemoradiotherapy or placebo. Effects on OS and PFS and also adverse events have been compared. In accordance with the selection criteria, a total of 13 studies with 3,513 patients in immunotherapy and 3,072 patients in chemotherapy/placebo, were selected. PFS (odds ratio 1.81, 95% CI 1.36, 2.42; P<0.0001) and OS (P<0.0001) are found to be greatly improved by immunotherapies. Immunotherapy of NSCLC patients was also found to prevent several adverse effects and to improve daily living ability of the patients. The present meta-analysis strongly suggests that immunotherapy improves OS and PFS of patients with NSCLC. [ABSTRACT FROM AUTHOR]

The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years. Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results. While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts. [ABSTRACT FROM AUTHOR]

Background: Spontaneous regression of metastatic melanoma and delayed responses more than one year after treatment with ipilimumab are rarely seen. Case presentation: Here, we present the case of a patient with in transit metastases from cutaneous melanoma on his right lower extremity who achieved complete regression of all metastatic lesions 13 months after the first of two consecutive palliative resections of dominant masses and more than two years after treatment with ipilimumab. Conclusion: The exact cause of our patient’s sudden onset of tumor regression remains speculative. We hypothesize that the operative trauma followed by the postoperative infections augmented an innate immune response. [ABSTRACT FROM AUTHOR]

Receptors for the Fc domain of immunoglobulins [Fc receptors (FcRs)] are essential for the maintenance of antibody-mediated immune responses. FcRs consist of activating- and inhibitorytype receptors that regulate adequate thresholds for various immune cells. In particular, polymorphisms and/or gene copy-number variations of FcRs for IgG (FcγRs) are closely associated with the development of inflammatory disorders, including autoimmune diseases. Recent evidence has implicated polymorphisms of FcRs in the efficacy of monoclonal antibody (mAb)-mediated therapy. This review provides an overview of genetic variations in human FcγRs and the clinical contribution of FcγR polymorphisms in mAb treatments for cancer, autoimmune diseases and allergies. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2. Treatment with IDO2-specific mAb alleviated arthritis in two independent preclinical arthritis models, reducing autoreactive T and B cell activation and recapitulating the strong anti-arthritic effect of genetic IDO2 deficiency. Mechanistic investigations identified FcγRIIb as necessary for mAb internalization, allowing targeting of an intracellular antigen traditionally considered inaccessible to mAb therapy. Taken together, our results offer preclinical proof of concept for antibody-mediated targeting of IDO2 as a new therapeutic strategy to treat RA and other autoantibody-mediated diseases. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated the importance of CD47 in protecting malignant B cells from antibody dependent cellular phagocytosis (ADCP). Combined treatment of anti-CD47 and −CD20 antibodies synergistically augment elimination of tumor B cells in xenograft mouse models. This has led to the development of novel reagents that can potentially enhance killing of malignant B cells in patients. B cell depleting therapy is also a promising treatment for autoimmune patients. In the current study, we aimed to investigate whether or not CD47 protects non-malignant B cells from ADCP. We show that CD47 is expressed on all B cells in mice, with the highest level on plasma cells in bone marrow and spleen. Although its expression is dispensable for B cell development in mice, CD47 on B cells limits antibody mediated phagocytosis. B cell depletion following in vivo anti-CD19 treatment is more efficient in CD47-/- mice than in wild type mice. In vitro, both naïve and activated B cells from CD47-/- mice are more sensitive to ADCP than wild type B cells. Lastly, we show in an ADCP assay that blocking CD47 can enhance anti-CD19 antibody mediated phagocytosis of wild type B cells. These results suggest that in addition to its already demonstrated benefit in cancer, targeting CD47 may be used as an adjunct in combination with B cell depletion antibodies for treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Objective The efficacy of mogamulizumab in adult T-cell leukemia/lymphoma ( ATLL) was reported in a previous phase 2 study. Compared with patients in clinical trials, however, most patients in real-life settings have demonstrated worse outcomes. Method We retrospectively analyzed 96 patients with relapsed/refractory ATLL who received mogamulizumab treatment. Results Relapsed/refractory ATLL patients with a median age of 70 years received a median of five courses of mogamulizumab. Hematologic toxicity and skin rash were the most common adverse events, and both were manageable. Of 96 patients, 87 were evaluable for efficacy. The overall response rate was 36%, and the median progression-free survival ( PFS) and overall survival ( OS) from the start of mogamulizumab therapy were 1.8 and 4.0 months, respectively. Of the original 96 patients, only 25 fulfilled the inclusion criteria of the phase 2 study. Those who met the criteria demonstrated longer median PFS and OS durations of 2.7 and 8.5 months, respectively. The median OS from diagnosis in relapsed/refractory ATLL patients receiving mogamulizumab was 12 months, longer than the 5.8 months in a historical cohort without mogamulizumab. Conclusion In clinical practice, mogamulizumab exhibited antitumor activity in patients with relapsed/refractory ATLL, with an acceptable toxicity profile. Mogamulizumab therapy improved the OS of ATLL patients. [ABSTRACT FROM AUTHOR]

Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death-1 protein, were suggested in previous phase 1 studies. The present phase 2, single-arm study ( JAPIC- CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression-free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3-4 drug-related adverse events were observed in 31.4% of patients. Pretreatment serum interferon-γ, and interleukin-6 and -10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy. [ABSTRACT FROM AUTHOR]

Background: Serum infliximab (IFX) and antibody-to-infliximab (ATI) levels are objective parameters, that may have a great role in the therapeutic decisions during maintenance biological therapy. Research design and methods: 48 inflammatory bowel disease patients receiving maintenance IFX therapy were prospectively enrolled and divided into adequate (complete remission N = 20) and inadequate responder (partial response, loss of response, dose escalation; N = 28) groups. Blood samples were collected just before (trough level, TL) and two (W2aTL) and six weeks (W6aTL) after the administration of IFX. Results: Single measurement of ATI titer was insufficient for predicting therapeutic response due to transient expression of ATI, however, using the three points’ measurements, significant difference has been detected between the adequate and inadequate responder group (5.0% vs 35.7%; p = 0.016). The mean value of TL was significantly higher in the adequate responder group (3.11±1.64 vs.1.19±1.11; p<0.001) without further difference on the second and sixth week. Sensitivity and specificity for predicting the therapeutic response were 85.0% and 71.4% based on the cut-off value of TL 2.0 μg/ml. Conclusion: Simultaneous measurement of serum IFX level prior to administration of regular IFX infusion and ATI titers significantly increase the diagnostic accuracy for the therapeutic decision in patients uncertainly responding to the therapy. The measurement of W2aTL and W6aTL levels did not result in further improvement in the prediction of therapeutic response. [ABSTRACT FROM AUTHOR]

Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. Objective: To investigate the longitudinal evolution of anti-JCV antibody index and to determine the predictive value of baseline anti-JCV antibody index for long-term stability of anti-JCV antibody status. Methods: MS patients from the MS centre of Medical University of Innsbruck, who had serum sampling for a time period of 4–6 years at intervals of 6±3 months, were included in this retrospective, longitudinal study. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. Results: 154 patients were included in this study. Median follow-up time was 63.7 months, with median 11 samples available per patient. At baseline, 111 (72.1%) patients were anti-JCV antibody positive. Baseline anti-JCV antibody index significantly correlated with age (R = 0.22, p = 0.005); there was no difference with respect to sex, disease duration or previously used disease-modifying treatment. During follow-up anti-JCV antibody status changed from negative to positive or vice versa in 17% of patients. In seronegative patients at baseline, baseline anti-JCV antibody index was significantly lower in those remaining seronegative at follow-up compared to those converting to seropositivity (median 0.16 vs. 0.24, p = 0.002). In seropositive patients at baseline, index was higher in those remaining seropositive compared to those reverting to seronegativity (2.6 vs. 0.45, p<10−7). Baseline anti-JCV antibody index >0.90 predicted stable positive serostatus (sensitivity 88.7%, specificity 96.5%) and <0.20 stable negative serostatus (sensitivity 61.3%, specificity 97.6%). Conclusions: Anti-JCV antibody index remained relatively stable over 6-year follow-up with annual serostatus change of ~3%. Baseline anti-JCV antibody index predicted stable negative and stable positive JCV serostatus. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is an important pathogen responsible for a variety of diseases ranging from mild skin and soft tissue infections, food poisoning to highly serious diseases such as osteomyelitis, endocarditis, and toxic shock syndrome. Proper diagnosis of pathogen and virulence factors is important for providing timely intervention in the therapy. Owing to the invasive nature of infections and the limited treatment options due to rampant spread of antibiotic-resistant strains, the trend for development of vaccines and antibody therapy is increasing at rapid rate than development of new antibiotics. In this article, we have discussed elaborately about the host-pathogen interactions, clinical burden due to S aureus infections, status of diagnostic tools, and treatment options in terms of prophylaxis and therapy. [ABSTRACT FROM AUTHOR]

Rapid upregulation of matrix metalloproteinase 9 (MMP-9) leads to blood-brain barrier (BBB) breakdown following stroke, but no MMP-9 inhibitors have been approved in clinic largely due to their low specificities and side effects. Here, we explored the therapeutic potential of a human IgG monoclonal antibody (mAb), L13, which was recently developed with exclusive neutralizing specificity to MMP-9, nanomolar potency, and biological function, using mouse stroke models and stroke patient samples. We found that L13 treatment at the onset of reperfusion following cerebral ischemia or after intracranial hemorrhage (ICH) significantly reduced brain tissue injury and improved the neurological outcomes of mice. Compared to control IgG, L13 substantially attenuated BBB breakdown in both types of stroke model by inhibiting MMP-9 activity-mediated degradations of basement membrane and endothelial tight junction proteins. Importantly, these BBB-protective and neuroprotective effects of L13 in wild-type mice were comparable to Mmp9 genetic deletion and fully abolished in Mmp9 knockout mice, highlighting the in vivo target specificity of L13. Meanwhile, ex vivo co-incubation with L13 significantly neutralized the enzymatic activities of human MMP-9 in the sera of ischemic and hemorrhagic stroke patients, or in the peri-hematoma brain tissues from hemorrhagic stroke patients. Overall, we demonstrated that MMP-9 exclusive neutralizing mAbs constitute a potential feasible therapeutic approach for both ischemic and hemorrhagic stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

We report 8 cases of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia in patients previously treated with anti-CD20 monoclonal antibodies. Polymerase chain reaction of nasopharyngeal swabs for SARS-CoV-2 was negative in most cases; viral cell cultures confirmed that viable SARS-Co-2 virus was present. Four patients were treated with anti-SARS-CoV-2 hyperimmune globulins with rapid resolution of disease., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Immune checkpoint blockade is a compelling approach in tumor immunotherapy. Blocking inhibitory pathways in T cells has demonstrated clinical efficacy in different types of cancer and may hold potential to also stimulate innate immune responses. A novel emerging potential target for immune checkpoint therapy is leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1). LILRB1 belongs to the superfamily of leukocyte immunoglobulin-like receptors and exerts inhibitory functions. The receptor is expressed by a variety of immune cells including macrophages as well as certain cytotoxic lymphocytes and contributes to the regulation of different immune responses by interaction with classical as well as non-classical human leukocyte antigen (HLA) class I molecules. LILRB1 has gained increasing attention as it has been demonstrated to function as a phagocytosis checkpoint on macrophages by recognizing HLA class I, which represents a 'Don't Eat Me!' signal that impairs phagocytic uptake of cancer cells, similar to CD47. The specific blockade of the HLA class I:LILRB1 axis may provide an option to promote phagocytosis by macrophages and also to enhance cytotoxic functions of T cells and natural killer (NK) cells. Currently, LILRB1 specific antibodies are in different stages of pre-clinical and clinical development. In this review, we introduce LILRB1 and highlight the features that make this immune checkpoint a promising target for cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zeller, Münnich, Windisch, Hilger, Schewe, Humpe and Kellner.)

Background: Despite recent advances in the treatment of aggressive lymphomas, a significant fraction of patients still succumbs to their disease. Thus, novel therapies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects., Methods: Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL)., Results: Three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 1/11 cell lines was primarily sensitive to tafasitamab and 2/11 to rituximab, the combination resulted in enhanced cell death in 8/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling, which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combination resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model., Conclusion: This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to single-agent treatments in models of aggressive B-cell lymphoma in vitro and in vivo ., Competing Interests: MP, KI, DM, SS and CH are employees of MorphoSys AG, KL, SS and JE own MorphoSys AG stocks. MP, JE and SS hold MorphoSys AG patents. This study received funding from MorphoSys AG. The funder was involved in study design, collection, analysis, interpretation of the data, writing of this article and decision to submit it for publication., (Copyright © 2023 Patra-Kneuer, Chang, Xu, Augsberger, Grau, Zapukhlyak, Ilieva, Landgraf, Mangelberger-Eberl, Yousefi, Berning, Kurz, Ott, Klener, Khandanpour, Horna, Schanzer, Steidl, Endell, Heitmüller and Lenz.)

The fact that many infectious diseases are not effectively controlled with etiotropic drugs determines the relevance of a search for alternative methods, particularly those based on the modulation of immunity. The review analyzes rational approaches to the immunotherapy of infectious diseases, such as regulation of acquired immunity; correction of the quantitative and qualitative composition of the intestinal microbiota; and modulation of innate immunity. Among the drugs affecting the innate components of an immune response, the derivatives of muramyl dipeptide (MDP), a structural subunit of bacterial cell wall peptidoglycan, stand out in the context of a detailed study of the cellular and molecular mechanisms of action. The fact that it is expedient to clinically apply these immunomodulators in many diseases accompanied by inadequate infection control is beyond question. It is demonstrated that muramyl peptides (MP) may be also used to prevent excessive inflammatory responses. The adjuvant properties of MDP and its analogues can be employed for therapeutic vaccination. The data that the signals transmitted through NOD-like receptors (MP sensors) regulate intestinal homeostasis suggest that there is some potential for the use of MDP derivatives for the correction of dysbiosis and related immune disorders. Whatever the purpose of immunomodulation, the key to its effectiveness is to personalize the choice and regimens of immunotropic drugs.