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Spreading of alpha-synuclein (αSyn) may play an important role in Parkinson’s disease and related synucleinopathies. Passive immunization with anti-αSyn antibodies is a promising method to slow down the spreading process and thereby the progression of synucleinopathies. Currently, it remains elusive which specific characteristics are essential to render therapeutic antibodies efficacious. Here, we established a neuronal co-culture model, in which αSyn species are being released from αSyn-overexpressing cells and induce toxicity in a priori healthy GFP-expressing cells. In this model, we investigated the protective efficacy of three anti-αSyn antibodies. Only two of these antibodies, one C-terminal and one N-terminal, protected from αSyn-induced toxicity by inhibiting the uptake of spreading-competent αSyn from the cell culture medium. Neither the binding epitope nor the affinity of the antibodies towards recombinant αSyn could explain differences in biological efficacy. However, both protective antibodies formed more stable antibody-αSyn complexes than the non-protective antibody. These findings indicate that the stability of antibody-αSyn complexes may be more important to confer protection than the binding epitope or affinity to recombinant αSyn.

Patients with hematologic malignancies are at high risk of exacerbated condition and higher mortality from coronavirus disease 2019 (COVID-19). Bamlanivimab, casirivimab/imdevimab combination, and sotrovimab are monoclonal antibodies (mABs) that can reduce the risk of COVID-19-related hospitalization. Clinical effectiveness of bamlanivimab and casirivimab/imdevimab combination has been shown for the Delta variant (B.1.617.2), but the effectiveness of the latter treatment against the Omicron variant (B.1.1.529) has been suggested to be reduced. However, the tolerability and clinical usage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific mABs in patients with hematologic malignancies are less specified. We present a retrospective case series analysis of all SARS-CoV-2-infected patients with hematologic malignancies who received SARS-CoV-2-specific mABs at our facility between February and mid-December 2021. A total of 13 COVID-19 patients (pts) with at least one malignant hematologic diagnosis received SARS-CoV-2-specific mABs at our facility, with 3 pts receiving bamlanivimab and 10 pts receiving casirivimab/imdevimab combination. We observed SARS-CoV-2 clearance in five cases. Furthermore, we observed a reduction in the necessity for oxygen supplementation in five cases where the application was administered off-label. To the best of our knowledge, we present the largest collection of anecdotal cases of SARS-CoV-2-specific monoclonal antibody use in patients with hematological malignancies. Potential benefit of mABs may be reduced duration and/or clearance of persistent SARS-CoV-2 infection.

In analyses of protein families that may serve as drug targets, membrane-associated G-protein-coupled receptors (GPCRs) dominate, followed by ion channels, transporters, and—to a lesser extent—membrane-bound enzymes. However, various challenges put such membrane proteins among key groups of underutilized opportunities for the application of therapeutic antibodies. Antibodies hold the promise of exquisite specificity, as they are able to target even specific conformations of a particular membrane protein, as well as adaptability through engineering into various antibody formats. However, the ease of raising and isolating specific, effective antibodies targeting membrane proteins depends on many factors. In particular, the generation of specific antibodies is easier when targeting larger, simpler, extracellular domains with greater uniqueness of amino acid sequence. The rareness of such ideal conditions is illustrated by the limited number of approved biologics for targeting GPCRs and other complex membrane proteins. Challenges in developing antibodies to complex membrane proteins such as GPCRs, ion channels, transporters, and membrane-bound enzymes can be addressed by the design of the antigen, antibody-generation strategies, lead optimization technologies, and antibody modalities. A better understanding of the membrane proteins being targeted would facilitate mechanism-based drug discovery. This review describes the advantages and challenges of targeting complex membrane proteins with antibodies and discusses the preparation of membrane protein antigens and antibody generation, illustrated by select examples of success.

Antibody therapies are typically based on high-concentration formulations that need to be administered subcutaneously. These conditions induce several challenges, inter alia a viscosity suitable for injection, sufficient solution stability, and preservation of molecular function. To obtain systematic insights into the molecular factors, we study the dynamics on the molecular level under strongly varying solution conditions. In particular, we use solutions of antibodies with poly(ethylene glycol), in which simple cooling from room temperature to freezing temperatures induces a transition from a well-dispersed solution into a phase-separated and macroscopically arrested system. Using quasi-elastic neutron scattering during in situ cooling ramps and in prethermalized measurements, we observe a strong decrease in antibody diffusion, while internal flexibility persists to a significant degree, thus ensuring the movement necessary for the preservation of molecular function. These results are relevant for a more dynamic understanding of antibodies in high-concentration formulations, which affects the formation of transient clusters governing the solution viscosity.

Similar to pediatric acute myeloid leukemia (AML) the subgroup of biphenotypic acute lymphoblastic leukemia (ALL) is a rare complex entity with adverse outcome, characterized by the surface expression of CD33. Despite novel and promising anti-CD19 targeted immunotherapies such as chimeric antigen receptor T cells and bispecific anti-CD19/CD3 antibodies, relapse and resistance remain a major challenge in about 30% to 60% of patients. To investigate the potential role of the fully humanized bispecific antibody CD16 × CD33 (BiKE) in children with CD33+ acute leukemia, we tested whether the reagent was able to boost NK cell effector functions against CD33+ AML and biphenotypic ALL blasts. Stimulation of primary NK cells from healthy volunteers with 16 × 33 BiKE led to increased cytotoxicity, degranulation and cytokine production against CD33+ cell lines. Moreover, BiKE treatment significantly increased degranulation, IFN-γ and TNF-α production against primary ALL and AML targets. Importantly, also NK cells from leukemic patients profited from restoration of effector functions by BiKE treatment, albeit to a lesser extent than NK cells from healthy donors. In particular, those patients with low perforin and granzyme expression showed compromised cytotoxic function even in the presence of BiKE. In patients with intrinsic NK cell deficiency, combination therapy of CD16xCD33 BiKE and allogeneic NK cells might thus be a promising therapeutic approach. Taken together, CD16xCD33 BiKE successfully increased NK cell effector functions against pediatric AML and biphenotypic ALL blasts and constitutes a promising new option for supporting maintenance therapy or “bridging” consolidation chemotherapy before hematopoietic stem cell transplantation. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-021-03008-0.

Introduction LDH-A, the enzyme responsible for transforming pyruvate into lactate, has been demonstrated to be up-regulated in many types of cancer and to give rise to more aggressive behavior by regulating proliferation and anti-apoptosis. However, its expression in gastric cancer (GC) has not been characterized thoroughly. The purpose of this study was to clarify the expression and potential impact of LDH-A in GC. Methods We examined LDH-A expression by immunohistochemistry on GC tissue microarray (TMA) and using Western blot on fresh GC tissues and cell lines. Prognostic value and correlation with other clinicopathologic factors were evaluated. We transfected siRNA into GC cells against LDH-A. LDH-A was analyzed by Western blotting and real-time RT-PCR. Cell growth was evaluated in vitro and in vivo. Lactate and ATP production by cells were determined. Results There was significantly higher LDH-A expression in carcinoma than in non-neoplastic mucosa (NNM). There was a positive correlation of LDH-A expression with age, histological type and Lymph node metastases. Survival analysis demonstrated that high expression of LDH-A in GC was associated with lower overall survival (OS). When stratified by Lauren grade and histological classification, significance appeared in diffuse type and undifferentiated type GC. In multivariate analysis, the LDH-A expression in GC was an independent prognostic risk factor for OS (hazard ratio = 1.829, 95%CI 1.375–2.433,P

Background: Covid-19 is a viral illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first reported during December, 2019, in Wuhan, Hubei in China. On Thursday, the first of October 2020, the White House of the USA declared that the president of the USA, Donald Trump had a positive test for SARS-CoV-2. He initially had mild symptoms which included mostly, hoarseness, lethargy, and fatigue. The treatment received by a patient “Donald Trump” who was considered the most powerful person in the world is studied, and this paper assumed that all the patients in the world are as important as Mr. Trump and tries to offer the best evidence-treatment for them. Patients and methods: Most media including the CNN television channel rightly confirmed that Mr. Trump has been treated by the best doctors in the world with best therapies that could possibly help him in defeating the virus. The CNN, in various programs during the first week of October, emphasized that, American citizens with Covid-19 are not receiving the same treatments as their president Donald Trump. Results: Trump aged 74 years and initially had mild symptoms which included mostly, hoarseness, lethargy, and fatigue. His age, obesity and mildly elevated cholesterol were considered risk factors that may reduce the likelihood of having very favorable outcome. It was reported that he initially took hydroxychloroquine, an anti-malarial drug. The use of a therapeutic approach including experimental antibody therapy, remdesivir and dexamethasone has not been reported as a treatment for one patient before other than Mr. Trump. Obviously, of the three important therapies, only dexamethasone can be offered to almost all the patients with covid-19. Conclusion: It seems that, the most important factors that made treatment of Donald Trump effective and successful are: 1-The early institution of therapy regardless of the generally accepted recommendations. 2-The use of multiple drugs as none of the available drug alone can guarantee successful treatment.

Introduction Systemic lupus erythematosus is an autoimmune disease associated with serious complications and high costs. The aim was to describe the clinical characteristics and health care resource utilization of a Colombian systemic lupus erythematosus outpatient cohort. Methods This was a retrospective descriptive study. Clinical records and claims data for systemic lupus erythematosus patients from ten specialized care centers in Colombia were reviewed for up to 12 months. Baseline clinical variables, Systemic Lupus Erythematosus Disease Activity Index, drug use, and direct costs were measured. Descriptive statistics were analyzed using SPSS. Results A total of 413 patients were included; 361 (87.4%) were female, and the mean age was 42 ± 14 years. The mean disease evolution was 8.9 ± 6.0 years; 174 patients (42.1%) had a systemic manifestation at baseline, mostly lupus nephritis (105; 25.4%). A total of 334 patients (80.9%) had at least one comorbidity, mainly antiphospholipid syndrome (90; 21.8%) and hypertension (76; 18.4%). The baseline Systemic Lupus Erythematosus Disease Activity Index score was 0 in 215 patients (52.0%), 1–5 in 154 (37.3%), 6–10 in 41 (9.9%) and 11+ in 3 (0.7%). All patients received pharmacological therapy, and the most common treatment was corticosteroids (293; 70.9%), followed by antimalarials (chloroquine 52.5%, hydroxychloroquine 31.0%), immunosuppressants (azathioprine 45.3%, methotrexate 21.5%, mycophenolate mofetil 20.1%, cyclosporine 8.0%, cyclophosphamide 6.8%, leflunomide 4.8%) and biologicals (10.9%). The mean annual costs were USD1954 per patient/year, USD1555 for antirheumatic drugs (USD10,487 for those with biologicals), USD86 for medical visits, USD235 for drug infusions and USD199 for laboratory tests. Conclusions Systemic lupus erythematosus generates an important economic and morbidity burden for the Colombian health system. Systemic lupus erythematosus outpatient attention costs in the observation year were mainly determined by drug therapy (especially biologics), medical visits and laboratory tests. New studies addressing the rate of exacerbations, long-term follow-up or costs related to hospital care are recommended.

ELISA or Western blot is known as a basic technique to be used for measurement of intracellular proteins, but in some cases, they cannot overcome problems such as normalization between samples or extraneous costs for required commercial kits. In order to address this problem, we developed a rapid and effective method (a hybrid of Western blot and ELISA). We use this new hybrid method to detect and normalize trace protein changes in gene expression intracellularly at a lower cost.

Background Identifying a specific threshold level of SARS-CoV-2 antibodies that confers protection in immunocompromised patients has been very challenging. The aim was to assess the threshold of 264 binding antibody units (BAU)/ml using four different SARS-CoV-2 antibody assays (Abbott, Beckman, Roche, and Siemens) and to establish a new optimal threshold of protection for each of the four antibody assays. Methods This study was performed on data retrieved from 69 individuals, who received at least one dose of the Pfizer/BioNTech BNT162b2 or Moderna COVID-19 vaccine (Spikevax) at the Alphabio Laboratory in Marseille, France (European Hospital, Alphabio–Biogroup). The results were compared to the percent inhibition calculated using a functional surrogate of a standardized virus neutralization test (Genscript). Results Samples from 69 patients were analyzed. For a reference cutoff of 264 BAU/ml, assays showed moderate to good overall concordance with Genscript: 87% concordance for Abbott, 78% for Beckman, 75% for Roche, and 88% for Siemens. Overall concordance increased consistently after applying new thresholds, i.e., 148 BAU/ml (Abbott), 48 (Beckman), 559 (Roche), and 270 (Siemens). Conclusion We suggest specific adjusted thresholds (BAU/ml) for the four commercial antibody assays that are used to assess pre-exposure prophylaxis in immunocompromised patients.

Patients with underlying medical conditions are at high risk of developing serious symptoms of the coronavirus disease 2019 than healthy individuals; therefore, it is necessary to evaluate the immune response to vaccination among them to formulate precision and personalized vaccination strategies. However, inconsistent evidence exists regarding whether patients with underlying medical conditions have lower anti-SARS-CoV-2 spike IgG antibody titers. We performed a cross-sectional study enrolling 2762 healthcare workers who received second doses of BNT162b2 vaccination from three medical and research institutes between June and July, 2021. Medical conditions were surveyed by a questionnaire, and spike IgG antibody titers were measured with chemiluminescent enzyme immunoassay using serum collected on the median of 62 days after the second vaccination. Multilevel linear regression model was used to estimate geometric mean and ratio of mean (95% confidence interval, CI) for the presence and absence of medical conditions and treatments. Among all participants (median age, 40 years [interquartile range, 30–50]; male proportion, 29.4%), the prevalence of hypertension, diabetes, chronic lung disease, cardiovascular disease, and cancer was 7.5%, 2.3%, 3.8%, 1.8%, and 1.3%, respectively. Patients with treated hypertension had lower antibody titers than those without hypertension; the multivariable-adjusted ratio of mean (95% CI) was 0.86 (0.76–0.98). Patients with untreated and treated diabetes had lower antibody titers than those without diabetes; the multivariable-adjusted ratio of mean (95% CI) was 0.63 (0.42–0.95) and 0.77 (0.63–0.95), respectively. No substantial difference was observed between the presence or absence of chronic lung disease, cardiovascular disease, or cancer. Patients with untreated hypertension and patients with untreated and treated diabetes had lower spike IgG antibody titers than participants without those medical conditions, suggesting that continuous monitoring of antibody titers and further booster shots could be necessary to maintain adaptive immunity in patients with hypertension or diabetes.

Transferrin receptor 1 (TfR1), also known as CD71, is a transmembrane protein involved in the cellular uptake of iron and the regulation of cell growth. This receptor is expressed at low levels on a variety of normal cells, but is upregulated on cells with a high rate of proliferation, including malignant cells and activated immune cells. Infection with the human immunodeficiency virus (HIV) leads to the chronic activation of B cells, resulting in high expression of TfR1, B-cell dysfunction, and ultimately the development of acquired immunodeficiency syndrome-related B-cell non-Hodgkin lymphoma (AIDS-NHL). Importantly, TfR1 expression is correlated with the stage and prognosis of NHL. Thus, it is a meaningful target for antibody-based NHL therapy. We previously developed a mouse/human chimeric IgG3 specific for TfR1 (ch128.1/IgG3) and showed that this antibody exhibits antitumor activity in an in vivo model of AIDS-NHL using NOD-SCID mice challenged intraperitoneally with 2F7 human Burkitt lymphoma (BL) cells that harbor the Epstein-Barr virus (EBV). We have also developed an IgG1 version of ch128.1 that shows significant antitumor activity in SCID-Beige mouse models of disseminated multiple myeloma, another B-cell malignancy. Here, we aim to explore the utility of ch128.1/IgG1 and its humanized version (hu128.1) in mouse models of AIDS-NHL. To accomplish this goal, we used the 2F7 cell line variant 2F7-BR44, which is more aggressive than the parental cell line and forms metastases in the brain of mice after systemic (intravenous) administration. We also used the human BL cell line JB, which in contrast to 2F7, is EBV-negative, allowing us to study both EBV-infected and non-infected NHL tumors. Treatment with ch128.1/IgG1 or hu128.1 of SCID-Beige mice challenged locally (subcutaneously) with 2F7-BR44 or JB cells results in significant antitumor activity against different stages of disease. Treatment of mice challenged systemically (intravenously) with either 2F7-BR44 or JB cells also showed significant antitumor activity, including long-term survival. Taken together, our results suggest that targeting TfR1 with antibodies, such as ch128.1/IgG1 or hu128.1, has potential as an effective therapy for AIDS-NHL.

In this review, we have summarized the current landscape of therapeutic antibody optimization for successful development. By engineering antibodies with display technology, computer-aided design and site mutagenesis, various properties of the therapeutic antibody candidates can be improved with the purpose of enhancing their safety, efficacy and developability. These properties include antigen binding affinity and specificity, biological efficacy, pharmacokinetics and pharmacodynamics, immunogenicity and physicochemical developability features. A best-in-class strategy may require the optimization of all these properties to generate a good therapeutic antibody.

BACKGROUND Faced with limited and inadequate treatment options for patients with advanced gastric cancer or gastroesophageal junction cancer (GC/GEJC), researchers have turned toward, with the support of promising clinical trials, anti-PD-1/anti-PD-L1 antibody therapy. But there are also different clinical trial results. To better assess its efficacy and safety, we integrated data from 13 eligible studies for a systematic review and meta-analysis. AIM To comprehensively evaluate the efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in the treatment of advanced GC/GEJC patients. METHODS PubMed, Web of Science, Cochrane Library ,and EMBASE databases were searched to identify eligible articles with outcomes including objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) of anti-PD-1/anti-PD-L1 antibody therapy. RESULTS Our study encompassed a total of 13 trials totaling 1618 patients. The outcomes showed a pooled ORR and DCR of 15% (95% confidence interval [CI]: 14%-18%) and 40% (95%CI: 33%-46%), respectively. The pooled 6-mo OS and PFS were 54% (95%CI: 45%-64%) and 26% (95%CI: 20%-32%), respectively, and the 12-mo OS and PFS were 42% (95%CI: 21%-62%) and 11% (95%CI: 8%-13%), respectively. In addition, the incidence of any-grade AEs and grade ≥ 3 AEs was 64% (95%CI: 54%-73%) and 18% (95%CI: 16%-20%), respectively. Most importantly, PD-L1 positive patients exhibited a higher ORR rate than PD-L1 negative patients (odds ratio = 2.54, 95%CI: 1.56-4.15). CONCLUSION Anti-PD-1/anti-PD-L1 antibody therapy has shown promising anti-tumor efficacy with manageable AEs in advanced GC/GEJC patients, with PD-L1 overexpressing patients exhibiting a higher ORR. What is more, the clinical efficacy of anti-PD-1/PD-L1 combined with traditional chemotherapy drugs is even better, although the occurrence of AEs still causes considerate concerns.

Contains fulltext : 229558.pdf (Publisher’s version ) (Closed access) Malaria eradication is a global priority but requires innovative strategies. Humoral immune responses attack different parasite stages, and antibody-based therapy may prevent malaria infection or transmission. Here, we discuss targets of monoclonal antibodies in mosquito sexual stages of Plasmodium.

Highlights • There are totally five kinds of traditional mechanisms of antibody-dependent enhancement. Mostly, the effect is reported to related with FcγR. • Antibody-dependent enhancement has been discovered in both SARS-CoV and MERS-CoV but the mechanism wasn’t thoroughly clear. Different researches may provide different opinions. • Many scientist have mentioned the potential existence of antibody-dependent enhancement in the 2019 novel coronavirus. • Latest study of both convalescent plasma transmission and application of inactivated vaccine haven’t report case of antibody-dependent enhancement., Antibody-dependent enhancement (ADE) exists in several kinds of virus. It has a negative influence on antibody therapy for viral infection. This effect was first identified in dengue virus and then was also described for coronavirus. The rapid spread of the newly emerged 2019 novel coronavirus (COVID-19) has sickened over 3.8 million people across the globe up to now. The novel coronavirus causes great challenge and arouses a wave of panic. In this review, antibody-dependent enhancements in dengue virus and two kinds of coronavirus are summarized. Solutions for the effects are mentioned, too. We also speculate that antibody-dependent enhancement may exist in COVID-19.

Hepatocellular carcinoma is a highly prevalent and lethal cancer that many therapeutics are being tested for this disease. It has the potential to be a highly immune-responsive tumor given its inflammatory origins. The first immunotherapies were anti-programmed death-1 monotherapies, which improved response rates and survival. Novel immunotherapy combinations and immunotherapy show promise in frontline treatment. The novel antibody therapy combination of atezolizumab and bevacizumab may be practice changing. Although these landmark studies seem to offer new treatment options, the role of immunotherapy in the liver transplant setting is uncertain until the safety of this approach is defined.

Since the introduction of proteasome inhibitors, immunomodulators, and monoclonal antibodies, the longevity of a patient with multiple myeloma has greatly improved. Although prognosis is improving, multiple myeloma remains an incurable disease and most patients will inevitably relapse. With new studies and prospective trials being published every few months, the landscape of multiple myeloma treatment is changing and sequencing treatments remains complex. In this review, we discuss the current data and approaches to treating a patient with relapsed/refractory multiple myeloma.

COVID-19 presents varied clinical features, ranging from asymptomatic, mild, to acute respiratory distress syndrome (ARDS). People of any age can be infected by the novel coronavirus but some people are at more risk than others of becoming seriously ill with COVID-19. Older people, and people with pre-existing medical conditions (such as asthma, diabetes, and heart disease) appear to be more vulnerable developing severe or even lethal illness. Children can be infected with SARS-CoV-2, and become ill with COVID-19. However, they appear to be less susceptible to infection than adults and their symptoms are generally milder. Immunoglobulin D (IgD) has remained an enigmatic antibody class since its discovery more than 50 years ago. The function of secreted IgD has been a longstanding puzzle in immunology. In this pandemic, it is the proper time to rediscover its role and find additional therapy to vaccine. In this article I will review IgD discovery, its role in immunity, its concentration in some groups and their susceptibility to infection with COVID 19.

Evidence-based treatment options for neuromyelitis optica spectrum disorders (NMOSD) patients are beginning to enter the market. Where previously, there was only the exclusive use of empiric and off-label immunosuppressants in this rare and devastating central nervous system autoimmune disease.In accordance to expanding pathogenetic insights, drugs in phase II and III clinical trials are presented in the context of the current treatment situation for acute attacks and immunopreventative strategies in NMOSD. Some such drugs are the 2019-approved complement inhibitor eculizumab, other compounds in late development include its modified successor ravulizumab, IL-6 receptor antibody satralizumab, CD19 targeting antibody inebilizumab and the TACI-Fc fusion protein telitacicept.Moving from broad immunosuppression to tailored treatment strategies, the prospects for efficient NMOSD therapy are positive. For the first time in this disease, class I treatment evidence is available, but long-term data will be necessary to confirm the overall promising study results of the compounds close to approval. While drug development still centers around AQP4 antibody seropositive patients, current and future research requires consideration of possible diverging treatment demands for the smaller group of seronegative patients and patients with presence of MOG antibodies.

TNB-383B is a fully human BCMA-targeting T-cell engaging bispecific monoclonal antibody (T-BsAb). We assessed ex vivo efficacy of this drug to mediate killing of bone marrow mononuclear cells (BMMCs) freshly isolated from 10 patients with relapsed multiple myeloma (MM). BMMC were treated ex vivo with TNB-383B at doses ranging from 0.001-1 μg. Plasma cell (PC) lysis, viability, BCMA expression, CTL distribution, and degranulation were assessed by flow cytometry. Cytokine response to TNB-383B was quantified by multiplex protein assay. Dose-dependent PC lysis was triggered in all cases by TNB-383B at doses as low as 0.001 μg (

Summary Introduction So far, anti-PD-1/anti-PD-L1 antibody therapy is reportedly in treating gastric cancer or gastro-oesophageal junction cancer (GC/GEJC) in a number of clinical trials. Based on this, we conducted current meta-analysis to assess the safety and efficacy of anti-PD-1/anti-PD-L1 antibody for previously treated advanced GC/GEJC patients. Methods We searched five electronic databases for eligible records. Outcomes were presented and analyzed by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse effects (AEs). Results Nine records involving 1388 participants were selected in our study. The pooled ORR, DCR, OS rate (6 month), PFS rate (6 month), OS rate (12 month) and PFS rate (12 month) were 10% (95% confidence interval [CI]: 6%–14%), 32% (95%CI: 25%–38%), 52% (95%CI: 44%–61%), 18% (95%CI: 13%–24%), 40% (95%CI: 31%–48%) and 8% (95%CI: 5%–10%), respectively. Meanwhile, grade ≥ 3 AEs rate was 12% (95% CI: 10%-15%). Programmed death ligand 1 (PD-L1) positive cases had higher rate of ORR (odds ratio [OR]: 3.75, 95%CI: 2.09–6.74, P = 0.58) compared with negative cases. Conclusion The results indicated that anti-PD-1/anti-PD-L1 antibody therapy has an effectual anti-tumor activity and controllable AEs in advanced GC/GEJC patients. Furthermore, overexpression of PD-L1 in advanced GC/GEJC patients had better ORR from anti-PD-1/anti-PD-L1 antibody therapy (PROSPERO registration number: CRD42018116480).

In solid tumors, the limited diffusion of therapeutic molecules in the perivascular space is a known limitation impacting treatment efficacy. Ultrasound Targeted Microbubble Cavitation (UTMC) has been shown to increase vascular permeability and improve the delivery of therapeutic compounds including small molecules, antibodies (mAb), nanoparticles and even cells, notably across the blood-brain-barrier (BBB). In this study, we hypothesized that UTMC could improve the accumulation and biodistribution of mAb targeting the adenosinergic pathway (i.e. CD73) in mice bearing bilateral subcutaneous 4T1 mammary carcinoma. METHODS: A bolus of fluorescently labeled mAb was given intravenously, followed by a slow infusion of microbubbles. UTMC therapy (1 MHz, 850 kPa) was given under ultrasound image guidance for 5 minutes to the right side tumor only, using three different pulse lengths with identical ultrasound energy (5000cyc “long”, 125x40cyc “mid” and 500x10cyc “short”), and leaving the left tumor as a paired control. Longitudinal accumulation at 0 h, 4 h and 24 h was measured using whole-body biofluorescence and confocal microscopy. RESULTS: Our data support an increase in antibody accumulation and extravasation (# extravasated vessels and extravasated signal intensity) at 0 h for all pulses and at 4 h for the mid and short pulses when compared to the control non treated side. However, this difference was not found at 24 h post UTMC, indicative of the transient nature of UTMC. Interestingly, confocal data supported that the highest extravasation range was obtained at 0 h with the long pulse and that the short pulse caused no increase in the extravasation range. Overall, the mid pulse was the only pulse to increase all our metrics (biofluorescence, fraction of extravasated vessels, amount of extravasated Ab, and extravasation range) at 0 h and 4 h time points. CONCLUSIONS: Our results support that UTMC can enhance antibody accumulation in solid tumors at the macroscopic and microscopic levels. This preferential accumulation was evident at early time points (0 h and 4 h) but had started to fade by 24 h, a time dependence that is consistent with the ultrasound blood brain barrier opening literature. Further development and optimization of this theranostic platform, such as repeated UTMC, could help improve antibody based therapies against solid cancer.

Endothelin receptor A (ETA), a class A G-protein-coupled receptor (GPCR), is involved in the progression and metastasis of colorectal, breast, lung, ovarian, and prostate cancer. We overexpressed and purified human endothelin receptor type A in Escherichia coli and reconstituted it with lipid and membrane scaffold proteins to prepare an ETA nanodisc as a functional antigen with a structure similar to that of native GPCR. By screening a human naive immune single-chain variable fragment phage library constructed in-house, we successfully isolated a human anti-ETA antibody (AG8) exhibiting high specificity for ETA in the β-arrestin Tango assay and effective inhibitory activity against the ET-1-induced signaling cascade via ETA using either a CHO-K1 cell line stably expressing human ETA or HT-29 colorectal cancer cells, in which AG8 exhibited IC50 values of 56 and 51 nM, respectively. In addition, AG8 treatment repressed the transcription of inhibin βA and reduced the ETA-induced phosphorylation of protein kinase B and extracellular regulated kinase. Furthermore, tumor growth was effectively inhibited by AG8 in a colorectal cancer mouse xenograft model. The human anti-ETA antibody isolated in this study could be used as a potential therapeutic for cancers, including colorectal cancer., Cancer: Human antibody shows therapeutic potential A therapeutic antibody that targets a receptor involved in cancer progression shows significant anti-cancer effects in trials in mice. Endothelin receptor A (ETA) promotes the progression and metastasis of several cancers, and patients with high ETA expression often have poor survival rates. Several small molecule drugs that target ETA are currently undergoing trials. Now, Sang Taek Jung at the Korea University in Seoul, together with scientists across South Korea, have identified and isolated a human antibody that specifically binds to ETA. The team developed an antigen that mimics ETA, and identified and isolated the antibody it bound to. The antibody exhibited potent anti-tumor effects in cell cultures and trials in mice. Such therapeutic antibodies show higher affinity for their targets than other drugs, resulting in fewer side effects and higher efficacy.

Background：Breast cancer is the most common female cancer in the world. Many scholars have devoted themselves to elucidating the pathogenesis of Breast cancer. In the past, dCTP pyrophosphatase 1 (DCTPP1) was thought to be overexpressed in several cancers. However, The mechanism by which DCTPP1 is regulated by non-coding RNA in Breast cancer and its relationship with immune infiltration have not been elucidated.Results：In this study, reliable databases from the Cancer Genome Atlas (TCGA) and Gene Expression Integration (GEO) showed that the expression of DCTPP1 in Breast cancer tissues was higher than in normal tissues. Bioinformatics analysis showed that DCTPP1 was negatively correlated with the expression of hsa-miR-125b-5p in BRCA,The expression of LncRNA LGALS8-AS1 is positively correlated with the expression of DCTPP1, and negatively correlated with the expression of hsa-miR-125b-5p. Therefore, we speculate that lncRNA LGALS8-AS1 promotes tumor progression through sponge hsa-miR-125b-5p and maintains the overexpression of DCTPP1 in Breast cancer. The survival analysis of 3 genes showed that the overexpression of DCTPP1 and LGALS8-AS1 is related to the poor prognosis of patients. By analyzing the relationship between DCTPP1 and immune infiltration, we found that the high copy of DCTPP1 is related to the infiltration of CD8+ T cells, and the high expression of DCTPP1 is related to the infiltration of CD4+ T cells in basal-like Breast cancer. DCTPP1 is positively correlated with the expression of immune checkpoint B7-H3.Conclusion: LNC LGALS8-AS1 can upregulate DCTPP1 by sponging with hsa-miR-125b-5p. DCTPP1 can be used as a new prognostic marker for B7-H3 antibody treatment of breast cancer.

Background Cancer is the leading cause of death in the geriatric dog population. Currently, the use of immune checkpoint inhibitors (ICIs) such as anti-CTLA4 antibodies has markedly improved the prognosis of several cancers in their advanced stages. However, ICIs targeting CTLA4 blockade to treat canine cancer patients are yet to define. In this study, we sought to develop, characterize and assess whether chimeric heavy chain only antibodies (cHcAbs) against CTLA4 are viable therapeutic candidates for the treatment of canine cancers.Methods Anti-CTLA4 nanobodies (Nbs) were identified from a yeast nanobody (Nb) library using magnetic-assisted cell sorting (MACS) and flow cytometry. cHcAbs were engineered by genetically fusing the DNA sequences coding for anti-CTLA4 Nbs with the Fc domain of the subclass B of canine IgG. Recombinant cHcAbs were purified from ExpiCHO-S cells. Stable cell lines expressing canine CTLA4 and FcγRI were used to elucidate the binding ability and specificity of cHcAbs. PBMCs isolated from healthy dogs were used to evaluate the ability of cHcAbs to activate canine PBMCs.Results Novel Nbs were identified using the extracellular domain of canine CTLA4 protein to screen a fully synthetic yeast nanobody library. Purified Nbs bind specifically to natïve canine CTLA4. We report that chimeric HcAbs, which were engineered by fusing the anti-CTLA4 Nbs and Fc region of subclass B of canine IgG, were half the size of a conventional mAb and formed dimers. The chimeric HcAbs specifically binds both with canine CTLA4 and FcƳ receptors. As the binding of Nbs overlapped with the MYPPPY motif of canine CTLA4, these Nbs were expected to sterically disrupt the interaction of canine CTLA4 to B-7s. Like their human counterpart, canine CTLA4 was expressed on helper T cells and a small subset of cytotoxic T cells. Canine Tregs also constitutively expressed CTLA4, and stimulation with PMA/Ionomycin dramatically increased expression of CTLA4 on the cell surface. Stimulation of canine PBMCs in the presence of agonistic anti-CD3 Ab and cHcAb6 significantly increased the expression of IFN-γ as compared to the isotype control.Conclusions This study identifies a novel nanobody-based CTLA4 inhibitor for the treatment of canine cancer patients. Furthermore, this approach provides a critical proof-of-concept for developing nanobody-based humanized anti-CTLA4 therapy for advanced stages of cancers.

Anti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn’s disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, humanised and engineered for intestinal protease resistance, V900, was combined with a previously-described TNFα-specific domain antibody, V565. V56B2 contains a central protease-labile linker to create a single molecule for oral administration. Incubation of V56B2 with trypsin or human faecal supernatant resulted in a complete separation of the V565 and V900 monomers without loss of neutralising potency. Following oral administration of V900 and V565 in mice, high levels of each domain antibody were detected in the faeces, demonstrating stability in the intestinal milieu. In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies.

Multiple myeloma is the second most common hematological malignancy in adults, accounting for 2% of all cancer-related deaths in the UK. Current chemotherapy-based regimes are insufficient, as most patients relapse and develop therapy resistance. This review focuses on current novel antibody- and aptamer-based therapies aiming to overcome current therapy limitations, as well as their respective limitations and areas of improvement. The use of computer modeling methods, as a tool to study and improve ligand-receptor alignments for the use of novel therapy development will also be discussed, as it has become a rapid, reliable and comparatively inexpensive method of investigation.

Targeting the immunological checkpoint PD-1/PD-L1 with antibodies has shown opportunities to improve cancer treatment in recent years. However, antibody therapy is a double-edged sword with high cost, low patient tolerance, lack of oral bioavailability, and a reaction to most solid tumors that prevents the adoption of antibodies. Advancement of small-molecule PD-1/PD-L1 inhibitors that could overwhelm these drawbacks is sluggish because of the poor pharmacodynamic properties and shallow pocket of the PD-1/PD-L1 binding interface. Recently, a number of compounds have been discovered to bind the PD-L1/PD-L1 dimer interface, providing an excellent alternative to inhibit the interaction between PD-1/PD-L1 and small molecules. Quantitative characterization of PD-L1 interactions with these inhibitors will advance the design of novel and efficient inhibitors in the future. Here, the binding free energies of 35 PD-L1 dimer inhibitors have been calculated using the alanine-scanning-interaction-entropy (AS-IE) method. Hotspot residues on PD-L1 and potential modification groups on the inhibitors were identified. The experimental results for the AS-IE method were better correlated than the classical MM/GBSA method. These results may set the stage for the design the more powerful PD-L1 inhibitors.Communicated by Ramaswamy H. Sarma.

Optimisation of protein binders relies on laborious screening processes. Investigation of sequence–function relationships of protein binders is particularly slow, since mutants are purified and evaluated individually. Here we developed peptide barcoding, a high-throughput approach for accurate investigation of sequence–function relationships of hundreds of protein binders at once. Our approach is based on combining the generation of a mutagenised nanobody library fused with unique peptide barcodes, the formation of nanobody–antigen complexes at different ratios, their fine fractionation by size-exclusion chromatography and quantification of peptide barcodes by targeted proteomics. Applying peptide barcoding to an anti-GFP nanobody as a model, we successfully identified residues important for the binding affinity of anti-GFP nanobody at once. Peptide barcoding discriminated subtle changes in KD at the order of nM to sub-nM. Therefore, peptide barcoding is a powerful tool for engineering protein binders, enabling reliable one-pot evaluation of sequence–function relationships., 遊離型抗体の構造活性相関解析を迅速に評価可能とする新手法を開発. 京都大学プレスリリース. 2021-11-08.

The successive emergences and accelerating spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and evolved resistance to some ongoing clinical therapeutics increase the risks associated with the coronavirus disease 2019 (COVID-19) pandemic. An urgent intervention for broadly effective therapies to limit the morbidity and mortality of COVID-19 and future transmission events from SARS-related coronaviruses (SARSr-CoVs) is needed. Here, we isolate and humanize an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody (MAb), named h11B11, which exhibits potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages. When administered therapeutically or prophylactically in the hACE2 mouse model, h11B11 alleviates and prevents SARS-CoV-2 replication and virus-induced pathological syndromes. No significant changes in blood pressure and hematology chemistry toxicology were observed after injections of multiple high dosages of h11B11 in cynomolgus monkeys. Analysis of the structures of the h11B11/ACE2 and receptor-binding domain (RBD)/ACE2 complexes shows hindrance and epitope competition of the MAb and RBD for the receptor. Together, these results suggest h11B11 as a potential therapeutic countermeasure against SARS-CoV, SARS-CoV-2, and escape variants., Here the authors report the isolation and structural and biological characterization of a humanized angiotensin-converting enzyme 2 (ACE2)-blocking antibody, which exterts potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages both in vitro and in hACE2 mouse model.

Outcomes in chronic lymphocytic leukemia (CLL) have been dramatically improved with the addition of anti-CD20 antibodies to chemotherapy, defining a new standard of care for many years. More recently, therapies targeting fundamental signaling and anti-apoptotic pathways within the CLL cell have demonstrated dramatic clinical responses, including in patients with high-risk prognostic markers, thus emerging as preferred therapy for many patients. While the addition of anti-CD20 antibodies to traditional chemotherapy resulted in significant improvements in outcomes, the role of monoclonal antibodies in the era of targeted agents remains an active area of investigation. Furthermore, since the advent of next-generation anti-CD20 antibodies, the role of specific anti-CD20 antibodies remains an open question.In this review, we highlight the important role that anti-CD20 antibody therapy has had in the field of CLL, both when used with chemotherapy and in combination with targeted therapy, as well as the current studies that are further exploring this treatment paradigm in the modern era.While anti-CD20 antibodies have played a pivotal role in the treatment of CLL, additional studies will be required to determine the optimal application of these therapies in combination with targeted therapy.

For anterior gradient 2 (AGR2), normal cells express the intracellular form iAGR2 localized to the endoplasmic reticulum while cancer cells express the extracellular form eAGR2 localized on the cell surface and secreted. Antibodies targeting eAGR2+ cancer cells for eradication will spare normal cells. Two AGR2 monoclonal antibodies, P1G4 and P3A5, were shown to recognize specifically eAGR2+ pancreatic tumors implanted in mice. In addition, P1G4 showed enhancement in drug inhibition of tumor growth. Human:mouse chimeric antibodies of IgG1, IgG2, IgG4 were generated for both antibodies. These human IgG were shown to lyse eAGR2+ prostate cancer cells in vitro with human serum. AGR2 has an important function in distal spread of cancer cells, and is highly expressed in prostate, pancreatic, bladder metastases. Therefore, immunotherapy based on AGR2 antibody-mediated ADCC and CDC is highly promising. Cancer specificity of eAGR2 predicts possibly minimal collateral damage to healthy tissues and organs. Moreover, AGR2 therapy, once fully developed and approved, can be used to treat other solid tumors since AGR2 is an adenocarcinoma antigen found in many common malignancies.

SARS-CoV-2 causes severe acute respiratory syndrome, which has led to significant morbidity and mortality around the world. Since its emergence, extensive prophylactic and therapeutic countermeasures have been employed to successfully prevent the spread of COVID-19. Extensive work has been undertaken on using monoclonal antibody therapies, mass vaccination programs, and antiviral drugs to prevent and treat COVID-19. However, since antiviral drugs could take years to become widely available, immunotherapy and vaccines currently appear to be the most feasible option. In December 2020, the first vaccine against SARS-CoV-2 was approved by the World Health Organization (WHO) and, subsequently, many other vaccines were approved for use by different international regulators in different countries. Most monoclonal antibodies (mAbs) and vaccines target the SARS-CoV-2 surface spike (S) protein. Recently, mutant (or variant) SARS-CoV-2 strains with increased infectivity and virulence that evade protective host antibodies present either due to infection, antibody therapy, or vaccine administration have emerged. In this manuscript, we discuss the different monoclonal antibody and vaccine therapies available against COVID-19 and how the efficacy of these therapies is affected by the emergence of variants of SARS-CoV-2. We also discuss strategies that might help society cope with variants that could neutralize the effects of immunotherapy and escape the protective immunity conferred by vaccines.

Significance This study demonstrates the efficacy of combining macrophage-checkpoint inhibition with tumor-specific antibodies for cancer immunotherapy. The combination of anti-CD47 (magrolimab) and anti-HER2 (trastuzumab) antibodies eliminated HER2+ breast cancer cells with increased efficacy due to the enhancement of antibody-dependent cellular phagocytosis by macrophages, even when the cancer cells were tolerant to trastuzumab-induced antibody-dependent cellular cytotoxicity by natural killer cells. We believe these findings present a promising therapeutic approach for treating HER2+ breast cancer patients whose tumors are either sensitive or resistant to trastuzumab treatment, as long as the cells harbor the HER2 trastuzumab-binding epitope. This study supports the notion that combining CD47 blockade with existing macrophage FcR-engaging tumor-specific antibodies may be an effective approach for treating a wide range of cancers., Trastuzumab, a targeted anti-human epidermal-growth-factor receptor-2 (HER2) monoclonal antibody, represents a mainstay in the treatment of HER2-positive (HER2+) breast cancer. Although trastuzumab treatment is highly efficacious for early-stage HER2+ breast cancer, the majority of advanced-stage HER2+ breast cancer patients who initially respond to trastuzumab acquire resistance to treatment and relapse, despite persistence of HER2 gene amplification/overexpression. Here, we sought to leverage HER2 overexpression to engage antibody-dependent cellular phagocytosis (ADCP) through a combination of trastuzumab and anti-CD47 macrophage checkpoint immunotherapy. We have previously shown that blockade of CD47, a surface protein expressed by many malignancies (including HER2+ breast cancer), is an effective anticancer therapy. CD47 functions as a “don’t eat me” signal through its interaction with signal regulatory protein-α (SIRPα) on macrophages to inhibit phagocytosis. Hu5F9-G4 (magrolimab), a humanized monoclonal antibody against CD47, blocks CD47’s “don’t eat me” signal, thereby facilitating macrophage-mediated phagocytosis. Preclinical studies have shown that combining Hu5F9-G4 with tumor-targeting antibodies, such as rituximab, further enhances Hu5F9-G4’s anticancer effects via ADCP. Clinical trials have additionally demonstrated that Hu5F9-G4, in combination with rituximab, produced objective responses in patients whose diffuse large B cell lymphomas had developed resistance to rituximab and chemotherapy. These studies led us to hypothesize that combining Hu5F9-G4 with trastuzumab would produce an anticancer effect in antibody-dependent cellular cytotoxicity (ADCC)-tolerant HER2+ breast cancer. This combination significantly suppressed the growth of ADCC-tolerant HER2+ breast cancers via Fc-dependent ADCP. Our study demonstrates that combining trastuzumab and Hu5F9-G4 represents a potential new treatment option for HER2+ breast cancer patients, even for patients whose tumors have progressed after trastuzumab.

The Wnt signaling pathway is intricately connected with bone mass regulation in humans and rodent models. We designed an antibody-based platform that generates potent and selective Wnt mimetics. Using this platform, we engineer bi-specific Wnt mimetics that target Frizzled and low-density lipoprotein receptor-related proteins and evaluate their effects on bone accrual in murine models. These synthetic Wnt agonists induce rapid and robust bone building effects, and correct bone mass deficiency and bone defects in various disease models, including osteoporosis, aging, and long bone fracture. Furthermore, when these Wnt agonists are combined with antiresorptive bisphosphonates or anti-sclerostin antibody therapies, additional bone accrual/maintenance effects are observed compared to monotherapy, which could benefit individuals with severe and/or acute bone-building deficiencies. Our data support the continued development of Wnt mimetics for the treatment of diseases of low bone mineral density, including osteoporosis., Antibody-based Wnt agonists are able to phenocopy Wnt signaling in vivo resulting in increased bone density, repair, and strength. Here, the authors show that Wnt agonists can reverse bone loss associated with ovariectomy and build stronger bone when administered after fracture.

Monoclonal antibodies (mAbs) are emerging as safe and effective therapeutics against SARS-CoV-2. However, variant strains of SARS-CoV-2 have evolved, with early studies showing that some mAbs may not sustain their efficacy in the face of escape mutants. Also, from the onset of the COVID-19 pandemic, concern has been raised about the potential for Fcγ receptor-mediated antibody-dependent enhancement (ADE) of infection. In this study, plaque reduction neutralization assays demonstrated that mAb 1741-LALA neutralizes SARS-CoV-2 strains B.1.351, D614 and D614G. MAbs S1D2-hIgG1 and S1D2-LALA mutant (STI-1499-LALA) did not neutralize B.1.351, but did neutralize SARS-CoV-2 strains D614 and D614G. LALA mutations did not result in substantial differences in neutralizing abilities between clones S1D2-hIgG1 vs STI-1499-LALA. S1D2-hIgG1, STI-1499-LALA, and convalescent plasma showed minimal ability to induce ADE in human blood monocyte-derived macrophages. Further, no differences in pharmacokinetic clearance of S1D2-hIgG1 vs STI-1499-LALA were observed in mice expressing human FcRn. These findings confirm that SARS-CoV-2 has already escaped some mAbs, and identify a mAb candidate that may neutralize multiple SARS-CoV-2 variants. They also suggest that risk of ADE in macrophages may be low with SARS-CoV-2 D614, and LALA Fc change impacts neither viral neutralization nor Ab clearance.

Activation of the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor by angiopoietin-1 (Ang1) is critical for vascular stabilization: it promotes survival signal transduction via auto-phosphorylation and reduces vascular permeability by strengthening tight junctions between endothelial cells. Thus, Tie2/Ang1 signaling is a promising therapeutic target for vascular diseases. However, in vivo use of existing Tie2 signaling modulators, such as recombinant Ang1, is restricted by limitations in manufacturability and stability. Here, we present a novel engineered tetra-valent agonistic antibody, ASP4021, which can specifically and fully activate the Tie2 receptor in an equivalent manner to Ang1. ASP4021 induced Tie2 self-phosphorylation and inhibited apoptosis in a human primary endothelial cell line. Additionally, single administration of ASP4021 significantly suppressed mustard-oil-induced vascular permeability in rats. ASP4021 may thus be a potential therapeutic candidate for diseases associated with vascular weakness such as diabetic retinopathy, diabetic macular edema and critical limb ischemia.

Donanemab, an antibody directed toward an N-terminal pyroglutamate Aβ epitope, was recently tested in a phase 2 trial of early symptomatic Alzheimer's disease patients (n=257) treated for 76 weeks [1]. The antibody therapy reduced plaque load by 80%. This accompanied a significant (P=0.04) delay in decline (~6 month) in the integrated Alzheimer's Disease Rating Scale (iADRS) scale, but not 4 other cognitive/functional scales. However, donanemab treated patients had accelerated brain volume loss (~5ml) as assessed by MRI.

The use of antibodies in the treatment of lung diseases is of increasing interest especially as the search for COVID-19 therapies has unfolded. Historically, the use of antibody therapy was based on multiple targets including receptors involved in local hyper-reactivity in asthma, viruses and micro-organisms involved in a variety of pulmonary infectious disease. Generally, protein therapeutics pose challenges with respect to formulation and delivery to retain activity and assure therapy. The specificity of antibodies amplifies the need for attention to molecular integrity not only in formulation but also during aerosol delivery for pulmonary administration. Drug product development can be viewed from considerations of route of administration, dosage form, quality, and performance measures. Nebulizers and dry powder inhalers have been used to deliver protein therapeutics and each has its advantages that should be matched to the needs of the drug and the disease. This review offers insight into quality and performance barriers and the opportunities that arise from meeting them effectively.

The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset (NCT04348656). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm—relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94–1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02–1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57–0.95 and OR = 0.66, 95% CI 0.50–0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14–2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care., A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

The epidemiological impact of viral diseases, combined with the emergence and reemergence of some viruses, and the difficulties in identifying effective therapies, have encouraged several studies to develop new therapeutic strategies for viral infections. In this context, the use of immunotherapy for the treatment of viral diseases is increasing. One of the strategies of immunotherapy is the use of antibodies, particularly the monoclonal antibodies (mAbs) and multi-specific antibodies, which bind directly to the viral antigen and bring about activation of the immune system. With current advancements in science and technology, several such antibodies are being tested, and some are already approved and are undergoing clinical trials. The present work aims to review the status of mAb development for the treatment of viral diseases.

Background/aim Amphiregulin (AREG) and epiregulin (EREG) mRNA expression levels are predictors of response to anti-EGFR antibody therapy. Left-sided colon cancer is more sensitive to anti-EGFR antibodies than right-sided, although the mechanism is unclear. The aim of this study was to determine the relationship between AREG, EREG mRNA expression levels and tumor location as well as the efficacy of anti-EGFR antibody agents. Materials and methods Real-time PCR was used to assess AREG and EREG mRNA expression in metastatic colorectal cancer (CRC) samples from 153 patients. Results Among KRASwt samples, high AREG expression (AREGHigh) was significantly more common in left-sided tumors than in right-sided. Among patients who received anti-EGFR antibody, response rates were significantly higher in AREGHigh than in AREGLow In the left-sided tumor group, overall survival was significantly longer in patients with high EREG levels than with low levels, whereas the right-sided tumor group showed no survival difference between them. Conclusion AREG and EREG mRNA expression levels in left-sided CRC were higher than in right-sided tumors. This may help explain why left-sided CRC is more responsive to anti-EGFR antibodies.

Asthma is characterized by airway hyperresponsiveness and inflammation, as well as underlying structural changes to the airways. Interleukin-4 (IL-4) is a key T-helper type 2 (Th2) cytokine that plays important roles in the pathogenesis of atopic and eosinophilic asthma. We developed a novel humanized anti-IL-4Rα antibody that can potently inhibit IL-4/IL-13-mediated TF-1 cell proliferation. Using monocytes isolated from human peripheral blood mononuclear cells (PBMCs), we revealed a critical role of CD32 in modulating the immune responses of monocytes in response to blockade of IL-4Rα signaling pathway. We, therefore, devised a new strategy to increase the efficacy of the anti-IL-4Rα monoclonal antibody for the treatment of asthma and other atopic diseases by co-engaging CD32 and IL-4Rα on monocytic cells by choosing IgG classes or Fc mutations with higher affinities for CD32. The antibody with selectively enhanced affinity for CD32A displayed superior suppression of IL-4-induced monocytes’ activities, including the down-regulation of CD23 expression. Intriguingly, further analysis demonstrated that both CD32A and CD32B contributed to the enhancement of antibody-mediated suppression of CD23 expression from monocytes in response to blockade of IL-4Rα signaling. Furthermore, inhibition of IgE secretion from human PBMC by the antibody variants further suggests that the complex allergic inflammation mediated by IL-4/IL-4Rα signaling might result from a global network where multiple cell types that express multiple FcγRs are all involved, of which CD32, especially CD32A, is a key mediator. In this respect, our study provides new insights into designing therapeutic antibodies for targeting Th2 cytokine-mediated allergic pathogenesis.

First attempts to use exogenous mRNA for protein expression in vivo were made more than 25 years ago. However, widespread appreciation of in vitro transcribed mRNA as a powerful technology for supplying therapeutic proteins to the body has evolved only during the past few years. Various approaches to turning mRNA into a potent therapeutic have been developed. All of them share utilization of specifically designed, rather than endogenous, sequences and thorough purification protocols. Apart from this, there are two fundamental philosophies, one promoting the use of chemically modified nucleotides, the other advocating restriction to unmodified building blocks. Meanwhile, both strategies have received broad support by successful mRNA-based protein treatments in animal models. For such in vivo use, specifically optimized mRNA had to be combined with potent formulations to enable efficient in vivo delivery. The present review analyzes the applicability of mRNA technology to antibody therapy in all main fields: antitoxins, infectious diseases, and oncology.

As more antibiotics are rendered ineffective by drug-resistant bacteria, focus must be shifted towards alternative therapies for treating infections. Although several alternatives already exist in nature, the challenge is to implement them in clinical use. Advancements within biotechnology, genetic engineering, and synthetic chemistry have opened up new avenues towards the search for therapies that can substitute for antibiotics. This review provides an introduction to the various promising approaches that have been adopted in this regard. Whilst the use of bacteriophages and antibodies has been partly implemented, other promising strategies, such as probiotics, lysins, and antimicrobial peptides, are in various stages of development. Propitious concepts such as genetically modified phages, antibacterial oligonucleotides, and CRISPR-Cas9 are also discussed.