Monoclonal Antibody-based Treatment Research Articles

Targeting TAG-72 in cutaneous T cell lymphoma

PurposeCurrent monoclonal antibody-based treatment approaches for cutaneous T cell lymphoma (CTCL) rely heavily on the ability to identify a tumor specific target that is essentially absent on normal cells. Herein, we propose tumor associated glycoprotein-72 (TAG-72) as one such target. TAG-72 is a mucin-associated, truncated O-glycan that has been identified as a chimeric antigen receptor (CAR)-T cell target in solid tumor indications. To date, TAG-72 targeting has not been considered in the setting of hematological malignancies. Experimental designCD3+ cells from patients with CTCL were analyzed for TAG-72 expression by flow cytometry. Immunohistochemistry was used to assess TAG-72 expression in CTCL patient skin lesions and a TAG-72 ELISA was employed to assess soluble TAG-72 (CA 72-4) in patient plasma. TAG-72 CAR transduction was performed on healthy donor (HD) and CTCL T cells and characterized by flow cytometry. In vitro CAR-T cell function was assessed by flow cytometry and xCELLigence® using patient peripheral blood mononuclear cells and proof-of-concept ovarian cancer cell lines. In vivo CAR-T cell function was assessed in a proof-of-concept, TAG-72+ ovarian cancer xenograft mouse model. ResultsTAG-72 expression was significantly higher on total CD3+ T cells and CD4+ subsets in CTCL donors across disease stages, compared to that of HDs. TAG-72 was also present in CTCL patient skin lesions, whereas CA 72-4 was detected at low levels in both CTCL patient and HD plasma with no differences between the two groups. In vitro cytotoxicity assays showed that anti-TAG-72 CAR-T cells significantly, and specifically reduced CD3+TAG-72+ expressing CTCL cells, compared to culture with unedited T cells (no CAR). CTCL CAR-T cells had comparable function to HD CAR-T cells in vitro and CAR-T cells derived from CTCL patients eradicated cancer cells in vivo. ConclusionThis study shows the first evidence of TAG-72 as a possible target for the treatment of CTCL.

Selinexor, Venetoclax, and Dexamethasone in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma (SELVEDge Study)

Background and Significance: Patients with multiple myeloma (MM) harboring translocation t(11;14) have been shown to benefit from the apoptosis-inducing drug venetoclax; however, the drug lacks FDA approval for the treatment of multiple myeloma thus far. Selinexor is an inhibitor of nuclear export that is FDA-approved for patients with multiple myeloma refractory to multiple lines of therapy. We recently reported that in four patients with multiple myeloma with t(11;14), the concomitant administration of venetoclax and selinexor was safe and associated with disease response (Nguyen et al. Nature Precision Oncology 2022). Moreover, the combination was synergistic in t(11;14) multiple myeloma cell lines and caused decreased levels of Cyclin D1 (which is overexpressed due to the CCND1-IGH fusion) when given in combination as compared to single agents ( Figure 1). These data suggested that the combination of venetoclax and selinexor is effective and t(11;14) may serve as a therapeutic marker for response and target for future clinical trials. We have therefore developed an investigator-initiated study of selinexor and venetoclax in patients with relapsed, refractory multiple myeloma harboring translocation t(11;14)- the SELVEDge study. Methods and Study Design:This is an investigator-initiated, Phase 2 clinical study (NCT05530421) that is being conducted at the Sylvester Comprehensive Cancer Center at the University of Miami of adult (≥18 years) patients with relapsed refractory MM (RRMM) harboring t(11;14) in which approximately 24 patients will be treated with selinexor, venetoclax, and dexamethasone (SELVEDge) to determine the primary objective of response rate (ORR). Therapy will be given in 28-day cycles. Patients will receive venetoclax orally for cycle 1 only at a dosage of 400 mg daily for the first 7 days followed by 800 mg daily for the remainder of the cycle with oral dexamethasone given weekly. From cycle 2 and beyond, patients will receive oral selinexor 80 mg weekly; venetoclax daily, and dexamethasone weekly. Using a Simon Optimal 2-stage design, in the first stage, 9 patients will be enrolled and if ≥2 clinical responses occur (≥PR), the study will continue to the second stage to enroll a total of 24 patients. Early termination for excessive toxicity has been incorporated. Patients will undergo BM biopsy prior to cycle 2 and between cycle 3-4 and/or at CR and/or PD. PET/CT imaging will be performed at the same time points as bone marrow biopsies. MM serum markers for response will be performed at baseline and the start of every cycle. Exploratory corollary research will be performed on research samples collected at clinical timepoints including BCL2/MCL1 biomarkers. The study design is shown in Figure 2. The primary objective of the study is to determine the overall response rate (ORR) of SELVEDge in t(11;14)-positive RRMM with secondary objectives of durability of response (DoR), measurable residual disease (MRD) negative remission rate, progression-free and overall survival, and safety and tolerability. For patients to be included in the study they must have documented evidence of receiving two prior lines of therapy and be refractory to, not a candidate for (ineligible), or intolerant of at least one immunomodulatory (IMiD), one proteasome inhibitor, and one anti-CD38 monoclonal antibody-based treatments. Patients with prior therapy with selinexor or another specific inhibitor of nuclear exporter (SINE) compound are excluded. Statistical Hypothesis: Historically, in patients who have RRMM and have progressed after receiving IMiD, PI, and anti-CD38 -based regimens, approved experimental agents have been associated with an ORR of ~25%. It would be desirable to demonstrate that XVenD has a substantially higher response rate with a clinically meaningful ORR of 50%. As such, the study would rule out an unacceptably low ORR of 25% (p0=0.25) in favor of an improved response rate of 50% (p1=0.50), with a one sided alpha = 0.05 (probability of accepting a poor treatment=0.05) and beta = 0.20 (probability of rejecting a good treatment=0.20). Current Status: This clinical trial is currently open to enrollment at the Sylvester Myeloma Institute, University of Miami and to date 5 patients have been thus far enrolled and treatment initiated.

Current and Emerging Role of Monoclonal Antibody-Based First-Line Treatment in Advanced Gastro-Esophageal and Gastric Cancer.

Gastric cancer is the fifth most common malignancy worldwide and one of the main causes of cancer-related death. While surgical treatment is the only curative option for early disease, many have inoperable or advanced disease at diagnosis. Treatment in this case would be a combination of chemotherapy and immunotherapy. Gastro-esophageal (GEJ) and gastric cancer (GC) genetic profiling with current molecular diagnostic techniques has significantly changed the therapeutic landscape in advanced cancers. The identification of key players in GEJ and GC survival and proliferation, such as human epidermal growth factor 2 (HER2), vascular endothelial growth factor (VEGF), and programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1), has allowed for the individualization of advanced cancer treatment and significant improvement in overall survival and progression-free survival of patients. This review comprehensively examines the current and emerging role of monoclonal antibody-based first-line treatments in advanced GEJ and GC. We explore the impact of monoclonal antibodies targeting HER2, VEGF, PD-1/PD-L1, and Claudin 18.2 (CLDN18.2) on the first-line treatment landscape by talking about key clinical trials. This review emphasizes the importance of biomarker testing for optimal treatment selection and provides practical recommendations based on ASCO guidelines.

Converting non-neutralizing SARS-CoV-2 antibodies into broad-spectrum inhibitors

Omicron and its subvariants have rendered most authorized monoclonal antibody-based treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ineffective, highlighting the need for biologics capable of overcoming SARS-CoV-2 evolution. These mostly ineffective antibodies target variable epitopes. Here we describe broad-spectrum SARS-CoV-2 inhibitors developed by tethering the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), to known non-neutralizing antibodies that target highly conserved epitopes in the viral spike protein. These inhibitors, called receptor-blocking conserved non-neutralizing antibodies (ReconnAbs), potently neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron. Neutralization potency is lost when the linker joining the binding and inhibitory ReconnAb components is severed. In addition, a bi-functional ReconnAb, made by linking ACE2 to a bi-specific antibody targeting two non-overlapping conserved epitopes, defined here, shows sub-nanomolar neutralizing activity against all VOCs, including Omicron and BA.2. Given their conserved targets and modular nature, ReconnAbs have the potential to act as broad-spectrum therapeutics against SARS-CoV-2 and other emerging pandemic diseases.

Hemagglutinin stalk-binding antibodies enhance effectiveness of neuraminidase inhibitors against influenza via Fc-dependent effector functions

SummaryThe conserved hemagglutinin stalk domain is an attractive target for broadly effective antibody-based therapeutics and next-generation universal influenza vaccines. Protection provided by hemagglutinin stalk-binding antibodies is principally mediated through activation of immune effector cells. Titers of stalk-binding antibodies are highly variable on an individual level and tend to increase with age as a result of increasing exposures to influenza virus. In our study, we show that stalk-binding antibodies cooperate with neuraminidase inhibitors to protect against influenza virus infection in an Fc-dependent manner. These data suggest that the effectiveness of neuraminidase inhibitors is likely influenced by an individual’s titers of stalk-binding antibodies and that neuraminidase inhibitors may enhance the effectiveness of future stalk-binding monoclonal antibody-based treatments.

Ixazomib, Daratumumab and Low Dose Dexamethasone in Intermediate-Fit Patients with Newly Diagnosed Multiple Myeloma (NDMM); Results of Induction Treatment of the Phase II HOVON 143 Study

Ixazomib, Daratumumab and Low Dose Dexamethasone in Intermediate-Fit Patients with Newly Diagnosed Multiple Myeloma (NDMM); Results of Induction Treatment of the Phase II HOVON 143 Study

Pan-ebolavirus protective therapy by two multifunctional human antibodies

Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here, we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies, rEBOV-515 and rEBOV-442, that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity, resisted viral escape, and possessed differing requirements for their Fc-regions for optimal invivo activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.

Immunomodulatory and cytotoxic activities of euphol

AimsThis study evaluated the effect of euphol isolated from Euphorbia umbellata (Pax) Bruyns latex on the activation of complement pathways (classical (CP), alternative (AP) and lectin (LP)), neutrophil chemotaxis, cytotoxic activity, cell morphology and death in HRT-18 and 3T3 cells lines. Main methodsCP and AP were assessed using hemolytic assays and ELISA for LP; neutrophil chemotaxis was performed using Boyden's chamber; cytotoxicity was evaluated by neutral red methodology and characteristics of cell death were assessed by cell morphology with hematological staining. Key findingsAlthough euphol increased CP activation (38% at a concentration of 976.1 μM), an inhibitory effect on AP, LP (31% and 32% reduction in the concentration of 976.1 μM) and neutrophil chemotaxis (inhibit 84% of neutrophil migration at a concentration 292.9 μM) was observed. In addiction euphol was able to induce significant cell death in a time-dependent manner, presenting an IC50 of 70.8 μM and 39.2 μM for HRT-18 and 3T3 cell lines respectively and it was also observed apoptotic characteristics as cellular rounding, chromatin condensation and blebs formation for both cell lines. SignificanceEuphol has a potential use for the treatment of complement-related inflammatory diseases due to its ability to downregulate inflammation. On the other hand, the controlled activation of CP can contribute to complement-dependent cytotoxicity in the context of monoclonal antibody-based cancer treatment.

Monoklonal Antikorlar ve Tedavide Kullanımı

Bağışıklık sistemi vücudu hastalık yapıcı patojenlere karşı koruyan temel savunma sistemidir. Bu savunma sistemi farklı mekanizmalarla etkili olmaktadır. Bağışıklık sistemi, antijen adı verilen vücudun kalıtsal yapısına yabancı olan her türlü yapıya karşı etki gösterir. Vücuda dışarıdan gelen hastalık etkenleri öncelikle doğal bariyerlerle karşılaşmaktadır. Doğal bariyerleri aşmayı başaran etkenler kemik iliği, timus, lenf bezleri ve dalak gibi özelleşmiş organlarda üretilen savunma hücreleri ile karşılaşır. İlk aşamada makrofajlar ve fagositler devreye girer daha sonraki aşamada ise B ve T lenfositleri sürece dahil olurlar. B lenfositlerinden salgılanan antikorlar bağışık sisteminin en önemli savunma mekanizmalarından birini oluşturmaktadır. Antikor moleküllerinin vücudun savunmasındaki bu önemi bilim insanlarını bu alanda çalışmaya yöneltmiştir. Bu doğrultuda 1975 yılında Georges Köhler ve Cesar Milstein, koyun alyuvarları ile immunize ettikleri farelerin B lenfositleri ile fare myeloma hücrelerini birleştirerek oluşturdukları hibrit hücreler ile yeni bir tedavi stratejisinin kapısını açmışlardır. Bu hibrit hücreler sadece istenen antijene bağlanan monoklonal antikor sentezleyebilme yeteneğine sahiptir. Monoklonal antikorlar tıp dünyasında hastalıkların teşhisi, tedavisi ve biyokimyasal analizler gibi birçok alanda kullanmaktadır. Günümüzde hala monoklonal antikora dayalı tedavi ve tedavi seçenekleri üzerinde çalışmalar devam etmektedir. Bu derlemede monoklonal antikorlar ve tedavide kullanımı üzerine genel bilgiler verilecektir.

A Review of Monoclonal Antibody-Based Treatments in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer worldwide. It metastasizes rapidly and has a poor prognosis. The first-line treatment for most patients is a combination of chemotherapy and radiation. In many subjects, using targeted treatments alongside chemoradiation has shown a better outcome in terms of progression and quality of life for patients. These targeted treatments include small biological inhibiting molecules and monoclonal antibodies. In this review, we have assessed studies focused upon the treatment of non-small cell lung cancer. Some therapies are approved, such as bevacizumab and atezolizumab, while some are still in clinical trials, such as ficlatuzumab and ipilimumab, and others have been rejected due to inadequate disease control, such as figitumumab.

Monoclonal Antibody-Based Therapies for Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune, neuromuscular disorder that produces disabling weakness through a compromise of neuromuscular transmission. The disease fulfills strict criteria of an antibody-mediated disease. Close to 90% of patients have antibodies directed towards the nicotinic acetylcholine receptor (AChR) on the post-synaptic surface of skeletal muscle and another 5% to the muscle-specific kinase, which is involved in concentrating the AChR to the muscle surface of the neuromuscular junction. Conventional treatments of intravenous immunoglobulin and plasma exchange reduce autoantibody levels to produce their therapeutic effect, while prednisone and immunosuppressives do so by moderating autoantibody production. None of these treatments were specifically developed for MG and have a range of adverse effects. The extensive advances in monoclonal antibody technology allowing specific modulation of biological pathways has led to a tremendous increase in the potential treatment options. For MG, monoclonal antibody therapeutics target the effector mechanism of complement inhibition and the reduction of antibody levels by FcRn inhibition. Antibodies directed against CD20 and signaling pathways, which support lymphocyte activity, have been used to reduce autoantibody production. Thus far, only eculizumab, an antibody against C5, has reached the clinic. We review the present status of monoclonal antibody-based treatments for MG that have entered human testing and offer the promise to transform treatment of MG.

Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma.

Despite the introduction of novel agents such as proteasome inhibitors, immunomodulatory drugs, and autologous stem cell transplant, multiple myeloma (MM) largely remains an incurable disease. In recent years, monoclonal antibody-based treatment strategies have been developed to target specific surface antigens on MM cells. Treatment with bispecific antibodies (bsAbs) is an immunotherapeutic strategy that leads to an enhanced interaction between MM cells and immune effector cells, e.g., T-cells and natural killer cells. With the immune synapse built by bsAbs, the elimination of MM cells can be facilitated. To date, bsAbs have demonstrated encouraging results in preclinical studies, and clinical trials evaluating bsAbs in patients with MM are ongoing. Early clinical data show the promising efficacy of bsAbs in relapsed/refractory MM. Together with chimeric antigen receptor-modified (CAR)-T-cells, bsAbs represent a new dimension of precision medicine. In this review, we provide an overview of rationale, current clinical development, resistance mechanisms, and future directions of bsAbs in MM.

Monoclonal Antibody-Based Treatments for Neuromyelitis Optica Spectrum Disorders: From Bench to Bedside.

Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) is a chronic, recurrent, antibody-mediated, inflammatory demyelinating disease of the central nervous system, characterized by optic neuritis and transverse myelitis. The binding of NMO-IgG with astrocytic aquaporin-4 (AQP4) functions directly in the pathogenesis of >60% of NMOSD patients, and causes astrocyte loss, secondary inflammatory infiltration, demyelination, and neuron death, potentially leading to paralysis and blindness. Current treatment options, including immunosuppressive agents, plasma exchange, and B-cell depletion, are based on small retrospective case series and open-label studies. It is noteworthy that monoclonal antibody (mAb) therapy is a better option for autoimmune diseases due to its high efficacy and tolerability. Although the pathophysiological mechanisms of NMOSD remain unknown, increasingly, therapeutic studies have focused on mAbs, which target B cell depletion, complement and inflammation cascade inactivation, blood-brain-barrier protection, and blockade of NMO-IgG-AQP4 binding. Here, we review the targets, characteristics, mechanisms of action, development, and potential efficacy of mAb trials in NMOSD, including preclinical and experimental investigations.

Novel monoclonal antibody-based treatment strategies in adults with acute lymphoblastic leukemia.

Adult acute lymphoblastic leukemia (ALL) has a poor overall survival compared with pediatric ALL where cure rates are observed in more than 90% of patients. The recent development of novel monoclonal antibodies targeting CD20, CD19, and CD22 has changed the long-term outcome of this disease, both in the frontline setting (e.g. rituximab) and for patients with relapsed/refractory disease (e.g. inotuzumab ozogamicin and blinatumomab). The CD3-CD19 bispecific T-cell-engaging antibody blinatumomab is also the first drug approved in ALL for patients with persistent or recurrent measurable residual disease, providing a new treatment paradigm for these patients. Several new agents are also in development that use novel constructs or target alternative surface epitopes such as CD123, CD25, and CD38. Herein, we review the role of monoclonal antibodies in adult ALL and summarize the current and future approaches in ALL, including novel combination therapies and the possibility of early incorporation of these agents into treatment regimens.

Natural History of Patients with Multiple Myeloma Refractory to CD38-Targeted Monoclonal Antibody-Based Treatment

Natural History of Patients with Multiple Myeloma Refractory to CD38-Targeted Monoclonal Antibody-Based Treatment

The Lebanese Experience of Monoclonal Antibody-Based Treatment in Hodgkin’s Lymphoma

The Lebanese Experience of Monoclonal Antibody-Based Treatment in Hodgkin’s Lymphoma

What sample preparation should be chosen for targeted MS monoclonal antibody quantification in human serum?

Monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies. In this work, we developed a workflow based on an automated protein-A capture and LC-MS/MS analysis to quantify bevacizumab on patient serum during treatment. This analytical approach was fully validated and compared with a commercially available Monoclonal antibody-based treatment preparation (nanosurface and molecular-orientation limited kit). The analytical comparison of the two preparative workflows based on protein-A capture gave similar results with a better lower limit of quantification for the nanosurface and molecular-orientation limited kit (0.26986 vs 1.9565μg/ml). LC-MS/MS has clear advantages compared with ELISA when considering method development time, multiplexing capacities and absolute quantification with internal standardization.

Application of allergen-specific immunotherapy in atopic dermatitis

Atopic dermatitis (AD) is a kind of allergic skin diseases, and allergens play important roles in the pathogenesis of AD. Allergen-specific immunotherapy (ASIT) can induce immune tolerance through repeated contact with low-dose allergens, and is considered to be the only effective way to change the course of allergic diseases. At present, ASIT has been widely applied to the treatment of allergic diseases, but its application is still controversial in AD due to insufficient understanding on this therapy and lack of evidences from large sample-sized clinical trials. Currently, subcutaneous injection immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been accepted. Recent studies have found that the combination with monoclonal antibody-based treatment can improve the safety of desensitization treatment. New therapeutic methods such as intralymphatic immunotherapy, transcutaneous immunotherapy, rush ASIT and cluster ASIT, have been developed and proved to be effective for the treatment of AD with no increase in the incidence of adverse reactions. However, ASIT based on food allergy is still controversial. Key words: Dermatitis, atopic; Allergens; Immunity; Therapeutic uses; Desensitization, immunologic

The safety of therapeutic monoclonal antibodies: implications for cancer therapy including immuno-checkpoint inhibitors.

Monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both hematologic malignancies and solid tumors. In addition to targeting cancer antigens antibodies can also modulate immunological pathways that are critical to immune surveillance. Antibody therapy directed against several negative immunologic regulators (checkpoints) is demonstrating significant success in the past few years. Immune checkpoint inhibitors, ipilimumab, pembrolizumab and nivolumab, have shown significant clinical benefit in several malignancies and are already approved for advanced melanoma and squamous NSCLC. Based on their mechanism of action, these agents can exert toxicities that are unlike conventional cytotoxic chemotherapy, whose nature is close to autoimmune diseases - immune related adverse events (irAEs). In this review we focus on the spectrum of irAEs associated with immune checkpoint antibodies, discussing the pharmacological treatment strategy and possible clinical impact.

Monoclonal Antibodies for the Management of Severe Asthma.

Asthma is a heterogeneous inflammatory disease. Most patients respond to current standard of care, i.e., bronchodilators, inhaled glucocorticosteroids and other anti-inflammatory drugs, but in some adequate asthma control cannot be achieved with standard treatments. These difficult-to-treat patients would be the target population for new biological therapies. At present, omalizumab is the only biological agent approved for the treatment of early-onset, severe IgE-dependent asthma. It is safe, effective, and well tolerated. Also, discovery of asthma subtypes suggests new treatments. Half of patients with severe asthma have T-helper type 2 (Th-2) inflammation and they are expected to benefit from monoclonal antibody-based treatments. The efficacy of the investigational monoclonal antibody mepolizumab which targets IL-5 has been well documented in late onset non-atopic asthma with persistent eosinophilic airway inflammation. Anti-IL-4 and IL-13 agents (dupilumab, lebrikizumab, and tralokinumab) which block different Th-2 inflammatory pathways and agents targeting the Th-17 inflammatory pathway in severe refractory asthma are under development. In clinical trials, these drugs reduce disease activity and improve lung function, asthma symptoms, and quality of life. However, studies on larger groups of patients are needed to confirm their safety and efficacy.