Combination Of Monoclonal Antibodies Research Articles

Efficacy of the combination of monoclonal antibodies against the SARS-CoV-2 Beta and Delta variants.

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the biggest healthcare issue worldwide. This study aimed to develop a monoclonal antibody against SARS-CoV-2 from B cells of recovered COVID-19 patients, which might have beneficial therapeutic purposes for COVID-19 patients. We successfully generated human monoclonal antibodies (hmAbs) against the receptor binding domain (RBD) protein of SARS-CoV-2 using developed hybridoma technology. The isolated hmAbs against the RBD protein (wild-type) showed high binding activity and neutralized the interaction between the RBD and the cellular receptor angiotensin-converting enzyme 2 (ACE2) protein. Epitope binning and crystallography results displayed target epitopes of these antibodies in distinct regions beneficial in the mix as a cocktail. The 3D2 binds to conserved epitopes among multi-variants. Pseudovirion-based neutralization results revealed that the antibody cocktail, 1D1 and 3D2, showed high potency in multiple variants of SARS-CoV-2 infection. In vivo studies showed the ability of the antibody cocktail treatment (intraperitoneal (i.p.) administration) to reduce viral load (Beta variant) in blood and various tissues. While the antibody cocktail treatment (intranasal (i.n.) administration) could not significantly reduce the viral load in nasal turbinate and lung tissue, it could reduce the viral load in blood, kidney, and brain tissue. These findings revealed that the efficacy of the antibody cocktail, 1D1 and 3D2, should be further studied in animal models in terms of timing of administration, optimal dose, and efficacy to mitigate inflammation in targeted tissue such as nasal turbinate and lung.

Abstract CT179: First-in-human study of ICT01, an anti-BTN3A activating monoclonal antibody in combination with low dose IL-2 in patients with advanced solid tumors (EVICTION-2 study)

Abstract Background: ICT01, an anti-BTN3A mAb, selectively activates γ9δ2 T cells resulting in remodeling of the tumor microenvironment by activated γ9δ2 T, CD8 T, and NK cells (EVICTION- NCT04243499; AACR 2022 CT188). Response to ICT01 depends on the baseline number of γ9δ2 T cells with many cancer patients having inadequate numbers due to prior chemotherapy and/or the underlying malignancy. ICT01 plus IL-2 induces selective expansion of γ9δ2 T cells with minimal Treg expansion in NHPs and is currently being tested in the EVICTION-2 Trial, a phase I/IIa, open-label study to characterize the safety, tolerability, pharmacodynamics, and antitumor activity of ICT01 in combination with low dose subcutaneous (LDSC) IL-2 in patients with advanced-stage solid tumors (NCT04243499). Methods: ICT01 (1, 5, 20 or 75 mg, IV Q3W) is given in combination with LDSC IL-2 (Proleukin®, 1 or 2 MIU/m2) on days 1-5 of the first 3 cycles and will be continued alone thereafter. Per dose combination two patients are enrolled for dose escalation based on the BOIN simulations to identify a safe and pharmacodynamically active dose combination(s) for Phase IIa expansion. Results: To date, 9 patients with colorectal (n=6), ovarian (n=2) or pancreatic cancer (n=1) with a mean/median of 6 prior lines of therapy have received at least their first cycle of ICT01 1, 5, 20 or 75 mg + IL-2 1MIU/m2 or ICT01 1mg + IL-2 2MIU/m2. Treatment-related adverse events (TRAE) were mainly infusion related reactions comprising fever and chills grade 1 and 2 in 8/9 patients, not different in severity from ICT01 or IL-2 monotherapy. No dose limiting toxicities were reported. By RECIST, Stable Disease was observed in 2/6 patients with a Week 8 assessment. In all patients, a 2-to-9-fold increase in γ9δ2 T cells was observed for each of the 3 combination cycles, which is accompanied by peripheral activation, mobilization, and proliferation of CD8 T cells, NKs and granulocytes, which is consistent with the expected contribution of IL-2. Increased IFNγ and IL-8 levels (2.4-to-140 fold and 2-to-94 fold respectively) were observed within 24h after each dose of ICT01/IL-2. Flow cytometry of Tregs in frozen PBMCs and IHC of tumor biopsies collected at baseline and on Day 28 are being analyzed to quantify tumor infiltration. Conclusions ICT01 plus LDSC IL-2 safely induced robust γ9δ2 T cell expansion leading to a broad immune response involving CD8 T cells, NKs, and granulocytes at lower doses than observed with ICT01 monotherapy. More patient data are needed to confirm that IL-2 potentiates the antitumor effects of ICT01 and that this leads to better clinical outcomes. Citation Format: Johann de Bono, Stéphane Champiat, Francois-Xavier Danlos, Martin Wermke, Volker Kunzmann, Aude De Gassart, Emmanuel Valentin, Marina Iche, Maelle Mairesse, Patrick Brune, Katrien Lemmens, Aurélien Marabelle, Daniel Olive, Paul Frohna. First-in-human study of ICT01, an anti-BTN3A activating monoclonal antibody in combination with low dose IL-2 in patients with advanced solid tumors (EVICTION-2 study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT179.

Sequencing and combination of current small-molecule inhibitors for chronic lymphocytic leukemia: Where is the evidence?

Small-molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL), a landscape once dominated by chemoimmunotherapy (i.e., an anti-CD20 monoclonal antibody in combination with systemic chemotherapy) in fit and unfit individuals. Key challenges include the management of refractory disease as well as the optimization of the therapy sequence. Decreased responsiveness has been observed with prolonged treatment, especially with Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase (PI3K) inhibitors which are given continuously, while venetoclax, an agent that targets dysregulations in intrinsic apoptosis signaling, has a fixed duration when combined with anti-CD20 monoclonal antibodies or BTK inhibitors. Combination therapy aims to synergistically target different oncogenic signaling pathways to abrogate the proliferation of resistant clones and thereby allows for fixed-duration treatments. An advantage of fixed-duration therapy is the potential to decrease financial and drug-induced toxicities. Sequencing of therapies is important to individualize treatment decisions based on factors such as age, comorbidities, tolerability, and patient preferences. However, to date, there are limited data to guide the rational sequencing or combination of these therapies, since conventional chemoimmunotherapy or chemotherapy regimens were used as comparators against these small-molecule inhibitors in trials that led to their regulatory approvals. In this article, we examined and evaluated the current evidence for sequencing versus the combination of small-molecule inhibitors for CLL by conducting comprehensive searches of the United States National Library of Medicine PubMed database, key meeting abstracts, and clinical practice guidelines. We also summarized findings from expert opinions to elucidate best practices for clinical scenarios with limited evidence to guide treatment selection.

Systematic review and meta-analysis of the clinical effectiveness of tixagevimab/cilgavimab for prophylaxis of COVID-19 in immunocompromised patients.

Immunocompromised patients, such as those with a haematological malignancy, are at higher risk of SARS-CoV-2 infection, severe outcomes and mortality. Tixagevimab/cilgavimab is a monoclonal antibody combination which binds to the SARS-CoV-2 spike protein. The PROVENT phase III clinical trial reported that tixagevimab/cilgavimab prophylaxis significantly reduced the risk of COVID-19 infection in immunocompromised participants. However, the trial was conducted before the Omicron variant became prevalent. This systematic review and meta-analysis provide an up-to-date summary of the real-world effectiveness of tixagevimab/cilgavimab in immunocompromised patients, including patients with haematological malignancies. Clinical studies from 1 January 2021 to 1 October 2022, which reported breakthrough COVID-19 infections after tixagevimab/cilgavimab, were included. COVID-19-related hospitalisations, intensive care admissions and mortality were also assessed. A meta-analysis was performed to ascertain overall clinical effectiveness. Eighteen studies, with 25 345 immunocompromised participants, including 5438 patients with haematological pathologies, were included in the review. The overall clinical effectiveness of tixagevimab/cilgavimab against COVID-19 breakthrough infection, hospitalisation, intensive care admission and COVID-19-specific mortality was 40.54%, 66.19%, 82.13% and 92.39%, respectively. This review highlights the clinical effectiveness of tixagevimab/cilgavimab at reducing COVID-19 infection and severe outcomes for immunosuppressed individuals, including patients with a haematological malignancy, during the Omicron-predominant era. Real-world studies are important to provide ongoing certainty of the clinical benefit for immunocompromised patients against new SARS-CoV-2 variants.

Clinical and Immunological Considerations of Monoclonal Antibody Therapy in COVID-19 A Review

Currently, effective methods for the prevention and treatment of coronavirus infections have not been developed. This could be attributed to the unique pathogenesis of the coronavirus infection and the rapid global spread of the pandemic, which have posed challenges to ongoing research efforts. Similar to other viral infections, coronavirus infection leads to the development and dissemination of the inflammatory process, resulting in viremia or the systemic spread of the infection. This uncontrolled inflammatory response is characterized by elevated levels of cytokines such as IFNy, IL-1, IL-6, and IL-12 in the bloodstream, transitioning the initial inflammatory reaction into a phase known as the cytokine storm. The cytokine storm is marked by severe clinical and laboratory manifestations. Consequently, it is crucial to implement appropriate therapies that target the uncontrolled inflammation induced by the virus rather than viremia itself. Hence, the aim of our study was to investigate the impact of monoclonal antibodies, specifically the medication "Kazirivimab + Imdevimab," which is a combination of recombinant monoclonal antibodies targeting the S-protein, on the clinical progression and laboratory parameters in patients with COVID-19.

Hodgkin-lymphomás betegek kezelésével szerzett tapasztalataink

Overall and disease-free survival of Hodgkin lymphoma patients has improved significantly since the 2000s. This is due to the use of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) polychemotherapy and modern radiotherapy. In recent years, further diagnostic and therapeutic changes have been made, which further improve patients' survival. The most significant role in this is the improvement of diagnostics, such as the 18FDG-PET/CT, which is now routinely used repeatedly during treatment, and the response-adapted treatment(s) based on it. The main role of ABVD treatment in first-line treatment is still clear, but the combination of anti-CD30 monoclonal antibody (brentuximab vedotin) and AVD (adriamycin, vinblastine, dacarbazine) is already available as a targeted treatment for patients at higher risk. The role of autologous hematopoietic stem cell transplantation in the treatment of high-risk, relapsing/refractory patients is still clear, but the new, targeted innovative drugs (brentuximab vedotin, pembrolizumab) can already be used in the previous salvage treatments. New therapeutic options have new side effects, which must be taken into account during treatment (and after it). In our summary, we present these new diagnostic and therapeutic approaches, based on our own practice and experience. Orv Hetil. 2023; 164(11): 403-410.

Development of a Novel Recombinant Full-Length IgY Monoclonal Antibody against Human Thymidine Kinase 1 for Automatic Chemiluminescence Analysis on a Sandwich Biotin-Streptavidin Platform for Early Tumour Discovery.

Serum thymidine kinase 1 protein (STK1p) concentration has been used successfully as a reliable proliferating serum biomarker in early tumour discovery and clinical settings. It is detected by an enhanced chemiluminescence (ECL) dot blot assay with the biotin-streptavidin (BSA) platform (a gold standard) based on chicken anti-human thymidine kinase 1 IgY polyclonal antibody (hTK1-IgY-pAb). However, ECL dot blotting is a semiautomatic method that has been limited to large-scale applications due to the differences among batches of antibodies from individual hens, and the skill level of operation technicians sometimes results in unstable STK1p values. Therefore, a highly stable recombinant chicken full-length IgY monoclonal antibody in combination with a fully automated sandwich biotin-streptavidin (sandwich-BSA) platform was developed. Hens were immunized with 31-peptide, a key sequence of human TK1 (hTK1), before constructing an immune phage display scFv library. Finally, a recombinant full-length IgY monoclonal antibody (hTK1-IgY-rmAb#5) with high-affinity binding with human recombinant TK1 (rhTK1) (3.95 × 10-10 mol/L), high sensitivity with hTK1 calibrators (slope of linear curve: 89.98), and high specificity with low/elevated STK1p (r ≈ 0.92-0.963) was identified. hTK1-IgY-rmAb#5 showed a specific immune response with thymidine kinase 1 (TK1) in TK1-positive/negative cell lysates by Western blotting and immunohistochemistry (IHC) in normal and cancer tissues. In particular, the detection of TK1 serum samples from health centres showed a high coincidence rate (r = 0.988, n = 90) between hTK1-IgY-rmAb#5 and hTK1-IgY-pAb and between the semiautomatic ECL dot blot BSA platform and the novel automatic chemiluminescence sandwich-BSA platform (r = 0.857, n = 292). hTK1-IgY-rmAb#5 is stable and highly sensitive for detecting the lowest STK1p value at 0.01 pmol/L (pM). The accuracy is high (SD < 2.5%) between different batches. It is easy to use the novel hTK1-IgY-rmAb#5 on a new automatic chemiluminescence sandwich-BSA platform. It will be beneficial for large-scale health screenings.

PD-1 Combined with VEGF/VEGFR2 Inhibitors for the Re-Treatment of Metastatic Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma has a good prognosis with intensity-modulated radiotherapy (IMRT) but recurrence occurs in 8–10% of patients, mostly in the form of distant metastases. Current systemic treatments for relapsed/metastatic (R/M) nasopharyngeal carcinoma are limited, resulting in poor overall survival rates. Immune checkpoint inhibitors have shown some activity, but their small sample size and lack of overall survival data limit their effectiveness. This study reports a patient with R/M nasopharyngeal carcinoma who had a durable response to salvage therapy with camrelizumab plus anlotinib, with no serious side effects and high quality of life. The combination of immune checkpoint inhibitors and antivascular monoclonal antibodies may have a mechanism for enhancing the antitumor response. VEGF/VEGFR2 inhibitors combined with PD-1 inhibitors are being clinically explored as a potential new treatment option for R/M nasopharyngeal carcinoma. These findings offer hope for the development of effective, tumor-specific treatments for patients with R/M nasopharyngeal carcinoma.

A review of the mechanism of action, safety, and efficacy of selinexor in multiple myeloma

In recent years, the armamentarium of routinely available treatments for relapsed and/or refractory multiple myeloma (RRMM) in Canada has dramatically expanded, but treatment gaps still exist. In early relapse (1-3 prior lines), monoclonal antibody (mAb) combinations on a backbone of lenalidomide or bortezomib (e.g. DRd, DVd) have been the mainstay, with combinations building on second generation backbones such as pomalidomide and carfilzomib (e.g. PCd, PVd, Kd) largely reserved for later relapse (after 2 prior lines). However, the increasing use of multi-class drug combinations in the frontline (e.g. DRd, RVd) and a shift towards ongoing therapy until progression, renders patients heavily drug-exposed and refractory at time of early relapse, needful of treatments with novel mechanisms of action. Selinexor is poised to fill an unmet need with a unique, non-overlapping mechanism of action to other available agents. XPOVIO® (selinexor) is indicated in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. SVd received Health Canada approval May 31, 2022. This review will present data on selinexor’s mechanism of action, efficacy in combination with dexamethasone and bortezomib (Sd, SVd), dosing and scheduling, as well as the management of its common and distinct toxicities.

Pre-exposure prophylaxis of new COVID-19 coronavirus infection with tixagevimab/cilgavimab in adult Moscow patients with primary immunodeficiencies

Primary immunodeficiencies (PIDs), now known as inborn errors of immunity, are a group of inherited diseases caused by defects in the genes that control the immune response. Patients with PIDs have risks of developing a severe course and/or death in COVID-19. Passive immunization with long-acting monoclonal antibodies (MABs) to SARS-CoV-2 should be considered as pre-exposure prophylaxis in patients with PIDs. Tixagevimab/cilgavimab is a combination of MABs that bind to the SARS-CoV-2 spike protein. To evaluate the efficacy and safety of pre-exposure prophylaxis of new SARS-CoV-2 infection in PIDs with the combination of tixagevimab/cilgavimab. Forty eight patients diagnosed with PIDs were included in the study. Median follow-up after drug administration was 174 days. The total number of confirmed coronavirus infections in patients with PIDs as well as 6 months before and after administration of MAT were assessed. In the analyzed cohort, the overall incidence of COVID-19 from pandemic onset to MABs administration was 75% (36/48), with 31% (11/36) of over-infected patients having had the infection more than once. The incidence of COVID-19 immediately 6 months before the introduction of tixagevimab/cilgavimab was 40%. All patients who had COVID-19 after pre-exposure prophylaxis had a mild infection. The incidence of COVID-19 6 months after tixagevimab/cilgavimab administration significantly decreased compared to the incidence 6 months before administration (7 and 40%, respectively; p<0.001). The use of tixagevimab/cilgavimab in patients with PIDs is effective as pre-exposure prophylaxis and reduces the risk of severe COVID-19.

The evolving use of measurable residual disease in chronic lymphocytic leukemia clinical trials.

Measurable residual disease (MRD) status in chronic lymphocytic leukemia (CLL), assessed on and after treatment, correlates with increased progression-free and overall survival benefit. More recently, MRD assessment has been included in large clinical trials as a primary outcome and is increasingly used in routine practice as a prognostic tool, a therapeutic goal, and potentially a trigger for early intervention. Modern therapy for CLL delivers prolonged remissions, causing readout of traditional trial outcomes such as progression-free and overall survival to be inherently delayed. This represents a barrier for the rapid incorporation of novel drugs to the overall therapeutic armamentarium. MRD offers a dynamic and robust platform for the assessment of treatment efficacy in CLL, complementing traditional outcome measures and accelerating access to novel drugs. Here, we provide a comprehensive review of recent major clinical trials of CLL therapy, focusing on small-molecule inhibitors and monoclonal antibody combinations that have recently emerged as the standard frontline and relapse treatment options. We explore the assessment and reporting of MRD (including novel techniques) and the challenges of standardization and provide a comprehensive review of the relevance and adequacy of MRD as a clinical trial endpoint. We further discuss the impact that MRD data have on clinical decision-making and how it can influence a patient's experience. Finally, we evaluate how upcoming trial design and clinical practice are evolving in the face of MRD-driven outcomes.

3D culture boosting fullerenol nanoparticles to induce calreticulin exposure on MCF-7 cells for enhanced macrophage-mediated cell removal

Calreticulin (CRT) on the cell surface that acts as an "eat me" signal is vital for macrophage-mediated programmed cell removal. The polyhydroxylated fullerenol nanoparticle (FNP) has appeared as an effective inducer to cause CRT exposure on cancer cell surface, but it failed in treating some cancer cells such as MCF-7 cells based on previous findings. Here, we carried out the 3D culture of MCF-7 cells, and interestingly found that the FNP induced CRT exposure on cells in 3D spheres via re-distributing CRT from endoplasmic reticulum (ER) to cell surface. Phagocytosis experiments in vitro and in vivo illustrated the combination of FNP and anti-CD47 monoclonal antibody (mAb) further enhanced macrophage-mediated phagocytosis to cancer cells. The maximal phagocytic index in vivo was about three times higher than that of the control group. Moreover, in vivo tumorigenesis experiments in mice proved that FNP could regulate the progress of MCF-7 cancer stem-like cells (CSCs). These findings expand the application of FNP in tumor therapy of anti-CD47 mAb and 3D culture can be used as a screening tool for nanomedicine.

Casivirimab/Imdevimab Effect on COVID-19 Outcome and Reinfection in a Real-World SARS-COV-2 Variant Transition Period Setting.

Monoclonal antibodies targeted against SARS-COV-2 have been recruited in the challenging treatment of COVID-19 with few clinically significant side effects. Casivirimab/imdevimab, a combination of monoclonal antibodies targeted against SARS-COV-2 spike protein, was shown to effectively prevent recently infected high-risk COVID-19 patients from developing severe disease. Its efficacy waned with the emergence of the resistant omicron variant in late 2021. We recorded the real-world effect of casivirimab/imdevimab on 116 high-risk COVID-19 patients. Cumulative need for hospitalization, mortality, new-onset disease, and reinfections was monitored. Casivirimab/imdevimab effect was independent from previous immunization. The cohort was further divided into two subgroups: patients infected during a delta variant prevalent period were more likely to become admitted but as likely to die than patients infected with the omicron variant, in support of its protective effect from clinical studies. Cumulative reinfection incidence in treated patients, interestingly, was lower than in the general population.

Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19.

LettersFebruary 2023Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19FREETeluguakula Narasaraju, PhD, Amita Krishnappa, MD, Marko Radic, PhD, Vincent T.K. Chow, MD, PhDTeluguakula Narasaraju, PhDAdichunchanagiri Institute of Medical Sciences, Karnataka, IndiaSearch for more papers by this author, Amita Krishnappa, MDAdichunchanagiri Institute of Medical Sciences, Karnataka, IndiaSearch for more papers by this author, Marko Radic, PhDUniversity of Tennessee Health Science Center, Memphis, TennesseeSearch for more papers by this author, Vincent T.K. Chow, MD, PhDNational University of Singapore, Kent Ridge, SingaporeSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L22-0455 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR: The ACTIV-3/TICO (Accelerating COVID-19 Therapeutic Interventions and Vaccines/Therapeutics for Inpatients with COVID-19) Study Group (1) analyzed the efficacy and safety of ensovibep. This designed ankyrin repeat protein inhibits the interaction of SARS-CoV-2 spike protein with its host receptor, angiotensin-converting enzyme 2. This randomized controlled trial was a follow-up of earlier studies that showed antiviral activity of ensovibep in a hamster model of COVID-19 as well as reduced hospitalizations and improved clinical outcomes in outpatients with mild to moderate COVID-19. In contrast to those findings, the ACTIV-3/TICO Study Group showed that administration of ensovibep in severely ill patients hospitalized with COVID-19 did not exhibit any protection. This trial was prematurely discontinued because it failed early futility assessment and could not establish the power of the primary outcome in patients hospitalized with COVID-19. The study design has several shortcomings.First, this trial failed to establish the proof of concept of antiviral efficacy of ensovibep.Second, randomly assigning and blinding participants provide an unbiased approach; however, the 7 ordinal pulmonary or pulmonary-plus outcome scales used are unlikely to provide any direct correlation or clinical signatures specific for ensovibep-mediated effects, including lung viral loads or virus-inflicted alveolar–epithelial cytopathic injury.Third, combining remdesivir with ensovibep in the treatment regimen is unlikely to establish any beneficial effects.Finally, the lack of realistic data on viral replication and kinetics at the onset of treatment raises questions about the rationale for this clinical trial. Several clinical trials that evaluated combinations of monoclonal antibodies (for example, tixagevimab–cilgavimab or sotrovimab and BRII-196 plus BRII-198) in patients hospitalized with COVID-19 on the basis of ordinal outcome scales similarly yielded inconsistent findings and fell short of proving their efficacy in these patients (2, 3).When drugs targeting virus entry or replication in the lungs are evaluated, the inclusion of additional criteria to support the proof of concept is essential. Viral titers in nasopharyngeal or oropharyngeal samples unfortunately do not correlate well with viral loads in the deeper lungs, and use of invasive methods to collect lung samples may not be possible in patients hospitalized with COVID-19. Instead, measuring plasma viral RNA may be a better indicator to determine the antiviral effects of ensovibep or monoclonal antibodies in these patients (4). In addition, markers of alveolar epithelial injury such as podoplanin (a marker of alveolar type I epithelium) and surfactant protein C (a marker of alveolar type II epithelium) (5) in the plasma or sputum may represent virus-inflicted alveolitis in the lungs. As such, evaluating COVID-19 pathophysiology and clinical outcomes on ordinal outcome scales must be substantiated by more prudent methods that are relevant to drug target–specific signatures.

Tixagevimab-Cilgavimab Rollout on Common Variable Immunodeficient Patients: Early Lessons from an Academic Allergy and Immunology Clinic

Tixagevimab-cilgavimab is a combination of two monoclonal antibodies against SARS-CoV-2. In December 2021, the FDA issued emergency use authorization for intramuscular injection of tixagevimab-cilgavimab for prophylaxis against SARS-CoV-2 in immunocompromised patients. Shortly thereafter, our clinic distributed tixagevimab-cilgavimab to patients with Common Variable Immunodeficiency (CVID). To our knowledge, no prior study has looked at effects of this monoclonal antibody combination on CVID patients.

Systemic investigation of inetetamab in combination with small molecules to treat HER2-overexpressing breast and gastric cancers.

Most patients with metastatic breast cancer or gastric cancer who are treated with trastuzumab, an anti-HER2 monoclonal antibody, become refractory to the drug within a year after the initiation of treatment. Although the combination of trastuzumab with pertuzumab produced synergetic effects in the treatment of HER2-overexpressing cancers, not all patients with HER2 overexpression benefited from the trastuzumab plus pertuzumab combination. To improve the clinical benefits of trastuzumab, we systemically investigated the combination of inetetamab (Cipterbin), an analog of trastuzumab, with a variety of small molecules, including tyrosine kinase inhibitors (TKIs) and chemotherapeutic agents in vivo. We showed that pan-TKIs-induced synergistic antitumor effects with inetetamab in the treatment of these two types of cancers and that adding chemotherapeutic agents to the existing TKI plus anti-HER2 monoclonal antibody combination strategies induced additional inhibitory effects, suggesting that such combination strategies may be choices for the treatment of these two tumors. Thus, combination therapies targeting distinct and broad pathways that are essential for tumor growth and survival can be effective for treating metastatic breast cancers and gastric cancers.

Subcutaneous REGEN-COV antibody administration in a community pharmacy

BackgroundREGEN-COV is a non-Food and Drug Adminstration approved monoclonal antibody combination of casirivimab/imdevimab. Casirivimab/imdevimab was previously used for the treatment of SARS-CoV-2 infection (COVID-19), under an emergency use authorization, and has demonstrated a reduction in hospitalizations and death. With the ability to administer this monoclonal antibody combination subcutaneously in an outpatient setting, limited community pharmacies became a treatment location for patients. ObjectivesThe objective of this study was to describe an innovative service and evaluate the safety of administering REGEN-COV, a monoclonal antibody combination of casirivimab and imdevimab, in a community pharmacy setting as treatment for COVID-19. Practice DescriptionThis study was conducted in a community pharmacy during traditional business hours. Practice InnovationA novel service of monoclonal antibody administration for the treatment of COVID-19 was implemented in a community pharmacy in response to community needs during the pandemic. Evaluation MethodsA retrospective, observational study was conducted from September 1, 2021 to December 31, 2021. Patients were required to have a positive SARS-CoV-2 test and meet all inclusion and exclusion criteria. Patients were assessed for adverse drug reactions at the time of monoclonal antibody administration and 60-minutes after administration. Patients were contacted by phone to complete a survey to assess patient reported adverse drug reactions post administration, number of patients hospitalized, and number of patients able to return to normal daily activities. ResultsOf the 93 patients included in this study, adverse effects were reported in 4.3% of patients at administration and 9.7% at follow-up. Included patients receiving this service generated $32,688.68 in revenue for the community pharmacy. ConclusionCommunity pharmacists can administer casirivimab/imdevimab safely and effectively in an outpatient setting with low adverse events. This innovative monoclonal antibody administration service should be used as an example for a Call to Action of expansion of pharmacist scope of practice.

Evaluation of Diagnostic Usefulness of CD200 Expression in B-cell Chronic Lymphoproliferative Disorders.

Immunophenotyping by flow cytometry (FCM) is a useful diagnostic tool for the evaluation of mature B-cell neoplasms (MBN). Here, CD200 expression may play a significant role and improve the distinction between various MBNs, but any potential as a prognostic marker is yet to be established. The present prospective study was conducted on all the suspected cases of MBNs. Immunophenotyping was done using a BD FACS Canto FCM using a panel of 4 to 6 color combinations of monoclonal antibodies; CD45, CD34, CD5, CD19, CD20, CD22, CD23, CD79b, FMC7, CD10, CD38, ZAP70, CD200, IgG, IgM, CD25, CD103, CD2, CD3, CD11c as well as κ and λ light chains. CD200 expression was compared in different subgroups. Of the total of 130 cases included in the study, CD200 was positive in 118 cases (90%). CD200 was expressed in 100% of the cases of CLL(86 cases), atypical CLL(06 cases), HCL(14 cases), FL(02 cases), SMZL(04 cases), LPL (01 case), and low-grade NHL (05 cases), with the highest intensity of fluorescence in HCL followed by CLL. All the cases of MCL and PLL were exclusively negative for CD200. In conclusion, the results of the present study support inclusion of this marker in the flow cytometric panels for the differential diagnosis of MBNs.

Evolving perspectives on the treatment of HR+/HER2+ metastatic breast cancer.

Breast cancer (BC) with expression of the estrogen receptor (ER) and/or progesterone receptor (PR) protein and with overexpression/amplification of the human epidermal growth factor receptor 2 (HER2), termed hormone receptor-positive (HR+)/HER2+ BC, represents ∼10% of all BCs in the United States. HR+/HER2+ BC includes HER2+ BCs that are ER+, PR+, or both ER+ and PR+ (triple-positive BC). Although the current guideline-recommended treatment combination of anti-HER2 monoclonal antibodies plus chemotherapy is an effective first-line therapy for many patients with HER2+ advanced disease, intratumoral heterogeneity within the HR+/HER2+ subtype and differences between the HR+/HER2+ subtype and the HR-/HER2+ subtype suggest that other targeted combinations could be investigated in randomized clinical trials for patients with HR+/HER2+ BC. In addition, published data indicate that crosstalk between HRs and HER2 can lead to treatment resistance. Dual HR and HER2 pathway targeting has been shown to be a rational approach to effective and well-tolerated therapy for patients with tumors driven by HER2 and HR, as it may prevent development of resistance by blocking receptor pathway crosstalk. However, clinical trial data for such approaches are limited. Treatments to attenuate other signaling pathways involved in receptor crosstalk are also under investigation for inclusion in dual receptor targeting regimens. These include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, based on the rationale that association of CDK4/6 with cyclin D1 may play a role in resistance to HER2-directed therapies, and others such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway inhibitors. Herein, we will review the scientific and clinical rationale for combined receptor blockade targeting HER2 and ER for patients with advanced-stage HR+/HER2+ disease.

When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy.

Despite the clinical success of the first bispecific antibody approved by the FDA against B cell malignancies (blinatumomab), many obstacles remain such as dosing, treatment resistance, and modest efficacy in solid tumors. To overcome these limitations, considerable efforts have been dedicated to the development of multispecific antibodies, opening up new avenues to address both the complex biology of cancer and the onset of anti-tumoral immune responses. Simultaneous targeting of two tumor-associated antigens is presumed to enhance cancer cell selectivity and reduce immune escape. Co-engagement of CD3, along with agonists of co-stimulatory molecules or antagonists of co-inhibitory immune checkpoint receptors in a single molecule, may revert T cell exhaustion. Similarly, targeting of two activating receptors in NK cells may improve their cytotoxic potency. And these are only examples of the potential of antibody-based molecular entities engaging three (or more) relevant targets. From the perspective of health care costs, multispecific antibodies are appealing, since a similar (or superior) therapeutic effect could be obtained with a single therapeutic agent as with a combination of different monoclonal antibodies. Despite challenges in production, multispecific antibodies are endowed with unprecedented properties, which may render them more potent biologics for cancer therapy.