Monoclonal Antibody-based Therapies Research Articles

How to use monoclonal antibody-based therapy in ALL

How to use monoclonal antibody-based therapy in ALL

The impact of high-risk cytogenetic abnormalities in extramedullary multiple myeloma in the era of novel agents: insights from a multicenter study

PurposeThis study aimed to examine the impact of high-risk cytogenetic abnormalities (HRA) on the survival outcomes of multiple myeloma patients with extramedullary disease (EMD) in the era of novel agents, utilizing the largest dataset of extramedullary multiple myeloma patients in China.MethodsThis study included a total of 371 patients with EMD, comprising 113 patients with de novo EME and 258 patients with EMB.ResultsPatients with one HRA and those with ≥ 2 HRA demonstrated significantly worse overall survival (OS) (P < 0.01) and progression-free survival (PFS) (P < 0.01) compared to patients without HRA. Additionally, 1q21 gain/amplification (1q21 +) remained a predictor of poor prognosis in EMD. CD38 monoclonal antibody-based therapy and single transplantation were less effective in improving survival outcomes for EMD with ≥ 2 HRA. Multivariable analysis identified LDH levels > 250 U/L, creatinine levels > 177 μmol/L, extramedullary extraosseous (EME), 1 HRA, and ≥ 2 HRA as independent adverse prognostic factors in patients with EMD.ConclusionPatients with EMD who had ≥ 2 HRA experienced an extremely poor prognosis, which could not be improved by single transplantation or CD38 monoclonal antibody-based treatment. The number of HRA could serve as an important factor in guiding treatment choices and predicting prognosis in patients with EMD. Furthermore, 1q21 + remained a significant factor associated with worse survival outcomes in EMD.

Targeting CCR5: A central approach to HIV treatment and cure strategies.

CCR5, a co-receptor critical for R5-tropic HIV entry into host cells, remains a key target for therapeutic interventions. HIV utilizes CCR5, expressed on T cells and macrophages, to facilitate viral entry. Genetic variants, such as the CCR5Δ32 homozygous mutation that confers protection to HIV infection, have made CCR5 a main target for gene-editing technologies, small-molecule inhibitors, and monoclonal antibody-based therapies. Recent studies emphasize the importance of regulating CCR5 expression at transcriptional and post-transcriptional levels and integrating this approach with traditional therapies. Particularly, the role of heterozygous CCR5Δ32 carriers who are HIV seropositive highlights the potential for targeting CCR5 in combination with other immune-regulatory mechanisms. This may lead to more effective treatment strategies and, ultimately, a functional cure for HIV. This minireview discusses the role of CCR5 in HIV pathogenesis and explores the potential of genetic and therapeutic interventions targeting CCR5 as an innovative strategy in the continued battle against HIV.

Sustained Endocytosis Inhibition via Locally-Injected Drug-Eluting Hydrogel Improves ADCC-Mediated Antibody Therapy in Colorectal Cancer.

The epidermal growth factor receptor (EGFR) is a validated therapeutic target for RAS/RAF wild-type colorectal cancer (CRC). However, monoclonal antibody-based anti-EGFR therapies such as cetuximab have limited effectiveness. Herein, it is identified that EGFR internalization is associated with poor treatment response and prognosis in patients with CRC, based on a retrospective analysis of patients treated with cetuximab. It is further demonstrated that the endocytosis inhibitor prochlorperazine (PCZ) can move EGFR, which is hidden inside the cell, to the cell surface to improve therapeutic antibody binding. Thus, a thermosensitive hydrogel co-loaded with cetuximab and PCZ (Gel@Cmab/PCZ) is constructed for sustained inhibition of endocytosis and effective cetuximab delivery. Peritumoral injection of Gel@Cmab/PCZ shows strong antitumor efficacy in subcutaneous and orthotopic CRC tumor models and completely abrogated liver metastasis when combined with chemotherapy. In a humanized patient-derived xenograft model, a single injection of Gel@Cmab/PCZ with one-third of theconventional cetuximab dose achieved 91% tumor growth inhibition, which promoted NK cell infiltration into tumor tissues and their antibody-dependent cell-mediated cytotoxicity effect. This study represents a novel strategy to boost the monoclonal antibody-mediated anti-tumor response in CRC.

Comparison of the Neutralization Power of Sotrovimab Against SARS-CoV-2 Variants: Development of a Rapid Computational Method.

The rapid evolution of SARS-CoV-2 imposed a huge challenge on disease control. Immune evasion caused by genetic variations of the SARS-CoV-2 spike protein's immunogenic epitopes affects the efficiency of monoclonal antibody-based therapy of COVID-19. Therefore, a rapid method is needed to evaluate the efficacy of the available monoclonal antibodies against the new emerging variants or potential novel variants. The aim of this study is to develop a rapid computational method to evaluate the neutralization power of anti-SARS-CoV-2 monoclonal antibodies against new SARS-CoV-2 variants and other potential new mutations. The amino acid sequence of the extracellular domain of the spike proteins of the severe acute respiratory syndrome coronavirus (GenBank accession number YP_009825051.1) and SARS-CoV-2 (GenBank accession number YP_009724390.1) were used to create computational 3D models for the native spike proteins. Specific mutations were introduced to the curated sequence to generate the different variant spike models. The neutralization potential of sotrovimab (S309) against these variants was evaluated based on its molecular interactions and Gibbs free energy in comparison to a reference model after molecular replacement of the reference receptor-binding domain with the variant's receptor-binding domain. Our results show a loss in the binding affinity of the neutralizing antibody S309 with both SARS-CoV and SARS-CoV-2. The binding affinity of S309 was greater to the Alpha, Beta, Gamma, and Kappa variants than to the original Wuhan strain of SARS-CoV-2. However, S309 showed a substantially decreased binding affinity to the Delta and Omicron variants. Based on the mutational profile of Omicron subvariants, our data describe the effect of the G339H and G339D mutations and their role in escaping antibody neutralization, which is in line with published clinical reports. This method is rapid, applicable, and of interest to adapt the use of therapeutic antibodies to the treatment of emerging variants. It could be applied to antibody-based treatment of other viral infections.

COVID-19 Vaccination-Induced Pityriasis Rubra Pilaris

Abstract: Amidst the COVID-19 pandemic, the rapid development of vaccines transformed immunization strategies. With 70.6% of the global population vaccinated with at least one dose and 13.53 billion doses administered worldwide, certain dermatological side effects like Pityriasis Rubra Pilaris (PRP) have been linked to the COVID-19 vaccination. This review aims to critically analyze the existing evidence on the correlation between COVID-19 vaccination and PRP, emphasizing its incidence and management strategies. A review of 62 articles was conducted, of which only 19 met the inclusion criteria. Out of these, 16 had complete information necessary for the review. The review identified 16 cases of PRP, predominantly in males (62.5%) with an average age of 59. A significant percentage (44%) of cases occurred approximately 12 days after the third dose (booster). Symptoms commonly included painful rashes, itching, and erythematous, reddish, scaly plaques. Treatments varied, with oral retinoids and monoclonal antibody-based biological therapies being the most common. The importance of continuous monitoring of dermatological side effects, such as PRP, is underscored, especially as the world population will require ongoing booster shots. Standardizing PRP treatment is a critical step toward ensuring optimal patient care.

Novel ERBB2 Variant Potentially Associated with Resistance against Anti-HER2 Monoclonal Antibody-Based Therapy in ERBB2-Amplified Metastatic Colorectal Cancer.

HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data. We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project. We analyzed paired genome and transcriptome data of tissue and genomic data of ctDNA collected pre- and postprogression in patients enrolled in the related trial, TRIUMPH, in ERBB2-amplified mCRC. In 155 patients with ERBB2-amplified solid tumors who received HER2-targeted therapy based on the SCRUM-Japan project, the objective response rate was 50%, 51%, and 35% in ERBB2 wild-type, variant of unknown significance, and pathogenic variant groups, respectively. In the paired genome and transcriptome data analyses in TRIUMPH, we identified the novel splicing-associated variant c.644-66_-2del in one of the 11 patients with paired whole-exome sequencing and whole-transcriptome sequencing data sets, which lacks the binding domain of pertuzumab, in progressed metastatic tumor as a variant with potential pathogenicity. The time-course ctDNA analysis detected c.644-66_-2del as an acquired variant. This study highlighted the importance of ERBB2 genomic status when evaluating the efficacy of HER2-targeted therapies in ERBB2-amplified mCRC. The identification of a novel splicing-associated variant may provide insights into potential mechanisms of treatment resistance. Furthermore, we demonstrated the utility of ctDNA to follow the acquired genomic status of mCRC tumors.

Outcomes of myeloma cast nephropathy in the era of anti-CD38 monoclonal antibody-based frontline therapy: A retrospective cohort study.

7555 Background: Myeloma cast nephropathy (MCN) has been a well-known negative predictive marker in newly diagnosed multiple myeloma (NDMM). Anti-CD38+ monoclonal antibodies (mAb) have improved outcomes, but little is known about their impact in patients with MCN. We performed a retrospective cohort study to investigate the outcomes of patients with MCN in the era of anti-CD38+ mAb-based frontline therapy. Methods: 115 NDDM patients received frontline anti-CD38+ mAb from 11/15/18 to 1/24/23. MCN was defined as evidence of light chain casts on biopsy, serum creatinine of &gt;2mg/dL, or 2021 CKD-EPI eGFR of &lt;40mL/min/1.73m2; ≥1g/d proteinuria; and involved FLC ≥50mg/dL. 23 had MCN; 92 were contemporary controls. We obtained data regarding clinical course. Results: 6 MCN patients needed hemodialysis (HD) at diagnosis. MCN patients had similar R2-ISS to controls. Median proteinuria in MCN patients was 5.7g/d more than in controls; serum creatinine (Cr) was 3.2mg/dL higher; and median hemoglobin was 1.5g/dL less. More MCN patients received quadruplet regimens (86.9% vs 62.0%, p = 0.010); similar proportions were transplanted. At 1, 3, and 6 months, serum Cr was higher in MCN patients (p &lt; 0.001, p = 0.002, p = 0.002). Urine protein:creatinine ratios trended toward difference at 1 month (2.04 vs 0.15g/g MCN vs controls, p = 0.061) but were similar at 3 and 6 months. Response rates at 6 months did not differ. 4 MCN patients still required HD after 6 months. Median follow-up was 23.0-23.5 months. 4 MCN patients died, 1 due to progressive disease. No significant difference in disease-free survival (DFS; HR = 0.58, 95% CI 0.20-1.64, p = 0.295), time to next treatment (TTNT; HR = 0.53, 95% CI 0.20-1.39, p = 0.191), or overall survival (OS; HR 0.610, 95% CI 0.19-1.98, p = 0.406) was seen at any point between MCN and control cohorts. 1 year DFS, TTNT, and OS were: 87.0% MCN, 94.5% control; 77.2% MCN, 91.7% control; 87.9% MCN, 96.1% control. By statistical equivalence testing, MCN DFS and TTNT were within 6 months of control DFS and TTNT (p = 0.038, p = 0.032); MCN OS was within 5 months of control OS (p = 0.034). Conclusions: Patients with NDMM and MCN who receive upfront anti-CD38+ mAb therapy experience prolonged survival compared to prior findings. Anti-CD38+ mAb may substantially reduce, though not fully eliminate, the negative survival impact of MCN. Multiple mechanisms, including time to proteinuria resolution, may be involved. Further study is warranted. [Table: see text]

Targeting BTLA with the peptide inhibitor HVEM(14-39) – A new way to restore the activity of T cells in melanoma

The complex of B- and T-lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) plays a critical role in immune regulation and has emerged as a promising therapeutic target for cancer treatment. In this study, we investigated the potential of the peptide inhibitor HVEM(14-39) to restore peripheral T cell activity in patients with advanced melanoma. In these patients, CD8+ T cells downregulated BTLA expression and increased HVEM expression upon activation. The addition of HVEM(14-39) reduced the percentage of BTLA+ CD8+ T cells and increased the subpopulation of HVEM+ CD8+ T cells. Additionally, HVEM(14-39) enhanced T cell activation, proliferation, and the shift toward effector memory T cell subpopulations. Finally, this peptide affected the proliferation rate and late apoptosis of melanoma cell line in co-culture with T cells. These findings suggest that HVEM(14-39) can overcome T cell exhaustion and improve antitumor responses. Peptide-based immunotherapy targeting the BTLA-HVEM complex offers a promising alternative to monoclonal antibody-based therapies, with the potential for fewer side effects and higher treatment efficacy.

Abstract PO3-09-05: Potential novel treatments for high-risk subsets of breast cancer in postpartum and African American women

Abstract Semaphorin 7a (SEMA7A) is a neuroimmune molecule first recognized for its roles in axonal guidance and inflammation. More recently, SEMA7A has emerged as a driver of tumor progression in multiple types of cancer including lung, glioblastoma and breast. Our studies have focused on the roles of SEMA7A in promoting tumor cell growth and survival as well as invasion and metastasis in mouse models including xenograft and syngeneic. Using patient samples and datamining we have shown that SEMA7A can predict for recurrence in women with postpartum breast cancer (PPBC), or breast cancers diagnosed within 10 years of recent childbirth, and SEMA7A mRNA expression in TCGA is highest in young and African American (AA) women with BC, who typically have poor prognosis. Additionally, our analysis of the Cancer Genome Atlas (TCGA) breast cancer (n=593) and METABRIC cohorts (n=2,136) revealed that SEMA7A is increased in invasive disease and in the top 9% and 27% of upregulated genes (p=1.09E-19&amp;p=0.009), respectively. Additionally, ~1.2 (TCGA) and ~1.1 (METABRIC) fold increases in SEMA7A mRNA conferred significantly decreased 5-year survival rates (p=0.009&amp;p=0.002) and SEMA7A was in the top 4% of mRNAs upregulated in patients who died within 5 years of diagnosis 20,24-26. Cumulatively, these results suggest that identifying therapeutic vulnerabilities of SEMA7A+BC, or direct targeting of SEMA7A, could improve prognosis for these high-risk populations. We have identified several targets in pre-clinical models of SEMA7A+BC that include clinically available, FDA approved drugs, as well as novel inhibitors that exhibit efficacy. In published studies, we have shown that venetoclax, a Bcl-2 inhibitor, reverses ER+SEMA7A+BC resistance to endocrine therapy in mouse models. In unpublished studies, we have extended our observations in ER+SEMA7A+BC to show that alpelisib and a novel PI3K kinase inhibitor, GCT-007, both inhibit growth of human and mouse mammary tumor cells. Furthermore, in models of ER-SEMA7A+BC where we have shown cells to be resistant to chemotherapy, we have utilized age matched cell lines from AA and CA women to dissect the downstream pro-survival signaling that is mediated by SEMA7A and we have shown that anti-PD-1 and anti-PD-L1 therapies are efficacious in reducing tumor growth in vivo. Finally, we have developed a novel monoclonal antibody-based therapy that directly targets SEMA7A signaling via pro-survival pathways and inhibits tumor growth in vivo and in vitro. Collectively our results suggest that SEMA7A+BC should be identified clinically, and alternative treatments advised for this high-risk subset of breast cancer. Citation Format: Traci Lyons, Lyndsey Crump, Rachel Steinmetz, Kelsey Kines, Heather Fairchild, Alan Elder. Potential novel treatments for high-risk subsets of breast cancer in postpartum and African American women [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-05.

Efficacy and safety of first-line treatment with anti-CD38 monoclonal antibody-based regimen for primary plasma cell leukemia

Objective: To analyze the efficacy and safety of first-line treatment with an anti-CD38 monoclonal antibody regimen for primary plasma cell leukemia (pPCL). Methods: Patients diagnosed with pPCL from December 1st, 2018 to July 26th, 2023, receiving first-line treatment of anti-CD38 monoclonal antibody-based regimens across multiple centers including Peking University People's Hospital, Fuxing Hospital of Capital Medical University, Qingdao Municipal Hospital, Shengjing Hospital of China Medical University, Handan Central Hospital, the First Affiliated Hospital of Harbin Medical University, the Fourth Hospital of Hebei Medical University and General Hospital of Ningxia Medical University were consecutively included. A total of 24 pPCL patients were included with thirteen being male and eleven being female. The median age [M(Q1, Q3)] was 60 (57, 70) years. Patients were grouped according to peripheral blood plasma cell (PBPC) percentage [5%-19% (n=14) vs ≥20% (n=10)]. Last follow-up date was September 26th, 2023. The median follow-up period was 9.1 (4.2, 15.5) months. Patients' data related with clinical baseline characteristics, efficacy, survival and safety were retrospectively collected. Cox proportional hazards regression model was used to analyze risk factors associated with survival. Results: Among 24 pPCL patients, 16 (66.7%) patients had anemia at diagnosis, 13(54.2%) patients had thrombocytopenia, 8 (33.3%) patients had a baseline estimated glomerular filtration rate (eGFR)<40 ml·min-1·(1.73m2)-1, 13 (54.2%) patients had elevated lactate dehydrogenase (LDH) levels. The median PBPC percentage was 16% (8%, 26%) . Fluorescence in situ hybridization testing indicated that patients harboring 17p deletion, t(4;14) or t(14;16) were 6 (25.0%), 4 (16.7%) and 4 (16.7%), respectively. The overall response rate was 83.3% (20/24). The median progression-free survival (PFS) was 20.5 (95%CI: 15.8-25.2) months, and the median overall survival (OS) was not reached. Estimated 1-year and 2-year PFS and OS rates were 75.0% and 89.1%, 37.5% and 53.4%, respectively. The median PFS and OS for patients with PBPC percentages 5%-19% and≥20% were not reached and 20.5 (95%CI:15.7-25.3) months, 17.8 months and not reached, respectively. There was no significant statistical difference of PFS and OS between two groups (all P>0.05). Multivariate Cox regression analysis showed that 1p32 deletion was the risk factor associated with PFS (HR=7.7, 95%CI: 1.1-54.9, P=0.043). Seventeen patients (70.8%) developed grade 3-4 hematologic toxicities. Twelve patients (50.0%) developed grade 3-4 thrombocytopenia. Sixteen patients (66.7%) developed infection. All hematologic toxicities and infections were improved after supportive treatment. Conclusion: First-line treatment with anti-CD38 monoclonal antibody-based therapy for pPCL is effective and safe.

Discovery of a Monoclonal Antibody That Targets Cell-Surface Pseudaminic Acid of Acinetobacter baumannii with Direct Bactericidal Effect.

The therapeutic effects of antibodies include neutralization of pathogens, activation of the host complement system, and facilitation of phagocytosis of pathogens. However, antibody alone has never been shown to exhibit bactericidal activity. In this study, we developed a monoclonal antibody that targets the bacterial cell surface component Pseudaminic acid (Pse). This monoclonal antibody, Pse-MAB1, exhibited direct bactericidal activity on Acinetobacter baumannii strains, even in the absence of the host complements or other immune factors, and was able to confer a protective effect against A. baumannii infections in mice. This study provides new insight into the potential of developing monoclonal antibody-based antimicrobial therapy of multidrug resistant bacterial infections, especially those which occurred among immunocompromised patients.

Identification of Mispairing Omic Signatures in Chinese Hamster Ovary (CHO) Cells Producing a Tri-Specific Antibody.

Monoclonal antibody-based therapy has shown efficacy against cancer, autoimmune, infectious, and inflammatory diseases. Multispecific antibodies (MsAbs), including trispecifics (tsAbs), offer enhanced therapeutic potential by targeting different epitopes. However, when co-expressed from three or more different polypeptide chains, MsAb production can lead to incorrect chain assembly and co-production of mispaired species with impaired biological activity. Moreover, mispairing carries significant challenges for downstream purification, decreasing yields and increasing the cost of bioprocess development. In this study, quantitative transcriptomics and proteomics analyses were employed to investigate which signaling pathways correlated with low and high mispairing clone signatures. Gene and protein expression profiles of Chinese hamster ovary (CHO) clones producing an tsAb were analyzed in the exponential growth and stationary (tsAb production) phase of fed-batch culture. Functional analysis revealed activated endoplasmic reticulum stress in high mispairing clones in both culture phases, while low mispairing clones exhibited expression profiles indicative of activated protein translation, as well as higher endocytosis and target protein degradation, suggesting the clearance of unfolded proteins through ubiquitin-mediated mechanisms. In addition, through transcriptomic profiling, we identified a group of genes that have the potential to be used as a biomarker panel tool for identifying high mispairing levels in the early stages of bioprocess development.

Phytochemicals for mitigating the COVID-19 crisis: evidence from pre-clinical and clinical studies

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in December 2019 quickly escalated to pandemic levels and had a severe impact on public health. There are 761 million confirmed coronavirus disease 2019 (COVID-19) cases, with over 6.88 million deaths worldwide till March 2023. Severe cases of the disease caused critical respiratory failure followed by multiorgan involvement. Clinical escalation of COVID-19 has been correlated with markedly increased plasma inflammatory markers [e.g., C-reactive protein (CRP)] and pro-inflammatory cytokine levels [e.g., interleukin (IL)-6, tumor necrosis factor-α (TNF-α)]. Therapeutic options have mostly utilized corticosteroids, antivirals (e.g., remdesivir), and monoclonal antibody-based immunomodulation (e.g., tocilizumab). These existing treatments have adverse side effects, inadequate efficacy, and limitations in administering to patients with comorbidities and other underlying diseases. Monoclonal antibody-based therapies and some of the antivirals are very costly. Many phytochemicals have previously reported anti-inflammatory, antiviral, and antioxidant properties. Studying the effectiveness of such phytochemicals against COVID-19 and identifying new plant-derived molecules with antiviral properties have been a focus since the SARS-CoV-2 outbreak. This review article has documented in vitro, in vivo, and clinical studies encompassing 28 different phytochemicals belonging to various chemical groups (e.g., polyphenols, alkaloids, terpenes) that show anti-COVID-19 activity. These findings suggest that multiple phytochemicals can interfere with virus entry and replication inside the host cell. Many of them can protect from cytokine storm by acting on intracellular signalling pathways in addition to inhibiting virus multiplication. Phytochemicals may prove useful in alleviating post-COVID complications associated with kidney injury, and central nervous system complications, as well. Plant-derived compounds are usually cheaper and have fewer side effects. But, developing new formulations with better absorption and bioavailability remains a priority. This review informs the readers of the current status and indicates the ongoing research in this highly relevant field.

Topical anti-TNF-a ssDNA aptamer decreased the imiquimod induced psoriatic inflammation in BALB/c mice

BackgroundTumor Necrosis Factor-α (TNF-α) is a pro-inflammatory factor that plays a pivotal role in psoriasis. Due to limitations of monoclonal antibody-based therapies, it is needed to discover new anti-TNF-α factors instead of usual anti-TNF-α monoclonal antibodies. Compared to antibodies, single-stranded DNA or RNA molecules named aptamers, have advantages such as time-saving, less risk for immunogenicity and cost-effectiveness. Therefore, the aim of the present study was to assess the therapeutic effects of T1-T4 dimer anti-TNF-ɑ ssDNA aptamer topical treatment in the imiquimod (IMQ)-induced psoriasis animal model. Methods5% IMQ cream was prescribed on the right ear of BALB/c to induce psoriasis model. The hydrogel-containing anti-TNF-ɑ aptamer or treatment control aptamer (anti- Interleukin (IL)17A) was topically prescribed to the mice's ears 10 min before IMQ cream treatment. The psoriasis area severity index (PASI) score was used to evaluate psoriasis intensity. Histopathology analysis was done for mice ears sections. Mass, size, and cell number of mice spleens were measured. The IL-17 level was determined in culture supernatants of axillary lymph node cells using ELISA. The mRNA expression levels of IL-17A, IL-1β, STAT3, and S100a9, were evaluated in mice treated ear with quantitative Real Time-PCR. ResultsThe anti-TNF-ɑ ssDNA aptamer lower doses had significant decrease in IMQ-induced PASI score (p < 0.05). In addition, in these groups, the IL-17A, STAT3, and S100a9 mRNA levels were significantly lower than the IMQ group (p < 0.05). ConclusionAccording to our findings, this aptamer seems to be a prospective candidate for treating psoriatic inflammation especially in lower concentrations.

Hepatitis B reactivation in patients with multiple myeloma treated with anti-CD38 monoclonal antibody-based therapies: a pharmacovigilance analysis.

Daratumumab and isatuximab are anti-CD38 monoclonal antibodies indicated for the treatment of multiple myeloma. These agents can increase the risk of infectious complications, including viral infections. Cases of hepatitis B virus (HBV) reactivation have been reported in the literature in patients receiving anti-CD38 monoclonal antibody-based therapies. The objective of this analysis was to determine if the association between anti-CD38 monoclonal antibody exposure and the development of hepatitis B reactivation had a detectable reporting signal in the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). We conducted a post marketing pharmacovigilance analysis by querying the FAERS for reports of HBV reactivation with daratumumab or isatuximab exposure reported between 2015 and 2022. Disproportionality signal analysis was conducted by calculating reporting odds ratios (RORs). Sixteen cases of hepatitis B virus reactivation were reported in the FAERS database among patients receiving daratumumab or isatuximab reported between 2015 and 2022. The ROR for HBV reactivation was statistically significant for both daratumumab (ROR 4.76, 95% CI 2.76-8.22) and isatuximab (ROR 9.31, 95% CI 3.00-28.92). Overall, our analysis demonstrates a significant reporting signal for HBV reactivation with daratumumab and isatuximab.

Novel monoclonal antibody-based therapies: implications for the treatment and prevention of HCMV disease.

Human cytomegalovirus (HCMV) is an important pathogen worldwide. Although HCMV infection is often asymptomatic in immunocompetent individuals, it can cause severe or even life-threatening symptoms in immunocompromised patients. Due to limitations of antiviral treatments, it is necessary to search for new therapeutic alternatives. Recent studies have highlighted the contribution of antibodies in protecting against HCMV disease, including neutralizing and non-neutralizing antibodies. Given the immunocompromised target population, monoclonal antibodies (mAbs) may represent an alternative to the clinical management of HCMV infection. In this context, we provide a synthesis of recent data revising the literature supporting and arguing about the role of the humoral immunity in controlling HCMV infection. Additionally, we review the state of the art in the development of therapies based on mAbs.

The Role of Monoclonal Antibodies in Breast Cancer

Monoclonal antibody-based therapy is a promising strategy to treat breast cancer because, as a targeted cancer drug, it locates and binds to a specific cancer cell. The importance of monoclonal antibodies to give an additional and efficient channel remains a serious issue because several kinds of breast cancer, particularly Triple-negative breast cancer (TNBC), have limited methods and a low response to conventional drug therapy. Although patients associated with metastatic diseases used to experience short survival and poor prognosis, developments have been achieved recently. The development of targeted cancer drugs is thought to improve clinical therapies for breast cancers and the overall survival length of patients. Expectations are that targeted cancer drugs will be pair used with chemotherapy, and data has already shown that patients lived nearly two times longer compared to before. This review provides an overview of three types of monoclonal antibodies, trastuzumab, pertuzumab, and trodelvy (sacituzumab govitecan) respectively, which all act as targeted cancer drugs in breast cancer treatments. Three main parts are included in this review, involving the historical development of the drugs, the mechanism of the drugs, and the issues of the drugs while being utilized to treat breast cancer, which is separated into two parts: the side effects and drug resistance.

Nanoparticles (NPs)-mediated systemic mRNA delivery to reverse trastuzumab resistance for effective breast cancer therapy.

Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy. The first monoclonal antibody authorized for treating human epidermal growth receptor 2 (HER2)-positive breast cancer is trastuzumab. However, resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes. To address this issue, tumor microenvironment (TME) pH-responsive nanoparticles (NPs) were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer (BCa). This nanoplatform is comprised of a methoxyl-poly (ethylene glycol)-b-poly (lactic-co-glycolic acid) copolymer with a TME pH-liable linker (Meo-PEG-Dlink m -PLGA) and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction. When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously, they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface. With the intracellular mRNA release to up-regulate PTEN expression, the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells, thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.

A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613.

140 Background: HER2 ( ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibody-based (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio &gt; 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (&gt;5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 – 7.6) months in TP group and 3.7 (95%CI: 1.6 – 6.7) months in CETIRI group (p = 0.35). Grade ≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of 31%. Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy. Clinical trial information: NCT03365882 . [Table: see text]