Efficacy and safety of the first-line systemic treatments in patients with advanced-stage urothelial carcinoma: a systematic review and network meta-analysis.

Introduction: In recent years, some clinical studies of first-line treatment for advanced-stage urothelial carcinoma (aUC) have reached the main endpoint, showing inconsistent clinical efficacy. We hope to explore the efficacy and safety of first-line treatment for aUC. Methods: The relevant literature from January 2000 to February 2024 was searched, and the R language (version 4.3.1) was used to perform a network meta-analysis based on the JAGS package and GEMTC package under the Bayesian framework. The main indicators included OS, PFS, ORR and adverse events of grade 3 or higher. This study has been registered in PROSPERO (CRD42024525372). Results: A total of 8 RCTs involving 5539 patients and 12 treatments were included. Pembrolizumab plus Enfortumab Vedotin (PEM+EV) was significantly better than other groups in OS, PFS and ORR. In terms of OS, PEM+EV was significantly better than nivolumab plus platinum-based chemotherapy (NIVO+platinumCT) (HR=0.60; 95% CI: 0.45-0.81), PEM+platinumCT (HR=0.55; 95%CI: 0.42-0.72), atezolizumab (ATE) + platinumCT (HR=0.57; 95%CI: 0.43-0.75) and platinumCT (HR=0.47; 95%CI: 0.38-0.58). In terms of PFS, PEM+EV was also significantly better than NIVO+platinumCT (HR=0.62; 95%CI: 0.48-0.82), PEM+platinumCT (HR=0.58; 95%CI: 0.45-0.74), ATE+platinumCT (HR=0.55; 95%CI: 0.43-0.69) and platinumCT (HR=0.45; 95%CI: 0.38-0.54). In terms of ORR, PEM+EV had a significant be nefit compared with other treatment measures, which was 2.63 times that of platinumCT (OR=2.63; 95%CI: 2.00-3.45). The adverse events of grade 3 or higher in immunotherapy (ATE, PEM, durvalumab) was significantly lower than other treatment measures. Conclusions: PEM+EV can significantly prolong OS and PFS compared with other treatments, and has a higher ORR. The adverse events of grade 3 or higher of ATE was the lowest. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024525372, identifier CRD42024525372.

Therapeutic antibodies in oncology: an immunopharmacological overview.

The biotechnological development of monoclonal antibodies and their immunotherapeutic use in oncology have grown exponentially in the last decade, becoming the first-line therapy for some types of cancer. Their mechanism of action is based on the ability to regulate the immune system or by interacting with targets that are either overexpressed in tumor cells, released into the extracellular milieu or involved in processes that favor tumor growth. In addition, the intrinsic characteristics of each subclass of antibodies provide specific effector functions against the tumor by activating antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, among other mechanisms. The rational design and engineering of monoclonal antibodies have improved their pharmacokinetic and pharmacodynamic features, thus optimizing the therapeutic regimens administered to cancer patients and improving their clinical outcomes. The selection of the immunoglobulin G subclass, modifications to its crystallizable region (Fc), and conjugation of radioactive substances or antineoplastic drugs may all improve the antitumor effects of therapeutic antibodies. This review aims to provide insights into the immunological and pharmacological aspects of therapeutic antibodies used in oncology, with a rational approach at molecular modifications that can be introduced into these biological tools, improving their efficacy in the treatment of cancer.

Cardiac toxicity of HER-2 targeting antibody-drug conjugates: overview and clinical implications.

Antibody-drug conjugates (ADCs) have recently emerged as a promising therapeutic option that combine the specificity of monoclonal antibodies and the cytotoxic effect of chemotherapy. With numerous ADCs approved and on the market, a particular concern of ADCs that target HER-2 has been their cardiac side effects, in view of the crucial role of HER-2 in cardiac development and physiology. While rarely toxic and generally safe, numerous publications have outlined the consistent association of trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) with the development of cardiac toxicity. Despite not being clinically relevant in most cases, cardiac baseline evaluation, monitoring and early detection of cardiac adverse events remain pivotal with HER-2 targeting ADCs. This review aims to summarize and better characterize the complete cardiac toxicity profile of HER-2 ADCs, with the goal of improving clinical understanding of this adverse event, leading to better recognition, monitoring and management.

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Review of Dose Justifications for Antibody-Drug Conjugate Approvals from Clinical Pharmacology Perspective: a Focus on Exposure-Response Analyses.

Antibody-drug conjugates (ADCs) are revolutionizing cancer treatment by specific targeting of the cancer cells thereby improving the therapeutic window of the drugs. Nevertheless, they are not free from unwanted toxicities mainly resulting from non-specific targeting and release of the payload. Therefore, the dosing regimen must be optimized through integrated analysis of the risk-benefit profile, to maximize the therapeutic potential. Exposure-response (E-R) analysis is one of the most widely used tools for risk-benefit assessment and it plays a pivotal role in dose optimization of ADCs. However, compared to conventional E-R analysis, ADCs pose unique challenges since they feature properties of both small molecules and antibodies. In this article, we review the E-R analyses that have formed the key basis of dose justification for each of the 12 ADCs approved in the USA. We discuss the multiple analytes and exposure metrics that can be utilized for such analysis and their relevance for safety and efficacy of the treatment. For the endpoints used for the E-R analysis, we were able to uncover commonalities across different ADCs for both safety and efficacy. Additionally, we discuss dose optimization strategies for ADCs which are now a critical component in clinical development of oncology drugs.

ADC: a deadly killer of platinum resistant ovarian cancer.

Platinum is a key component of ovarian cancer systemic therapy. However, most patients will eventually face a recurrence, leading to chemotherapy resistance, especially against platinum. For individuals with platinum-resistant ovarian cancer (PROC), treatment options are limited, and their survival prospects are grim. The emergence of antibody-drug conjugates (ADCs) shows promises as a future treatment for PROC. This review synthesizes current research on the effectiveness of ADCs in treating PROC. It encapsulates the advancements and clinical trials of novel ADCs that target specific antigens such as Folate Receptor alpha (FRα), MUC16, NaPi2b, Mesothelin, Dipeptidase 3(DPEP3), and human epidermal growth factor receptor 2 (HER2), as well as tissue factor, highlighting their potential anti-tumor efficacy and used in combination with other therapies. The ADCs landscape in ovarian cancer therapeutics is swiftly evolving, promising more potent and efficacious treatment avenues.

Recent advances in targeted drug delivery systems for multiple myeloma.

Despite significant therapeutic advances, multiple myeloma (MM) remains a challenging, incurable, hematological malignancy. The efficacy of traditional chemotherapy and currently available anti-MM agents is in part limited by their adverse effects, which restrict their therapeutic potential. Nanotherapeutics is an emerging field of cancer therapy that can overcome the biological and chemical barriers of existing anticancer drugs. This review presents an overview of recent advancements in nanoparticle- and immunotherapy-based drug delivery systems for MM treatment. It further delves into the targeting strategies, mechanism of controlled drug release, and challenges associated with the development of drug delivery systems for the treatment of MM.

Pre-treatment [18F]FDG PET/CT biomarkers for the prediction of antibody-drug conjugates efficacy in metastatic breast cancer.

PURPOSE: This study aimed to evaluate the association between pretreatment [18F]FDG PET/CT-derived biomarkers and outcomes in metastatic breast cancer (mBC) patients treated with antibody-drug conjugates (ADCs) Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd). METHODS: A retrospective bicentric analysis was conducted on triple-negative mBC (mTNBC) patients treated with SG and HER2-low mBC patients treated with T-DXd, who underwent [18F]FDG PET/CT scans before therapy. Key biomarkers, including maximum standardized uptake value (SUVmax), total metabolic tumor volume (TMTV) and maximum tumor dissemination (Dmax), were measured. Their prognostic value for progression-free survival (PFS) and overall survival (OS) was assessed using Cox models and Kaplan-Meier curves. RESULTS: 128 patients were included: 71 mTNBC treated with SG and 57 HR-positive and -negative HER2-low mBC treated with T-DXd. Median follow-up was 12.9 months. In the SG cohort, median PFS and OS were 4.8 and 8.9 months, respectively. High Dmax (HR 2.1, 95% CI 1.1-4.3) and high TMTV (HR 2.9, 95% CI 1.2-6.6) were independently associated with shorter OS. In the T-DXd cohort, median PFS and OS were 5.8 and 9.0 months, respectively. High Dmax (HR 2.1, 95% CI 1.2-3.9) and high TMTV (HR 2.4, 95% CI 1.0-6.5) independently correlated with shorter PFS and shorter OS, respectively. CONCLUSION: Pretreatment [18F]FDG PET/CT-derived biomarkers, namely TMTV and Dmax, have significant prognostic value in patients with mTNBC and HER2-low mBC treated with SG and T-DXd. These biomarkers improve prognostic prediction and may optimize treatment strategies, warranting their clinical use, but larger studies are needed to validate these findings.

Novel bispecific antibody-drug conjugate targeting PD-L1 and B7-H3 enhances antitumor efficacy and promotes immune-mediated antitumor responses.

BACKGROUND: Antibody-drug conjugates (ADCs) offer a promising approach, combining monoclonal antibodies with chemotherapeutic drugs to target cancer cells effectively while minimizing toxicity. METHODS: This study examined the therapeutic efficacy and potential mechanisms of a bispecific ADC (BsADC) in laryngeal squamous cell carcinoma. This BsADC selectively targets the immune checkpoints programmed cell death ligand-1 (PD-L1) and B7-H3, and the precise delivery of the small-molecule toxin monomethyl auristatin E. RESULTS: Our findings demonstrated that the BsADC outperformed its bispecific antibody and PD-L1 or B7-H3 ADC counterparts, particularly in terms of in vitro/in vivo tumor cytotoxicity, demonstrating remarkable immune cytotoxicity. Additionally, we observed potent activation of tumor-specific immunity and significant induction of markers of immunogenic cell death (ICD) and potential endoplasmic reticulum stress. CONCLUSION: In conclusion, this novel BsADC, through immune checkpoint inhibition and promotion of ICD, amplified durable tumor immune cytotoxicity, providing novel insights and potential avenues for future cancer treatments and overcoming resistance.

Clinical characterization, prognostic, and predictive values of HER2-low in patients with early breast cancer in the PALLAS trial (ABCSG-42/AFT-05/BIG-14-13/PrE0109).

BACKGROUND: Bidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET). Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC). METHODS: PALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC. To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression's value as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH). All pathologic evaluation was performed locally. Prognostic and predictive power of HER2 were assessed with Cox models. RESULTS: From the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis. Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +). Median follow-up was 59.8 months. HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p < 0.001) and was more frequent in patients enrolled in North America (63.1%) than in Europe (53.4%) or other regions (53.4%) (p < 0.001). HER2 status was not significantly associated with iDFS in a multivariable Cox model (hazard ratio 0.93, 95% confidence interval 0.81 - 1.06). No significant interaction was observed between treatment arm and HER2 status for iDFS (p = 0.43). Similar results were obtained for DRFS and OS. CONCLUSIONS: In this large, prospective, global patient cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes.

Developing combination therapies with biologics in triple-negative breast cancer.

INTRODUCTION: Novel compounds have entered the triple-negative breast cancer (TNBC) treatment algorithm, namely immune checkpoints inhibitors (ICIs), PARP inhibitors and antibody-drug conjugates (ADCs). The optimization of treatment efficacy can be enhanced with the use of combination treatments, and the incorporation of novel compounds. In this review, we discuss the combination treatments under development for the treatment of TNBC. AREAS COVERED: The development of new drugs occurring in recent years has boosted the research for novel combinations to target TNBC heterogeneity and improve outcomes. ICIs, ADCs, tyrosine kinase inhibitors (TKIs), and PARP inhibitors have emerged as leading players in this new landscape, while other compounds like novel intracellular pathways inhibitors or cancer vaccines are drawing more and more interest. The future of TNBC is outlined in combination approaches, and based on new cancer targets, including many chemotherapy-free treatments. EXPERT OPINION: A large number of TNBC therapies have either proved clinically ineffective or weighted by unacceptable safety profiles. Others, however, have provided promising results and are currently in late-stage clinical trials, while a few have actually changed clinical practice in recent years. As novel, more and more selective drugs come up, combination strategies focusing the concept of synergy are fully warranted for the future.

The role of antibody therapies in treating relapsed chronic lymphocytic leukemia: a review.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adult patients. The landscape of CLL therapy has changed in the last decades with the introduction of antibody-based therapies and novel targeted agents resulting in improved outcomes. AREAS COVERED: This article describes the use of monoclonal antibodies, bispecific antibodies and antibody-drug conjugates in the treatment of relapsed and refractory CLL. The mechanism of action and clinical applications and safety of antibody-based therapies, both as monotherapy and in combination with other drugs, are discussed. A literature search was performed using PubMed, Web of Science, and Google Scholar for articles published in English. Additional relevant publications were obtained by reviewing the references from the chosen articles. EXPERT OPINION: Antibody-based therapeutic strategies have drastically changed the treatment of CLL, as they have introduced the concept of boosting immune responses against tumor cells. While immunotherapy is generally effective, some treatment failure can occur due to antigen loss, mutation, or down-regulation, and this remains the main obstacle to cure. The development of novel antibody therapies, including their combinations with targeted drugs and bispecific antibodies, might help to reduce toxicity and improve efficacy.

Next-Generation Therapeutic Antibodies for Cancer Treatment: Advancements, Applications, and Challenges.

The field of cancer treatment has evolved significantly over the last decade with the emergence of next-generation therapeutic antibodies. Conventional treatments like chemotherapy pose significant challenges, including adverse side effects. Monoclonal antibodies have paved the way for more targeted and effective interventions. The evolution from chimeric to humanized and fully human antibodies has led to a reduction in immunogenicity and enhanced tolerance in vivo. The advent of next-generation antibodies, including bispecific antibodies, nanobodies, antibody-drug conjugates, glyco-engineered antibodies, and antibody fragments, represents a leap forward in cancer therapy. These innovations offer increased potency, adaptability, and reduced drug resistance. Challenges such as target validation, immunogenicity, and high production costs exist. However, technological advancements in antibody engineering techniques provide optimism for addressing these issues. The future promises a paradigm shift, where ongoing research will propel these powerful antibodies to the forefront, revolutionizing the fight against cancer and creating new preventive and curative treatments. This review provides an overview of three next-generation antibody-based molecules, namely bispecific antibodies, antibody-drug conjugates, and nanobodies that have shown promising results in cancer treatment. It discusses the evolution of antibodies from conventional forms to next-generation molecules, along with their applications in cancer treatment, production methods, and associated challenges. The review aims to offer researchers insights into the evolving landscape of next-generation antibody-based cancer therapeutics and their potential to revolutionize treatment strategies.

Antibody-drug conjugates (ADCs): a novel therapy for triple-negative breast cancer (TNBC).

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Pharmacovigilance study of the association between peripheral neuropathy and antibody-drug conjugates using the FDA adverse event reporting system.

Antibody-drug conjugates (ADCs) are among the fastest-growing classes of anticancer drugs, making it crucial to evaluate their potential for causing peripheral neuropathy. We analyzed data from the FAERS database (January 1, 2014, to June 30, 2023) using disproportionality and Bayesian methods. We identified 3076 cases of ADC-associated peripheral neuropathy. Our study revealed significant signals for all ADCs (ROR 1.82, 95% CI 1.76-1.89). ADCs with tubulin-binding payloads showed significant peripheral neuropathy signals (ROR 2.31, 95% CI 2.23-2.40), whereas those with DNA-targeting (ROR 0.48, 95% CI 0.39-0.59) and topoisomerase 1 inhibitor (ROR 0.56, 95% CI 0.48-0.66) payloads exhibited non-significant signals. Signals for peripheral sensory neuropathy were 4.83, 2.44, 2.74, and 2.21 (calculated based on IC025) for brentuximab vedotin, trastuzumab emtansine, enfortumab vedotin, and polatuzumab vedotin, while signals for peripheral motor neuropathy were 5.31, 0.34, 2.27, and 0.03, respectively. The median time to onset for all ADCs was 127 days (interquartile range 40-457). Tisotumab vedotin had the highest hospitalization rate at 26.67%, followed by brentuximab vedotin at 25.5%. Trastuzumab emtansine had the highest mortality rate ,with 80 deaths (11.96%) among 669 cases. Based on FAERS database, only ADCs with tubulin-binding payloads exhibited significant peripheral neuropathy signals. Brentuximab vedotin and enfortumab vedotin showed similar profiles for peripheral sensory neuropathy and motor neuropathy. Given the delayed time to onset and potentially poor outcomes, ADC-related peripheral neuropathy warrants significant attention.

Future AI Will Most Likely Predict Antibody-Drug Conjugate Response in Oncology: A Review and Expert Opinion.

The medical research field has been tremendously galvanized to improve the prediction of therapy efficacy by the revolution in artificial intelligence (AI). An earnest desire to find better ways to predict the effectiveness of therapy with the use of AI has propelled the evolution of new models in which it can become more applicable in clinical settings such as breast cancer detection. However, in some instances, the U.S. Food and Drug Administration was obliged to back some previously approved inaccurate models for AI-based prognostic models because they eventually produce inaccurate prognoses for specific patients who might be at risk of heart failure. In light of instances in which the medical research community has often evolved some unrealistic expectations regarding the advances in AI and its potential use for medical purposes, implementing standard procedures for AI-based cancer models is critical. Specifically, models would have to meet some general parameters for standardization, transparency of their logistic modules, and avoidance of algorithm biases. In this review, we summarize the current knowledge about AI-based prognostic methods and describe how they may be used in the future for predicting antibody-drug conjugate efficacy in cancer patients. We also summarize the findings of recent late-phase clinical trials using these conjugates for cancer therapy.

Ocular adverse events associated with antibody-drug conjugates in oncology: a pharmacovigilance study based on FDA adverse event reporting system (FAERS).

Background: Antibody-drug conjugates (ADCs) have emerged as the focus and hotspots in the cancer field, yet the accompanying ocular toxicity has often been underestimated. We aimed to comprehensively and comparatively analyze the risk of ocular toxicity associated with various ADCs using the FDA Adverse Event Reporting System (FAERS) database. Methods: Data were extracted from the FAERS database from Q3 2011 to Q3 2023. We analyzed the clinical characteristics of ADCs-related ocular adverse events (AEs). These data were further mined by proportional analysis and Bayesian approach to detect signals of ADCs-induced ocular AEs. Moreover, the time to onset of ocular toxicity was also evaluated. Results: A total of 1,246 cases of ocular AEs were attributed to ADCs. Ocular toxicity signals were observed in patients treated with belantamab mafodotin, brentuximab vedotin, enfortumab vedotin, mirvetuximab soravtansine, sacituzumab govitecan, trastuzumab deruxtecan, and trastuzumab emtansine. Of these, belantamab mafodotin, trastuzumab emtansine, and mirvetuximab soravtansine, whose payloads are microtubule polymerization inhibitors, were more susceptible to ocular toxicity. The ten most common ADCs-related ocular AEs signals are keratopathy [ROR = 1,273.52, 95% CI (1,129.26-1,436.21)], visual acuity reduced [ROR = 22.83, 95% CI (21.2-24.58)], dry eye [ROR = 9.69, 95% CI (8.81-10.66)], night blindness [ROR = 259.87, 95% CI (228.23-295.89)], vision blurred [ROR = 1.78, 95% CI (1.57-2.02)], photophobia [ROR = 10.45, 95% CI (9.07-12.05)], foreign body sensation in eyes [ROR = 23.35, 95% CI (19.88-27.42)], ocular toxicity [ROR = 144.62, 95% CI (117.3-178.32)], punctate keratitis [ROR = 126.21, 95% CI (101.66-156.69)], eye disorder [ROR = 2.71, 95% CI (2.21-3.32)]. In terms of onset time, sacituzumab govitecan displayed an earlier onset of 21 days, while trastuzumab deruxtecan exhibited the latest onset of 223 days. Conclusion: ADCs may increase the risk of ocular toxicity in cancer patients, leading to serious mortality. With the widespread application of newly launched ADCs, combining the FAERS data with other data sources is crucial for monitoring the ocular toxicity of ADCs. In addition, novel ocular toxicity signals not documented in product labeling were detected. Further research will be necessary to validate our findings in the future.

Revolutionizing triple-negative metastatic breast cancer treatment: sacituzumab Govitecan's role in advancing chemotherapy.

Purpose: This review aims to discuss the role and efficacy of Sacituzumab Govitecan in the management of breast cancer. Summary: Breast cancer is the most prevalent type of cancer among women worldwide. This comprehensive review delves into the advancements brought about by Sacituzumab Govitecan in the treatment of metastatic triple-negative breast cancer (TNBC). With a focus on its mode of action, efficacious role, clinical trials, and comparative advantages over conventional chemotherapy, the review highlights the therapy's precision in targeting cancer cells through monoclonal antibodies. Sacituzumab Govitecan's ability to deliver a chemotherapeutic payload specifically to cancer cells with the Trop-2 receptor sets it apart from traditional chemotherapy, minimizing collateral damage and reducing severe side effects. The impact of Sacituzumab Govitecan on improving progression-free survival, tumor response rates, and, significantly, the quality of life for patients is discussed. This article also sheds light on ongoing trials, FDA recognition, and the therapy's potential to transform breast cancer treatment. Conclusion: In conclusion, Sacituzumab Govitecan shows potential as an innovative therapeutic option for breast cancer, particularly in metastatic breast cancer and triple-negative breast cancer, but it warrants additional research.

Antibody-drug conjugates-related interstitial lung diseases: data mining of the FAERS database.

BACKGROUND: Interstitial lung diseases (ILD) is a serious adverse event (AE) associated with antibody-drug conjugates (ADCs). This study aims to delve deeply into the signals of AE associated with ILD linked to ADCs. RESEARCH DESIGN AND METHODS: The AE reports were extracted from the first quarter of 2004 to the fourth quarter of 2023 based on the FDA Adverse Event Reporting System (FAERS) database. Signal mining was performed using the reporting odds ratio (ROR) method and the multi-item gamma Poisson shrinker (MGPS) method. Data management, analysis, and visualization were carried out using Python, R software, and MySQL. RESULTS: A total of 1389 AE reports related to ILD with 11 types of ADCs as the primary suspected drugs were obtained. The age groups most represented were 61-80 age group. ILD-related AE signals were detected for 11 ADCs in the study. Trastuzumab deruxtecan showed the strongest signals in both for ROR and MGPS methods. The median onset time vary from 8 days to 207 days. CONCLUSIONS: The signals of ILD AE associated with ADCs are notably strong. ILD should be closely monitored and assessed in the clinical use of ADCs taking full account of the efficacy and risks of these drugs.

In-depth characterization of a cysteine-linked ADC disitamab vedotin by multiple LC-MS analysis methods and cutting-edge imaged capillary isoelectric focusing coupled with native mass spectrometry.

The characterization of cysteine-linked antibody‒drug conjugates (ADCs) can be more challenging than that of monoclonal antibodies (mAbs) and lysine-linked ADCs because the interchain disulfide bonds are reduced for payload conjugation, and the chains are noncovalently bonded to each other. Furthermore, payload conjugation and disulfide bond reduction/scrambling may introduce additional charge heterogeneity to biomolecules. This study illustrates an innovative workflow employing multiple separation techniques and tandem high-resolution mass spectrometry for comprehensive and in-depth characterization of disitamab vedotin, a recent-generation cysteine-linked ADC, including reversed-phase liquid chromatography (RPLC), ion exchange chromatography (IEX) and image capillary isoelectric focusing (icIEF). RPLC was employed for reduced chains analysis, subunit analysis and peptide mapping. IEX and icIEF were used for charge heterogeneity analysis. The innovation of the integrated methodology emphasizes the importance of cutting-edge icIEF-MS online coupling under near-native conditions to reveal the heterogeneity of disitamab vedotin.

Antibody drug conjugates in recurrent or metastatic cervical cancer: a focus on tisotumab vedotin state of art.

Cervical cancer (CC) is still characterized by a poor prognosis despite the progress made in its treatment in recent years. Although immunotherapy has improved outcomes for advanced/recurrent disease, there is a significant gap in addressing patients' needs when they progress after platinum and immunotherapy treatments. In this setting, traditional chemotherapy showed limited effectiveness. In this context, antibody-drug conjugates (ADCs) emerged as a promising tool within targeted cancer therapies. Tisotumab vedotin (TV), an ADC targeting tissue factor, represents the first ADC approved by the US Food and Drug Administration for the treatment of recurrent or metastatic CC with disease progression on or after chemotherapy. In phase I-III published trials, TV has already demonstrated an advantage in terms of objective response rate (17.8%-54.4%) and progression-free survival (3.1-6.9 months) in patients who progressed to the first-line standard therapy. Data concerning the addition of TV to platinum/pembrolizumab first-line chemotherapy are still under analysis and strongly expected. However, several questions are still unresolved: (1) the identification of the most suitable timing for ADCs administration in the treatment sequence of advanced/recurrent CC; (2) the evaluation of combination therapies as a tool to minimize the emergence of resistant clones and to enhance overall effectiveness; and (3) the assessment of tolerability and correct management of special toxicities (e.g. ocular and neurological adverse events). In the near future, an improvement in patient selection via biomarker-driven strategies should be crucial for optimizing both treatment benefits and maintaining an acceptable toxicity profile.