Multiple Formats Research Articles

Phishing Websites Spotting with Help of using Machine Learning Tools

Abstract: Phishing assaults cost internet users billions of dollars every year and are a constantly growing hazard in the cyberspace. It is illegal to gather sensitive information from consumers through a number of social engineering techniques. Email, instant messaging, pop-up messages, web pages, and other forms of communication can all be used to identify phishing tactics. This work offers a model that can determine whether a URL link is genuine or fraudulent. The data set used for the classification was sourced from the University of New Brunswick dataset bank, which has a collection of benign, spam, phishing, malware, and defacement URLs, as well as from an open source service called "Phish Tank," which contains phishing URLs in multiple formats such as CSV, JSON, etc. Phishing URLs are identified using a combination of deep neural network methods and more than six machine learning models. The goal of this study is to create a web application software that can identify phishing URLs from a database of more than 5,000 URLs that have been randomly selected, divided into 80,000 training samples and 20,000 testing samples, and then divided again into equal portions of phishing and legitimate URLs. To distinguish between legal and phishing URLs, the URL dataset is trained and tested using feature selections like address bar-based features, domain-based features, HTML & JavaScript-based features. Finally, the study provided a model for classifying URLs as phishing or legitimate. This would be extremely useful in assisting individuals and businesses in identifying phishing attacks by authenticating any link provided to them to prove its validity.

Reducing the inherent auto-inhibitory interaction within the pegRNA enhances prime editing efficiency.

Prime editing systems have enabled the incorporation of precise edits within a genome without introducing double strand breaks. Previous studies defined an optimal primer binding site (PBS) length for the pegRNA of ∼13 nucleotides depending on the sequence composition. However, optimal PBS length characterization has been based on prime editing outcomes using plasmid or lentiviral expression systems. In this study, we demonstrate that for prime editor (PE) ribonucleoprotein complexes, the auto-inhibitory interaction between the PBS and the spacer sequence affects pegRNA binding efficiency and target recognition. Destabilizing this auto-inhibitory interaction by reducing the complementarity between the PBS-spacer region enhances prime editing efficiency in multiple prime editing formats. In the case of end-protected pegRNAs, a shorter PBS length with a PBS-target strand melting temperature near 37°C is optimal in mammalian cells. Additionally, a transient cold shock treatment of the cells post PE-pegRNA delivery further increases prime editing outcomes for pegRNAs with optimized PBS lengths. Finally, we show that prime editor ribonucleoprotein complexes programmed with pegRNAs designed using these refined parameters efficiently correct disease-related genetic mutations in patient-derived fibroblasts and efficiently install precise edits in primary human T cells and zebrafish.

Monitoring Snake Venom-Induced Extracellular Matrix Degradation and Identifying Proteolytically Active Venom Toxins Using Fluorescently Labeled Substrates.

Snakebite envenoming is an important public health issue with devastating consequences and annual mortality rates that range between 81,000 and 138,000. Snake venoms may cause a range of pathophysiological effects affecting the nervous system and the cardiovascular system. Moreover, snake venom may have tissue-damaging activities that result in lifelong morbidities such as amputations, muscle degeneration, and organ malfunctioning. The tissue-damaging components in snake venoms comprise multiple toxin classes with various molecular targets including cellular membranes and the extracellular matrix (ECM). In this study, we present multiple assay formats that enable investigation of snake venom-induced ECM degradation using a variety of (dye-quenched) fluorescently labeled ECM components. Using a combinatorial approach, we were able to characterise different proteolytic profiles for different medically relevant snake venoms, followed by identification of the responsible components within the snake venoms. This workflow could provide valuable insights into the key mechanisms by which proteolytic venom components exert their effects and could therefore prove useful for the development of effective snakebite treatments against this severe pathology.

“MedEd” on Twitter: A Social Network Analysis

Background. In the current era, Twitter is an increasingly popular tool for the dissemination of information as a social media voice. Social media is a valid, but underutilized, education tool at medical education institutions. Social media technologies provide opportunities for the presentation of information in alternative and multiple formats to enhance engagement, content creation, and motivation for individual and collaborative learning.
 Objective. This study examined the type of social structure and sub-clusters do exist regarding “MedEd” on the Twitter network. Additionally, it determined the top opinion leaders in these networks and which type of topics generates users’ interest regarding “MedEd”.
 Methods. This study applied NodeXL to analyze the results and retrieved Twitter data on November 1, 2022 by using the keywords “MedEd”. The data were saved and interpreted in the “vertices” and “edges” on the NodeXL worksheets.
 Results. We found that the top opinion leader (vertex) “Cryptovitas” had the highest in- betweenness and out-degree centrality. “Innov_medicine” had the in-degree centrality for networks. “In-Degree” and “Out-Degree” are the count of Tweets an opinion leader gets and forwards messages out, correspondingly. The study found that although “Cryptovitas” had the highest in-betweenness centrality, “taylorswift13” had the maximum number of followers (91,523,045) with in-betweenness centrality of 0.0. This indicates that the vertex having maximum influence with the largest number of in-betweenness centrality has not linked with several followers.
 Conclusions. Using Twitter embodies a potential prospect to engage the medical education community. The content of top networks’ tweets was around the number of “MedEd” innovations with the potential to significantly improve medical education delivery and innovative technologies in healthcare services. There is no link between the number of followers and in-betweenness centrality to influence the strength of social media voice. Although clinical and social tweets were there, not much was discussed regarding the curriculum reforms, continued professional development, technical issues in MedEd, and assessments. This triggers the insistence for rapid and innovative adaptations to the new learning environments and remarkable revolutions in medical education, including the encouragement of evidence-based education. The Twitter discussions promoted a research network circulating a wide range of informative innovations and collaborations.

Performing Childhood: Maddie Ziegler and the Presentation of Young Girls in Video Clips

Since the 1980s, the production of video clips has been on the rise. Over the past couple of years, clips showing dance choreographies, often embedded within a rather conceptual fictional framework, have greatly increased in popularity. Although the musicians are usually adults, it is not uncommon to cast children and young adults to perform in the videos. At the same time, multiple reality TV formats in which children and young adults compete performing dance choreographies to famous pop songs have become a popular form of entertainment. The American TV series Dance Moms is a prominent example of this phenomenon. One of the best-known young artists in the field is Maddie Ziegler, who made her debut in this show and subsequently appeared in several music videos by the singer Sia. Maddie, born in 2002, was eleven years old when she first performed in a video clip. Her career is emblematic of the presentation of young girls in a popular culture and media that is dominated by the deliberate play with expectations of age and the blurring of categorical distinctions. Drawing on Maddie Ziegler as an example, the following article provides a close analysis of the presentation of young girls in video clips and reality shows. Special attention is given to the atemporal image of adolescence in these adult reconstructions, which, instead of celebrating the rebellious potential of youth, oscillate between the angelic outer appearance of the child and the serious demeanour of the adult.

Oeste smart region. An intermunicipal integrated analytical territorial intelligence platform

Smart regions are described as an instrument to achieve sustainable planning at the regional level, promoting knowledge-based development through continuous learning as an integral part of the development of regional resources that solves challenges through the knowledgeable application of new technologies, the organization of processes and reasonable and future-proof decision-making. With this work we intend to present a territorial intelligence platform, in particular the spatial data infrastructure that supports it. Based on the potential of multiple sources and formats of data available (Big Data), from the systems of twelve Portuguese municipalities. Along with the Internet of Things and collective intelligence the developed model, sets out as an ambition to take advantage of the potential of data science and artificial intelligence, to promote a regional model of governance based on the management of information capable of leveraging the creation of a territorial intelligence center constituting a new paradigm of territorial planning and management based on facts.

Tree Visualization By One Table (tvBOT): a web application for visualizing, modifying and annotating phylogenetic trees.

tvBOT is a user-friendly and efficient web application for visualizing, modifying, and annotating phylogenetic trees. It is highly efficient in data preparation without requiring redundant style and syntax data. Tree annotations are powered by a data-driven engine that only requires practical data organized in uniform formats and saved as one table file. A layer manager is developed to manage annotation dataset layers, allowing the addition of a specific layer by selecting the columns of a corresponding annotation data file. Furthermore, tvBOT renders style adjustments in real-time and diversified ways. All style adjustments can be made on a highly interactive user interface and are available for mobile devices. The display engine allows the changes to be updated and rendered in real-time. In addition, tvBOT supports the combination display of 26 annotation dataset types to achieve multiple formats for tree annotations with reusable phylogenetic data. Besides several publication-ready graphics formats, JSON format can be exported to save the final drawing state and all related data, which can be shared with other users, uploaded to restore the final drawing state for re-editing or used as a style template for quickly retouching a new tree file. tvBOT is freely available at: https://www.chiplot.online/tvbot.html.

Research and Evaluation in a Child-Focused Place-Based Initiative: West Philly Promise Neighborhood.

Place-based initiatives attempt to reduce persistent health inequities through multisectoral, cross-system collaborations incorporating multiple interventions targeted at varying levels from individuals to systems. Evaluations of these initiatives may be thought of as part of the community change process itself with a focus on real-time learning and accountability. We described the design, implementation, challenges, and initial results of an evaluation of the West Philly Promise Neighborhood, which is a comprehensive, child-focused place-based initiative in Philadelphia, Pennsylvania. Priorities for the evaluation were to build processes for and a culture of ongoing data collection, monitoring, and communication, with a focus on transparency, accountability, and data democratization; establish systems to collect data at multiple levels, with a focus on multiple uses of the data and future sustainability; and adhere to grant requirements on data collection and reporting. Data collection activities included the compilation of neighborhood-level indicators; the implementation of a program-tracking system; administrative data linkage; and neighborhood, school, and organizational surveys. Baseline results pointed to existing strengths in the neighborhood, such as the overwhelming majority of caregivers reporting that they read to their young children (86.9%), while other indicators showed areas of need for additional supports and were programmatic focuses for the initiative (e.g., about one-quarter of young children were not engaged in an early childhood education setting). Results were communicated in multiple formats. Challenges included aligning timelines, the measurement of relationship-building and other process-focused outcomes, data and technology limitations, and administrative and legal barriers. Evaluation approaches and funding models that acknowledge the importance of capacity-building processes and allow the development and measurement of population-level outcomes in a realistic timeframe are critical for measuring the success of place-based approaches.

Updated MS²PIP web server supports cutting-edge proteomics applications.

Interest in the use of machine learning for peptide fragmentation spectrum prediction has been strongly on the rise over the past years, especially for applications in challenging proteomics identification workflows such as immunopeptidomics and the full-proteome identification of data independent acquisition spectra. Since its inception, the MS²PIP peptide spectrum predictor has been widely used for various downstream applications, mostly thanks to its accuracy, ease-of-use, and broad applicability. We here present a thoroughly updated version of the MS²PIP web server, which includes new and more performant prediction models for both tryptic- and non-tryptic peptides, for immunopeptides, and for CID-fragmented TMT-labeled peptides. Additionally, we have also added new functionality to greatly facilitate the generation of proteome-wide predicted spectral libraries, requiring only a FASTA protein file as input. These libraries also include retention time predictions from DeepLC. Moreover, we now provide pre-built and ready-to-download spectral libraries for various model organisms in multiple DIA-compatible spectral library formats. Besides upgrading the back-end models, the user experience on the MS²PIP web server is thus also greatly enhanced, extending its applicability to new domains, including immunopeptidomics and MS3-based TMT quantification experiments. MS²PIP is freely available at https://iomics.ugent.be/ms2pip/.

PlasMapper 3.0-a web server for generating, editing, annotating and visualizing publication quality plasmid maps.

PlasMapper 3.0 is a web server that allows users to generate, edit, annotate and interactively visualize publication quality plasmid maps. Plasmid maps are used to plan, design, share and publish critical information about gene cloning experiments. PlasMapper 3.0 is the successor to PlasMapper 2.0 and offers many features found only in commercial plasmid mapping/editing packages. PlasMapper 3.0 allows users to paste or upload plasmid sequences as input or to upload existing plasmid maps from its large database of>2000 pre-annotated plasmids (PlasMapDB). This database can be searched by plasmid names, sequence features, restriction sites, preferred host organisms, and sequence length. PlasMapper 3.0 also supports the annotation of new or never-before-seen plasmids using its own feature database that contains common promoters, terminators, regulatory sequences, replication origins, selectable markers and other features found in most cloning plasmids. PlasMapper 3.0 has several interactive sequence editors/viewers that allow users to select and view plasmid regions, insert genes, modify restriction sites or perform codon optimization. The graphics for PlasMapper 3.0 have also been substantially upgraded. It now offers an interactive, full-color plasmid viewer/editor that allows users to zoom, rotate, re-color, linearize, circularize, edit annotated features and modify plasmid images or labels to improve the esthetic qualities of their plasmid map and textual displays. All the plasmid images and textual displays are downloadable in multiple formats. PlasMapper 3.0 is available online at https://plasmapper.ca.

A qualitative study of stress experiences, health behaviors, and intervention preferences in young adult cancer survivors.

To inform behavioral intervention development, this study examined experiences and unmet needs related to stress, diet, and physical activity in young adult (YA) cancer survivors. Twenty-three semi-structured interviews were conducted with a purposive sample of YA cancer survivors (n = 12 aged 18-29years; n = 11 aged 30-39years; 57% racial or ethnic minority) between May and July 2022 via Zoom. Data were analyzed using a coding reliability approach to thematic analysis. Stressor-related themes included health and health care, economic stability, social and community context, and balancing responsibilities. Transition to independent adulthood was discussed among younger participants (18-29years). Coping-related themes included letting go, keeping anchored in faith, and distraction. Older participants (30-39years) reported more diverse coping strategies. Routine and consistency and the impact of stress were themes aligning with health behaviors. Control was a cross-cutting theme regarding stressors, coping, and health behaviors. Themes related to intervention preferences included individualized approach, expert-based content, peer support, integrative self-care, and manageability. Younger participants preferred multiple intervention formats (e.g., website, tracking logs). Findings highlighted unmet needs regarding social and environmental stressors in YA cancer survivors and a preference for individualized, expert-based content and peer support in stress management-enhanced behavioral interventions. Such interventions may be tailored for specific age groups to account for differences in stress experiences and intervention preferences.

Faculty development initiatives critical to navigate multicultural Business Schools

Due to the increasing complexity of higher educational institutions and the rising mobility of students from new nations and cultures entering higher education, business school environments and their faculty are experiencing greater challenges in providing an inclusive learning experience across multiple classrooms and instructional formats. Business schools need to rise to the occasion to develop their faculty to meet these new challenges, rather than the onus being on faculty alone. This paper reviews the literature and ends with recommendations for business school administrators and management to help foster a business school culture of diversity, inclusion, and acceptance for faculty, staff, and students.

Abstract LB011: Development of novel protein drug conjugates (PDCs) for the selective targeting of ALPP/ALPPL2 expressing tumors

Abstract The placental alkaline phosphatases, ALPP and ALPPL2, are glycosylphosphatidylinositol (GPI)-anchored cell-surface proteins that are expressed in the placenta during fetal development but have very little expression on normal adult tissue. These proteins are over-expressed in a number of different solid tumor indications including ovarian, endometrial, gastric, pancreatic and non-small cell lung cancers. As a result of the highly restricted normal tissue expression and over-expression in cancer, ALPP and ALPPL2 are attractive targets for antibody and protein-drug conjugate (ADC and PDC) approaches. The recent initiation of a Phase I clinical trial utilizing a full-length antibody ADC has fueled further interest in these oncology targets. Small protein domain binders, which have the capacity to penetrate deeper into solid tumors and can be engineered into multiple therapeutic formats in a modular fashion, offer a number of potential benefits over full-length antibodies as the targeting vehicle in PDC therapeutics. We report the identification and characterization of a series of high affinity ALPP/ALPPL2 specific single domain VHH binders which, importantly, show no binding to the closely related ALPI or ALPL isoforms (which have high normal tissue expression). Through application of the Almac Discovery PDC technology platform, these VHH domains have been reformatted into a suite of homogenous site-specifically labelled drug conjugates, with defined drug to antibody ratios, in high yields. These conjugates, which are based on mono- and bi-paratopic Fc fusion formats, employ both clinically established and novel linker-toxin combinations. In pre-clinical studies, the lead bi-paratopic PDCs were well tolerated in vivo and showed excellent anti-tumor efficacy in ALPP/ALPPL2 positive cell-line derived xenograft models of gastric and pancreatic carcinoma, with sustained regressions still observed 10 weeks after administration of the final dose of agent. These agents have physicochemical and pharmaceutical properties suitable for further development and we anticipate that the excellent pre-clinical efficacy profile of lead PDCs will translate to a highly differentiated product for the treatment of a variety of solid tumor indications. Citation Format: Graham Cotton, Paul Trumper, Estelle McLean, Mark Wappett, Stacey Bell, Greg Papadakos, Jennifer Thom, Chiara Saladino, Aaron Cranston, Georgiana Parau, Stephanie Gatdula, Stephanie Burton, Aidan McCann, Tim Harrison. Development of novel protein drug conjugates (PDCs) for the selective targeting of ALPP/ALPPL2 expressing tumors [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 LB011.

Father contribution to human resilience.

Fathers have been an important source of child endurance and prosperity since the dawn of civilization, promoting adaptation to social rules, defining cultural meaning systems, teaching daily living skills, and providing the material background against which children developed; still, the recent reformulation in the role of the father requires theory-building. Paternal caregiving is rare in mammals, occurring in 3-5% of species, expresses in multiple formats, and involves flexible neurobiological accommodations to ecological conditions and active caregiving. Here, we discuss father contribution to resilience across development. Our model proposes three tenets of resilience - plasticity, sociality, and meaning - and discussion focuses on father-specific contributions to each tenet at different developmental stages; newborn, infant, preschooler, child, and adolescent. Father's style of high arousal, energetic physicality, guided participation in daily skills, joint adventure, and conflict resolution promotes children's flexible approach and social competence within intimate bonds and social groups. By expanding children's interests, sharpening cognitions, tuning affect regulation, encouraging exploration, and accompanying the search for identity, fathers support the sense of meaning, enhancing the human-specific dimension of resilience. We end by highlighting pitfalls to paternal contribution, including absence, abuse, rigidity, expectations, and gender typing, and the need to formulate novel theories to accommodate the "involved dad."

Exploring Web-Based Information and Resources That Support Adolescents and Young Adults With Cancer to Resume Study and Work: Environmental Scan Study.

Adolescents and young adults (AYAs) diagnosed with cancer experience physical, cognitive, and psychosocial effects from cancer treatment that can negatively affect their ability to remain engaged in education or work through cancer treatment and in the long term. Disengagement from education or work can have lasting implications for AYAs' financial independence, psychosocial well-being, and quality of life. Australian AYAs with cancer lack access to adequate specialist support for their education and work needs and report a preference for web-based support that they can access from anywhere, in their own time. However, it remains unclear what web-based resources exist that are tailored to support AYAs with cancer in reaching their educational or work goals. This study aimed to determine what web-based resources exist for Australian AYAs with cancer to (1) support return to education or work and (2) identify the degree to which existing resources are age-specific, cancer-specific, culturally inclusive, and evidence-based; are co-designed with AYAs; use age-appropriate language; and are easy to find. We conducted an environmental scan by searching Google with English search terms in August 2022 to identify information resources about employment and education for AYAs ever diagnosed with cancer. Data extraction was conducted in Microsoft Excel, and the following were assessed: understandability and actionability (using the Patient Education and Materials Tool), readability (using the Sydney Health Literacy Laboratory Health Literacy Editor), and whether the resource was easy to locate, evidence-based, co-designed with AYAs, and culturally inclusive of Aboriginal and Torres Strait Islander peoples. The latter was assessed using 7 criteria previously developed by members of the research team. We identified 24 web-based resources, comprising 22 written text resources and 12 video resources. Most resources (21/24, 88%) were published by nongovernmental organizations in Australia, Canada, the United States, and the United Kingdom. A total of 7 resources focused on education, 8 focused on work, and 9 focused on both education and work. The evaluation of resources demonstrated poor understandability and actionability. Resources were rarely evidence-based or co-designed by AYAs, difficult to locate on the internet, and largely not inclusive of Aboriginal and Torres Strait Islander populations. Although web-based resources for AYAs with cancer are often available through the websites of hospitals or nongovernmental organizations, this environmental scan suggests they would benefit from more evidence-based and actionable resources that are available in multiple formats (eg, text and audio-visual) and tailored to be age-appropriate and culturally inclusive.

Survey of Existing Electronic Readers for the Blind

Thanks to advancements in technology, a wide variety of electronic readers are available for the visually challenged with multiple input and output format options. We found out that the cost of most devices on offer is quite high. So, there exists a place for a new low cost, high translation accuracy and highly portable (small in size) device. Key Words: Blind, Electronic Readers, Stand-Alone Readers, Screen Readers, Speech Output, Braille Displays

Interactive Digital Notice Boards for Universities in Ghana

Purpose: The purpose of this study was to design and implement an Interactive Digital Notice Board (IDNB) for universities to address the limitations of traditional notice boards and improve communication among students, faculty, and staff.
 Design/Methodology/Approach: The study employed a mixed-methods approach, combining quantitative data collection through surveys and qualitative data collection through interviews with key stakeholders. The data were analyzed using descriptive statistics and thematic analysis.
 Findings: The study found that the IDNB was an effective communication tool that enhanced information dissemination and facilitated interaction among students, faculty, and staff. The IDNB was also perceived as user-friendly and visually appealing.
 Research Limitation/ Implication: The study was limited to the CCTU campus, and the findings may not be generalizable to other contexts. The study also did not evaluate the long-term sustainability and cost-effectiveness of the IDNB.
 Practical Implications: The IDNB has practical implications for CCTU as it can improve communication efficiency and reduce paper wastage associated with traditional notice boards. The IDNB can also serve as a platform for targeted advertising, event promotion, and student engagement.
 Social Implications: The IDNB can enhance social interactions and create a sense of community among students, faculty, and staff. It can also promote inclusivity by providing access to information in multiple languages and formats, catering to the diverse student body at CCTU.
 Originality/Value/ Novelty: The IDNB is novel in its interactive and user-friendly design, which sets it apart from traditional notice boards. It also integrates multimedia features, such as videos and images, to enhance engagement and information retention. The IDNB can serve as a blueprint for other institutions looking to adopt innovative communication strategies.

Abstract 2982: TriTCE CPI, next generation trispecific T cell engagers with integrated checkpoint inhibition (CPI) for the treatment of solid tumors

Abstract CD3-bispecific T cell engager (TCE) therapies have exhibited clinical utility against hematological malignancies, but successes in solid tumor indications have been limited. Compared to heme malignancies, treatment of solid tumors is hindered by immunosuppressed microenvironments that can be refractory to traditional CD3-bispecific TCEs. Immunosuppression in the tumor microenvironment limits treatment responses in part due to the expression of inhibitory immune checkpoints, such as PD-1 on exhausted T cells and PD-L1 on tumor cells. To improve T cell responses and anti-tumor activity in immunosuppressed solid tumors, we generated trispecific TCE antibodies (Abs) that target a tumor associated antigen (TAA), CD3 and PD-L1 (via a PD1 moiety) to stimulate tumor-directed T cell killing and checkpoint blockade at the tumor site. In this engineering approach we harnessed the flexibility of our AzymetricTM technology to screen multiple antibody formats, geometries, paratopes, and PD-1 domain affinities in parallel. We screened the TriTCE CPI antibodies, targeting different TAAs, for tumor-directed T cell cytotoxicity and CPI activity on TAA+PD-L1+ and TAA-PD-L1+ tumor cells. We identified multiple TriTCE CPI Abs that induced potent TAA-dependent T cell killing of TAA+PD-L1+, but not TAA-PD-L1+, tumor cells. Evaluation of CPI using a PD-1/PD-L1 checkpoint reporter gene assay identified antibody formats that stimulated simultaneous TAA dependent T cell engagement and enhanced checkpoint inhibition superior to bispecific Ab plus anti-PD-L1 Ab combination treatments. Additionally, in a human PBMC-engrafted xenograft model, TriTCE CPI Abs showed increased anti-tumor activity compared to a bispecific Ab control +/- anti-PD-L1 Ab treatment. Furthermore, the benefits of increased anti-tumor activity and CPI was observed across multiple TriTCE CPI Abs targeting different TAAs. We generated multiple TriTCE CPI Abs that combine tumor-dependent T cell cytotoxicity with checkpoint blockade, which may translate to improved T cell responses in immunosuppressed solid tumors. The evaluation of multiple Ab formats, geometries and paratope affinities allowed for optimization of TAA-dependent cytotoxicity and CPI to identify Abs with enhanced anti-tumor activity and superior site-specific CPI, key factors that may contribute to a wide therapeutic index and improved clinical outcomes. Citation Format: Maya C. Poffenberger, Meghan M. Verstraete, Anna Von Rossum, Patricia Zwierzchowski, Matteo Zago, Veronica Luu, Sifa Arrafi, Siran Cao, Harsh Pratap, Chayne L. Piscitelli, Nina E. Weisser, Thomas Spreter von Kreudenstein. TriTCE CPI, next generation trispecific T cell engagers with integrated checkpoint inhibition (CPI) for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2982.

Abstract 1865: Development of CTIM-76, a highly specific Claudin 6 bispecific antibody for treatment of ovarian cancer

Abstract Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for many late-stage solid tumors are lacking. Ovarian cancer alone kills 14,000 people each year, and many patients do not respond to currently available treatments. Here we introduce CTIM-76, a CLDN6 T-cell engager antibody as a potential treatment of ovarian, endometrial, and other solid tumors. The tight junction protein Claudin 6 (CLDN6) is a validated therapeutic target for many solid tumor types, including ovarian, endometrial, testicular, and gastric. It is differentially expressed on cancer cells with no reported expression in normal, healthy tissue. Despite being an attractive target, therapeutic monoclonal antibodies (MAbs) targeting CLDN6 are difficult to discover due to an abundance of closely related family members and an absolute need for high specificity. The extracellular region of CLDN6 closely resembles the widely expressed family member CLDN9 (3 amino acids different). The few CLDN6 MAbs in clinical development have demonstrated significant binding to other CLDN family members and most have now been halted from further development. Starting with a panel of highly specific CLDN6 antibodies, we engineered a large set (> 50) of CLDN6xCD3 bispecific antibodies (CLDN6 bispecifics) using multiple formats and CD3 arms that encompass different geometries and binding stoichiometries, as these factors are expected to play a critical role in the potency of these molecules both in vitro and in vivo. In vitro T cell cytotoxicity and cytokine release assays as well as developability studies were used to select a small panel of antibodies. These were tested in vivo and demonstrated efficacy in xenograft studies in PBMC-engrafted mice. From this smaller panel, we chose a lead molecule, CTIM-76 for IND-enabling studies. CTIM-76 shows a combination of potent killing of CLDN6-expressing cells, no killing of cells expressing other closely related claudin family members, and excellent productivity and developability. The exquisite specificity of CTIM-76 suggests the potential to address the need for potent therapeutic modalities for ovarian and other cancers without compromising patient safety. Citation Format: Joseph Rucker, Ileine Sanchez, Kyle Doolan, Breanna Tyrell, Anna Lobley, Nicholas Molino, Kristen Shema, Kyle Guldner, Hayley Roth, Alyssa Cunningham, Kate Slovik, Riley Payne, Eric Butz, Evan Dick, Edward Calamai, Ross Chambers. Development of CTIM-76, a highly specific Claudin 6 bispecific antibody for treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1865.

Abstract 2249: Development and validation of a pharmacodynamic (PD) assay for TOS-358, the first covalent inhibitor of PI3Kα in clinical development

Abstract TOS-358 is a first-in-class covalent inhibitor of PI3Kα and is currently in clinical development in a variety of solid malignancies. We have developed a fit-for-purpose pharmacodynamic assay to evaluate the target occupancy of TOS-358 in in vitro and in vivo setting at multiple timepoints. The PI3Kα assay allows direct measurement of both occupied and total protein in multiple different samples and tissue types. Signals of occupied and unoccupied PI3Kα proteins can be readily measured in cellular and in vivo samples. The assay was utilized in a large panel of cancer cell lines, revealing a direct correlation between target occupancy and pathway inhibition of markers such as phosphoAKT and phosphoS6. Critically, these correlations revealed the need to achieve near complete suppression of PI3Kα to enable sustained pathway inhibition and cancer cell death. We furthermore utilized this assay to explore the turnover rate of PI3Kα across multiple diverse tumor types, mutations, and tissues. This approach enables highly sensitive target engagement analysis of TOS-358 across multiple formats. Citation Format: John R. MacDougall, Raymond Mak, John Bradley, Allison Simpson, Claire May, Lan Wei, Kendra Ouellette, Marty Olbrot, Jimmy Blair, Neil Dhawan, Wei Chen. Development and validation of a pharmacodynamic (PD) assay for TOS-358, the first covalent inhibitor of PI3Kα in clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2249.