bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2868: ADG206, an anti-CD137 agonistic POWERbody࣪ with tailor-made efficacy and safety profiles by strong crosslinking and tumor selective activation for single and combinational cancer immunotherapy
Authors: Liu Guizhong , Dai Zhengxi , Qu Jiagui , Shi Jianfeng , Zhao Qi , Qu Linhai , Li Yan , Zheng Songmao , Xu Jiangchun , Du Felix , Luo Peter 
Published: June 2022

Abstract
Targeting CD137 by agonistic antibodies faces various challenges in the clinic. Utomilumab appears safe but has modest efficacy, while urelumab is more efficacious but causes severe dose-dependent liver toxicity. To unlock the full potential of CD137 immunotherapy, we engineered a ADG206 POWERbody࣪ by combining our SAFEbody® technology’s precision masking of the antigen binding sites with the Fc engineering in order to achieve improved safety and efficacy profiles. In normal tissues, the CD137 antigen binding interfaces of ADG206 are masked using a covalently linked designer peptide to limit on-target off-tumor toxicities, whereas in the tumor microenvironment (TME), the masked antibody can be activated to selectively bind CD137, promoting costimulatory signaling in situ. The activity of ADG206 is further heightened by incorporating Fc mutations with increased FcγR-mediated crosslinking, resulting in enhanced T cell responses and antitumor activity. In vitro nonclinical studies demonstrate that activated ADG206 binds to CD137, with agonistic activity strictly dependent on FcγR-mediated crosslinking, in contrast to FcγR-independent stimulation of CD137 by urelumab. When activated, ADG206 exhibits up to ~4-fold stronger anti-CD137 agonistic activity than urelumab for T cell activation in the presence of a primary stimulatory signal, while masked ADG206 has much lower activity. In vivo nonclinical studies demonstrate that ADG206 has robust single agent antitumor activities in multiple syngeneic murine tumor models and synergistic efficacy when combined with other immunomodulatory agents. Moreover, ADG206 is well-tolerated in rats and cynomolgus monkeys in nonclinical toxicology studies, with normal pharmacokinetic behaviors and minimal activation in circulation. These results demonstrate that ADG206 POWERbody acquires a tailor-made product profile toward a best-in-class anti-CD137 immunotherapeutic agent that combines conditional activation in the TME with strong agonistic activity through heightened FcγR-mediated crosslinking. Further clinical development of ADG206 POWERbody may hold promises for achieving the long-awaited desirable tolerability and efficacy outcome of an anti-CD137 immunotherapy in either single agent or combination regimens.
Citation Format: Guizhong Liu, Zhengxi Dai, Jiagui Qu, Jianfeng Shi, Qi Zhao, Linhai Qu, Yan Li, Songmao Zheng, Jiangchun Xu, Felix Du, Peter Luo. ADG206, an anti-CD137 agonistic POWERbody࣪ with tailor-made efficacy and safety profiles by strong crosslinking and tumor selective activation for single and combinational cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2868.
Abstract 2905: A novel therapeutic antibody against CD73 that ameliorates the tumor microenvironment and improves the efficacy of cancer immunotherapy
Authors: Matsumoto Noriko , Mishima Yuji , Obonai Toshifumi , Ban Haruka , Mie Motoya , Nakamura Norihiro 
Published: June 2022

Abstract
Background: CD73, also known as ecto-5’-nucleotidase (NT5E), is a GPI-anchored cell surface enzyme expressed on certain types of immune cells and tumor cells. This enzyme catalyzes the hydrolytic conversion of extracellular adenosine monophosphate (AMP) to adenosine (Ado) that suppresses tumor-infiltrating immune cells via the adenosine receptors, allowing tumors to escape the immune system. Here, we introduce a novel anti-human CD73 antibody called BP1200 that strongly blocks the generation of Ado by CD73 and thereby reverses immune suppression in tumors.
Methods: We screened anti-CD73 antibodies by antigen-specific single B cell sorting from mice immunized with recombinant human CD73. CDRs of the antibodies that inhibit the enzyme activity of CD73 were engrafted into human IgG1 framework carrying the mutations of Fc silent. The proliferation and cytotoxicity of T cells were analyzed using human peripheral blood mononuclear cells (PBMC) in the presence of ATP. Efficacy of BP1200 in vivo was investigated by using mice bearing human CD73 knock-in-MC38 cells and mice implanted with human NSCLC cell line (NCI-H292) and PBMC.
Results: The humanized anti-CD73 antibody (BP1200) binds to both human and cynomolgus CD73 expressed on cell surface with KD value of 0.2 nM (human CD73). BP1200 blocked the hydrolysis of AMP by CD73 expressed as both membrane-bound and soluble form without the hook effect. BP1200 induced internalization of CD73 and remarkably decreased the cell surface CD73, indicating that BP1200 inhibits the enzyme activity as well as downregulates the protein level of CD73 at the cell surface. BP1200 induced in vitro proliferation, cytokine production, and cytotoxic activity of T cells even in the presence of high level of ATP, suggesting that BP1200 enhances the T cell immunity in immunosuppressive tumor micro-envelopment (TME). In vivo studies showed that the combination treatment of BP1200 with anti-PD-1/PD-L1 antibodies remarkably retarded tumor growth. Moreover, the mice administrated with BP1200 and anti-PD-1 exhibited long-term immune memory effects that rendered them resistant to rechallenge with tumors.
Conclusions: The novel anti-human CD73 antibody, BP1200, ameliorates immunosuppressive TME caused by adenosine and enhances antitumor immune responses. The combination of BP1200 and immune-checkpoint inhibitors for cancer treatment will be a promising therapeutic option in clinical practice.
Citation Format: Noriko Matsumoto, Yuji Mishima, Toshifumi Obonai, Haruka Ban, Motoya Mie, Norihiro Nakamura. A novel therapeutic antibody against CD73 that ameliorates the tumor microenvironment and improves the efficacy of cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2905.
Abstract 2944: Rapid and accurate variant calling of FFPE samples with the Genexus System
Authors: Casuga Iris , Chan Frances , Huynh Milton , Govoni Gregory R. , Zochowski Kayla , Jayaweera Thilanka , Au-Young Janice 
Published: June 2022

Abstract
Next-Generation Sequencing technology has enhanced oncology research by enabling the detection of all cancer related variants into one assay for research and drug discovery programs. The Oncomine࣪ Comprehensive Assay v3, a pan-cancer panel, used with the Ion Torrent࣪ Genexus࣪ System allows for formalin-fixed paraffin embedded (FFPE) samples to be examined across 161 unique genes in an automated sample to result workflow in 30hrs. This study demonstrates ≥ 95% Sensitivity and PPV for detecting SNV, Indel, and Copy Number variants of clinical FFPE samples along with fusions. When tested using analytical controls, the Genexus System achieves ≥ 98% Sensitivity for hotspot variants, ≥ 95% for de novo variants, and 100% Sensitivity for fusion variants. The Ion Torrent࣪ Genexus࣪ System is fully automated and consists of two software linked instruments, the Ion Torrent࣪ Genexus࣪ Purification System and the Ion Torrent࣪ Genexus࣪ Integrated Sequencer. For this study, the purification system was used to sequentially extract and quantify DNA & RNA samples from human colon and lung FFPE tumor tissue. The purification instrument provides minimal hands-on-time, ease of use and compatibility with the integrated sequencer. It extracts and quantifies the nucleic acids, records the quantitation values and transfers the nucleic acids to an output plate. The plate is transferred from the purification instrument directly to the sequencer for sample dilution, library preparation, and sequencing using the Oncomine࣪ Comprehensive Assay v3 panel. Variant calling analysis of the DNA & RNA pairs is completed immediately following sequencing. Results show that the variants are detected reproducibly with ≥ 95% Sensitivity and PPV when compared to the Ion GeneStudio࣪ S5 System as an orthogonal method. All variants in the report were correct with p-values ≤ 10-5. Additionally, a subset of the extracted samples was evaluated using Sanger Sequencing to verify hotspot mutations found in samples sequenced on both the Genexus࣪ System and GeneStudio࣪ S5 System. Results show that all expected hotspot variants were detected. In summary, the Ion Torrent࣪ Genexus࣪ System is a reliable and fast turnaround solution for sample-to-variant calling results. When used with the Oncomine࣪ Comprehensive Assay v3 panel, the system provides accurate identification of tumor markers for oncology research.
Citation Format: Iris Casuga, Frances Chan, Milton Huynh, Gregory R. Govoni, Kayla Zochowski, Thilanka Jayaweera, Janice Au-Young. Rapid and accurate variant calling of FFPE samples with the Genexus System [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2944.
Abstract 312: Redirecting T cells to tumor targets with functionally diverse CD3-binding antibodies
Authors: DeVorkin Lindsay , Jacobs Tim M. , Tonikian Raffi , Hervé Karine , Caldwell Kate , Hwang Yuri , Faralla Cristina , Wei Wei , Lam Katherine J. , Dhupar Harveer , Tran Tran NT , Cid Melissa , Bolten Lena M. , Pinsky Tova , Dalal Kush , Heyries Kevin A. , Barnhart Bryan C. 
Published: June 2022

Abstract
Bispecific antibodies that redirect cancer-killing T cells towards tumors are promising next-generation cancer therapies. While there are hundreds of T cell engagers (TCEs) in development, there is only one approved and marketed CD3-binding TCE. The high rate of attrition is largely attributable to dose-limiting toxicities, including cytokine release syndrome, due in part to the small pool of high affinity CD3-binding antibodies that are commonly used. The discovery of safe and effective TCEs is limited because diverse panels of parental CD3 antibodies are hard to produce, the pairing of parentals is hard to perfect, and the sheer complexity and volume of data is hard to action. In this study, we will present a panel of functionally diverse, fully human CD3-binding parental antibodies. We will present data characterizing the diversity of our panel across multiple parameters, including sequence diversity, CD3 affinity, epitope binding, T cell activation, cytokine release, and tumor cell killing. Using OrthoMab࣪, our clinically-validated bispecific engineering platform, allows this panel to be tested with a series of tumor-associated antigens (TAAs) in a matrix format. Results from high-throughput production and characterization of bispecific antibodies will be presented. These multidimensional datasets of TCE composition and function allow for the identification of pairs that are optimal candidates for clinical development. This work will show how the diversity of our CD3-binding panel, combined with a robust bispecific protein engineering technology, can be used to quickly assess large and diverse TAA-binding panels discovered through our technology stack. An integrated workflow that doubles the data with diverse panels of parentals, assembles stable, safe, and manufacturable TCEs, and visualizes multidimensional datasets are critical to successfully identifying lead therapeutic candidates to bring the next generation of cancer therapies to patients sooner.
Citation Format: Lindsay DeVorkin, Tim M. Jacobs, Raffi Tonikian, Karine Hervé, Kate Caldwell, Yuri Hwang, Cristina Faralla, Wei Wei, Katherine J. Lam, Harveer Dhupar, Tran NT Tran, Melissa Cid, Lena M. Bolten, Tova Pinsky, Kush Dalal, Kevin A. Heyries, Bryan C. Barnhart. Redirecting T cells to tumor targets with functionally diverse CD3-binding antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 312.
Abstract 3170: Human retroviral sequences transcription in glioma/glioblastoma sample
Authors: Lassak Adam J. , Rak Monika , Baddoo Melody C. , Lin Hui-Yi , Reiss Krzysztof 
Published: June 2022

Abstract
In glioblastoma patients, expansion of glioma initiating cells (GICs), a discrete population of cells demonstrating stem-like phenotype, is often associated with drug resistance development and ultimately cancer recurrence. Therefore a better understanding of the molecular and cellular mechanisms underlying the origin of GICs is critical to develop new therapies better targeting glioblastoma. Human endogenous retroviral sequences (HERVs), present in approximately 500,000 copies and comprising nearly 8% of the human genome, may serve as an abundant genetic material equipping GIC with phenotypic plasticity needed to develop stem-like phenotype. Recent epigenomic and transcriptomic data show HERV activation during early human development. Moreover, increased HERV transcription is observed in OCT4/SOX2/KLF4/c-MYC induced pluripotent cells. Finally, activation of HERV loci transcription is also commonly observed in different tumor types. Using publicly available The Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) RNA-seq data collection, we have quantified transcripts for all 13,208 HERV loci annotated in the RepBase database. To improve the accuracy of quantifying the HERV transcriptomic landscape, we reassigned already mapped fragments to the most probable transcript using the Telescope software. Our comprehensive approach allowed us to identify the set of HERV loci uniquely dysregulated in the glioblastoma compared to normal brain tissue. In addition, we compared 540 low-grade glial tumors from TCGA-LGG project (classified as grade II and III gliomas) with 165 glioblastoma samples from TCGA-GBM (classified as grade IV gliomas) using the same bioinformatics pipeline. Comprehensive analysis of transcript levels allowed us to identify HERV assemblage differentially expressed between these two patient cohorts. The correlation between HERV and ORF transcript levels show strong coregulation of HERVs expression with genes involved in establishing/maintaining embryonic/neural/glial stem cells phenotype. To confirm our observations we have up- or downregulated HERV loci combining guide RNA array targeting robustly approximately 90% of HERV LTR5Hs elements with a vector expressing CRISPR-based transcriptional activator or repressor. Downregulation of HERV transcription with this system was associated with the inhibition of clonogenic growth in cell culture. In summary, this study sets the stage for identifying HERV loci that could serve as potential GIC biomarkers, as well as the molecular targets for GIC elimination.
Citation Format: Adam J. Lassak, Monika Rak, Melody C. Baddoo, Hui-Yi Lin, Krzysztof Reiss. Human retroviral sequences transcription in glioma/glioblastoma sample [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3170.
Abstract 3175: Methylmalonic acid in TME signaling
Authors: Low Vivien , Li Zhongchi , Laughney Ashley , Jin Wenbing , Dephoure Noah , Luga Valbona , Earlie Ethan , Parang Bobak , Guo Chunjun , Cantley Lewis , Blenis John 
Published: June 2022

Abstract
The importance of metabolic reprogramming in cancer has been long demonstrated by the association of systemic metabolic changes, such as aging, diet and exercise, with cancer outcomes. These systemic shifts, combined with local metabolic alterations within the tumor microenvironment (TME), can all cooperate to foster an environment conducive to cancer progression. In cells derived from primary and metastatic patient tumors, we found that mesenchymal-like cells displayed dysregulated propionate metabolism, leading to increased accumulation and secretion of methylmalonic acid (MMA), a novel aging-induced oncometabolite. This tumor cell-secreted MMA, in addition to increased MMA in the serum of elderly individuals, combine to form high local accumulation of MMA in the TME. We discovered that MMA acts on fibroblasts in the TME, activating them to cancer-associated fibroblasts (CAFs). MMA modifies the cargo of CAF-secreted extracellular vesicles (EVs), which function as a messenger to tumor cells, further promoting epithelial-to-mesenchymal transition, drug resistance, and increased metastasis in vivo. Here, we reveal a novel function of MMA in cancer, demonstrating for the first time that tumor-secreted MMA recruits the tumor microenvironment to drive cancer progression and metastatic reprogramming.
Citation Format: Vivien Low, Zhongchi Li, Ashley Laughney, Wenbing Jin, Noah Dephoure, Valbona Luga, Ethan Earlie, Bobak Parang, Chunjun Guo, Lewis Cantley, John Blenis. Methylmalonic acid in TME signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3175.
Abstract 3177: Liver endothelium secreted LRG1 is a novel ligand of HER3 to promote metastatic colorectal cancer growth
Authors: Rathore Moeez Ghani , Zhang Wei , Wright Michel'le , Winter Jordan , Li Yamu , Wang Zhenghe , Wang Rui 
Published: June 2022

Abstract
Background: Liver is the most common site of developing distant metastasis in colorectal cancer (CRC). Patients with metastatic CRC (mCRC) have a 5-year survival rate at 14%. We previously showed that liver endothelial cells (EC), a key component of the liver microenvironment, secrete soluble factors to promote CRC growth and chemoresistance via activating human epidermal growth factor receptor (ERBB3, also known as HER3). However, we found that the ECs activated HER3 by a previously unknown mechanism that is independent of the established HER3 ligand neuregulins. Identifying a new HER3 ligand will potentially give rise to novel therapeutic target for treating patients with mCRC.
Methods: We first fractionated conditioned medium (CM) from liver ECs by fast protein liquid chromatography. The specific fractions that activated HER3 and AKT in CRC cells were subjected to mass spectrometry (MS) for protein identification. In parallel, we used a His-tagged HER3 Extracellular domain (ECD) and pulled down EC-secreted factors that directly bound to HER3 and then subjected to protein identification by MS. Candidate proteins identified in both MS analyses were subjected for further validations by siRNA or immunoprecipitation depletion from EC CM to determine their roles in HER3 activation and CRC growth.
Results: We identified a specific fraction of liver EC CM increased phosphorylation of HER3 and AKT in CRC cells (determined by Western blotting). Meanwhile, the HER3-ECD affinity binding assay showed that HER3 ECD-depleted EC CM could no longer activate HER3 or promote growth, and the soluble factor(s) eluted from HER3-ECD increased phosphorylation of HER3 and AKT, and promoted growth in CRC cells. Results from both MS analyses revealed that LRG1 is a potential ligand that binds to and activate HER3 in CRC cells. We depleted LRG1 from EC CM, either by siRNA knockdown LRG1 in ECs or immunoprecipitation, and found that LRG1-depleted EC CM could no longer activate HER3 and AKT in CRC cells, and LRG1-depleted EC CM failed to promote growth of CRC cell in vitro and CRC xenografts in vivo.
Conclusions: We identified LRG1 as a new HER3 ligand and demonstrated that liver EC-secreted LRG1 mediates EC paracrine effects on activating HER3 and promoting CRC cell growth. Our findings suggest an oncogenic role of EC-secreted LRG1 in the surrounding liver microenvironment of mCRC, and highlighted a potential of blocking LRG1 with monoclonal antibodies for treating patients with mCRC.
Citation Format: Moeez Ghani Rathore, Wei Zhang, Michel'le Wright, Jordan Winter, Yamu Li, Zhenghe Wang, Rui Wang. Liver endothelium secreted LRG1 is a novel ligand of HER3 to promote metastatic colorectal cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3177.
Abstract 3192: EBV-products containing exosomes remodel NPC tumor microenvironment by activating fibroblasts
Authors: Lee Po-Ju , Sui Yun-Hua , Huang Chen-Han , Liu Tzu-Tung , Tsang Ngan-Ming , Liu Shu-Chen 
Published: June 2022

Abstract
Epstein-Barr virus (EBV) infection is intimately associated with type III nasopharyngeal carcinoma (NPC). Most NPCs respond well to chemoradiation. Nevertheless, approximately 20% of patients experience recurrence and distant metastasis. Tumor desmoplastic responses and high densities of cancer-associated fibroblasts (CAFs) within tumors have been correlated with poorer prognosis. In this study, we demonstrate that EBV activates fibroblasts via exosomes to remodel a pro-tumoral microenvironment. Exosomes derived from NPC cells contained a high level of fibroblast activation protein alpha (FAPα) and EBV-encoded latent membrane protein 1 (LMP1). Treating primary fibroblasts with these exosomes induced functional changes resembling CAFs. Transcriptomic analysis on exosome-treated fibroblasts revealed genes involved in fibrosis-associated pathways were enriched. Noticeably, treating with EBV products-containing exosomes in fibroblasts enhanced the production of several immune-suppressive cytokines, including IL6, IL8, and MCP-1. Moreover, stimulation with these exosomes enhanced activation of YAP1 signaling, a key pathway linking to fibrosis. The in vivo mouse xenografted NPC studies showed that EBV products-containing exosomes markedly enhanced the severity of tissue fibrosis and tumor growth. IHC analysis on mouse NPC xenografts and human NPC biopsies showed a positive correlation between levels of nuclear YAP1 and FAPα, which were further correlated with an enhanced fibrotic response within tumors. Pharmaceutical intervention with YAP1 inhibitors blocked the exosome-mediated effects on fibroblasts. Collectively, our data suggest that EBV products-containing exosome is a causal factor in CAF formation, which constitutes a pro-tumoral microenvironment to benefit the survival of both tumor and virus itself.
Citation Format: Po-Ju Lee, Yun-Hua Sui, Chen-Han Huang, Tzu-Tung Liu, Ngan-Ming Tsang, Shu-Chen Liu. EBV-products containing exosomes remodel NPC tumor microenvironment by activating fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3192.