bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB214: Discovery of EPIM-001, a tumor targeted engineered IL2 with biased IL2Rβ agonist activities
Authors: Zhao Kehao , Hassan Sam , Chen Yan , Nguyen Jenna , Jiang Ning , Zhang Gening , Li Irene , Feng Ryan 
Published: June 2022

Abstract
Background: The cytokine Interleukin 2 (IL2) has been approved for cancer treatment. However, its application has been limited due to severe toxicities associated with its high concentration administration. These side effects are attributed to the strong binding of IL2 to its receptor IL2Rα which is enriched on regulatory T Cells and Lung epithelial cells. We have engineered IL2 to significantly reduce IL2Rα binding and enhance IL2Rβ binding. We further developed EPIM-001, a bi-functional IL2Rβ agonist and Anti-PDL1 biologic, aiming to treat a broad set of solid tumors with improved therapeutic index.
Methods: We used mSCAFold࣪, a unique protein engineering platform to redefine and improve pharmacologic properties of the cytokine through structure-based rationally designed libraries and mRNA display selection. The optimal IL2 candidate with enhanced IL2Rβ and reduced IL2Rα binding was engineered with an internally discovered anti-PD-L1 antibody to generate EPIM-001, a bispecific IL2/PD-L1 biologic drug candidate. EPIM-001 was characterized in vitro for receptor binding activity, immune cell activation, proliferation, and tumor cell killing assays. In vivo efficacy was evaluated in xenograft humanized mouse models, and PK/PD and toxicity has been studied in Non-Human Primates (NHPs).
Results: We have shown that EPIM-001 is a strong agonist of IL2Rβ, with significantly reduced binding to IL2Rα. It demonstrated much stronger CD8+ T cells and NK cell activation and proliferation compared WT-IL2, whilst only weaker activation and minimal proliferation with Tregs. In vitro cell killing assays showed that EPIM-001 promoted better immune cell killing of PD-L1 expressing target cells than WT IL2. In xenograft in vivo studies, EPIM-001 has shown significant tumor growth inhibition against the human lung cancer cell line H1975, which whilst expressing high levels of PD-L1, does not respond to PD-L1/PD-1 blockade. Furthermore, in the human breast cancer cell line MDA-MB-231, EPIM-001 showed stronger tumor growth inhibition compared to Keytruda. PK/PD and toxicity studies in NHPs showed that EPIM-001 is well tolerated. EPIM-001 greatly expanded CD8+ T cells, whilst having minimal effect on TRegs and Eosinophils associated with toxicity.
Conclusions: EPIM-001 is a promising immune modulating drug candidate that selectively activates CD8+ T cells and NK Cells with strong anti-tumor activity and safe profile for both immune checkpoint sensitive and insensitive PD-L1 positive tumors.
Citation Format: Kehao Zhao, Sam Hassan, Yan Chen, Jenna Nguyen, Ning Jiang, Gening Zhang, Irene Li, Ryan Feng. Discovery of EPIM-001, a tumor targeted engineered IL2 with biased IL2Rβ agonist activities [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 LB214.
Abstract LB225: Toward comprehensive, single-molecule proteomics: Protein identification by short-epitope mapping
Authors: Egertson Jarrett D. , Stawicki Cassandra , Gillies Taryn E. , Joly James H. , Steiner Noah , Cardenas Kevin , Leano Jonathan B. , Chen Kevin , Watts Sophie , Boyce Hunter B. , DiPasquo Dan , Killeen Alana , Lobanov Vadim , Kapp Greg , Patel Sujal , Mallick Parag 
Published: June 2022

Abstract
Protein Identification by Short-epitope Mapping (PrISM) is a novel proteomics method with the goal of comprehensive proteome quantification at single-molecule sensitivity. In this work, we present computational modeling demonstrating the feasibility of this goal and experimental application of the approach leveraging single-molecule protein measurements to identify a small number of model proteins. The implementation of PrISM as presented works by acquiring sequential affinity reagent binding measurements on single protein molecules. Counterintuitively, using affinity reagents with “poor” specificity (i.e. cross-reacting to many proteins) enables identification of tens of thousands of proteins with only hundreds of affinity reagents. To experimentally demonstrate PrISM, we use a small number of affinity reagents to quantify a larger number of proteins. In simulations, PrISM is able to identify more than 98% of proteins in human, mouse, yeast, and E. coli using 300 affinity reagents targeting short trimer epitopes. PrISM is robust to experimental confounders including non-specific binding and noisy, incomplete, or inaccurate estimation of affinity reagent to protein binding characteristics. Simulations of the approach with a chip containing 10 billion protein molecules measured in parallel show a dynamic range of detection of up to 9.5 and 11.5 orders of magnitude for HeLa cells and plasma, respectively. Using such a chip, the PrISM method can identify and quantify over 90% of the human proteome in a single experiment, potentially revolutionizing biomarker discovery and cancer research.
Citation Format: Jarrett D. Egertson, Cassandra Stawicki, Taryn E. Gillies, James H. Joly, Noah Steiner, Kevin Cardenas, Jonathan B. Leano, Kevin Chen, Sophie Watts, Hunter B. Boyce, Dan DiPasquo, Alana Killeen, Vadim Lobanov, Greg Kapp, Sujal Patel, Parag Mallick. Toward comprehensive, single-molecule proteomics: Protein identification by short-epitope mapping [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 LB225.
Abstract LB509: ZG033, a novel CD137 agonist, induces superior anti-tumor activity without hepatotoxicity rely on Fc-mediated crosslinking
Authors: Li Liangwei , Liu Wenting , Shen Guodong , Zhang Dayan , Zheng Xiaoli , Cheng Liansheng 
Published: June 2022

Abstract
CD137 (TNFRSF9, 4-1BB) is a member of the tumor necrosis factor receptor superfamily that functions as a co-stimulatory molecule of immunocytes. Agonistic antibodies against CD137 have shown promising therapeutic activity in mouse tumor models. However, molecules in the clinical development have shown limitations due to either dose-dependent severe liver toxicity (e.g. Urelumab), or modest antitumor activity (e.g. Utomilumab). We developed ZG033, a fully human IgG4 agonist of CD137 that engages with a exclusive epitope, to achieve a better efficacy and safety profile for immunotherapy. The biophysical properties and anti-tumor activities were determined using in vitro assays and in vivo mice xenograft models, respectively. ZG033 is a safe and potent antibody targeting a ligand competitive epitope, that conserved in human, cynomolgus monkey, and is associated with a differentiated pharmacology and toxicology profile. The complex structure of ZG033/CD137 was determined by X-ray crystallography. The binding affinity to human 4-1BB of ZG033 determined by Surface plasmon resonance (SPR) was moderate (KD=10 nM). ZG033 increased the production of IFN-γ by human CD8+T,CD4+T, NK cells in a Fcγ receptor-dependent manner, displaying an intermediate activation level between that of Urelumab and Utomilumab. In addition, it led to a dose-dependent increase in the CD137-driven NFκB reporter gene activation. In syngeneic mouse tumor models, ZG033 showed robust single agent anti-tumor activity starting from 0.3 mg/kg and induced durable antigen-specific immunological memory that prevents the growth of the same tumor cells in the mice re-challenged as compared to Utomilumab. Furthermore, ZG033 combined with an anti-PD-L1 antibody (Atezolizumab) significantly inhibited the growth of colorectal tumor in a human PBMC-engrafted humanized mouse model. Data from toxicology test in humanized CD137 transgenic mice showed that ZG033 was well-tolerated with normal ALT and AST levels. Even high dose of ZG033 (MTD≥180mg/kg) was achieved in cynomolgus monkeys with no abnormality in hematological indexes, important organs. These data demonstrate that ZG033 is a novel CD137 agonist that displays an favorable safety profile and has a potential in either mono- or combinational immunotherapies.
Citation Format: Liangwei Li, Wenting Liu, Guodong Shen, Dayan Zhang, Xiaoli Zheng, Liansheng Cheng. ZG033, a novel CD137 agonist, induces superior anti-tumor activity without hepatotoxicity rely on Fc-mediated crosslinking [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 LB509.
Abstract LB522: Fibroblast activation protein triggers the release of drug payload from non-internalizing small molecule-drug conjugates in solid tumors
Authors: Zana Aureliano , Galbiati Andrea , Gilardoni Ettore , Millul Jacopo , Sturm Theo , Stucchi Riccardo , Bocci Matilde , Elsayed Abdullah , Nadal Lisa , Cirillo Martina , Neri Dario , Cazzamalli Samuele 
Published: June 2022

Abstract
Small Molecule-Drug Conjugates (SMDCs) are modular anti-cancer pro-drugs that include a tumor-targeting small ligand, a cleavable linker and a potent cytotoxic agent. SMDC products that have been developed for clinical applications are targeting internalizing tumor-associated antigens expressed on the surface of tumor cells. We have recently developed a novel non-internalizing small organic ligand (named OncoFAP) of Fibroblast Activation Protein (FAP), a tumor-associated antigen highly expressed in the stroma of most of solid human malignancies. The tumor targeting performance of OncoFAP has been validated by nuclear medicine studies in patients with various solid tumors. In a previous study, we showed that OncoFAP can be used to produce non-internalizing SMDCs that are effective and well tolerated. Here, we describe a new series of OncoFAP-Drug derivatives based on the MMAE tubulin poison and dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment. We benchmarked the new SMDCs against OncoFAP-MMAE conjugates displaying linker modules which are widely used in approved and clinical stage Antibody-Drug Conjugates, including structures cleaved by Cathepsin B and by reducing agents. We selected OncoFAP-GlyPro-MMAE as the most efficacious and safe SMDC for further clinical development after quantitatively analyzing the biodistribution of MMAE released by OncoFAP-MMAE conjugates. OncoFAP-GlyPro-MMAE selectively delivers high amounts of MMAE at the site of disease, with a tumor-to-kidney ratio of 7-to-1 and of 16-to-1 at 6- and 24-hours post-injection, respectively. Our molecules based on the OncoFAP tumor-targeting ligand and FAP-cleavable linkers promise to be safe and effective against most of human malignancies.
Citation Format: Aureliano Zana, Andrea Galbiati, Ettore Gilardoni, Jacopo Millul, Theo Sturm, Riccardo Stucchi, Matilde Bocci, Abdullah Elsayed, Lisa Nadal, Martina Cirillo, Dario Neri, Samuele Cazzamalli. Fibroblast activation protein triggers the release of drug payload from non-internalizing small molecule-drug conjugates in solid tumors [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 LB522.
Abstract LB538: Characterization of GB263T, a tri-specific antibody against EGFR/cMET/cMET for NSCLC
Authors: Du Qinglin , Zeng Wengang , Yang Xueyan , Liang Liwen , Li Xueqin , Li Yan , Cao Yiqi , Xia Zongjun , Zhang Jing , Ding Qian , Han Shuhua 
Published: June 2022

Abstract
Background: The EGFR tyrosine kinase inhibitors (TKIs) have been effectively used for non-small cell lung cancer (NSCLC) driven by EGFR mutations. However, patients eventually develop drug resistance via various mechanisms such as secondary EGFR mutations and activation of alternative pathways. The cMET amplification is one of the resistant mechanisms. Amivantamab, a bispecific antibody to EGFR/c-Met has shown that concurrent inhibition of EGFR and c-Met can overcome resistance of EGFR-TKIs and improve patient outcomes. Thus, amivantamab has been approved for the treatment of advanced NSCLC patients with EGFR exon20ins mutations in the US. GB263T is a novel EGFR/cMET/cMET tri-specific antibody with enhanced ADCC function. The current study has demonstrated GB263T exhibited robust anti-tumor activity by in vitro and in vivo studies.
Methods: GB263T has been extensively characterized. The binding/blocking activities were analyzed by SPR and ELISA. The protein levels and phosphorylation of EGFR/cMET were detected by Western Blot. Internalization ability was evaluated by confocal microscope. ADCC function was tested by Jurkat-CD16A-NFAT-Luc reporter system. Various CDX and PDX models were used to evaluate the in vivo efficacy in tumor inhibition.
Results: GB263T showed high affinity binding to EGFR and cMET, with robust blocking activity. Moreover, GB263T induced receptor internalization and EGFR/cMET phosphorylation in NSCLC cell lines. GB263T dose-dependently inhibited the proliferation of cells containing EGFR exon 20 insertion mutations and C797S mutations. In addition, potent ADCC function against NSCLC cell lines was observed. Significant in vivo anti-tumor efficacy was demonstrated by multiple tumor models of EGFR exon 20 insertion, EGFR C797S mutation, cMET amplification, and cMET exon 14 skipping mutation.
Conclusions: GB263T is a novel tri-specific antibody that exhibited robust anti-tumor activity. The preclinical data indicate that GB263T has great potential to become an effective therapeutics in the treatment of NSCLC.
Citation Format: Qinglin Du, Wengang Zeng, Xueyan Yang, Liwen Liang, Xueqin Li, Yan Li, Yiqi Cao, Zongjun Xia, Jing Zhang, Qian Ding, Shuhua Han. Characterization of GB263T, a tri-specific antibody against EGFR/cMET/cMET for NSCLC [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 LB538.
Abstract LB543: tmHRD: Accurately estimating the homologous recombination deficiency status from clinical panel sequencing data
Authors: Wang Xuwen , Xu Ying , Guan Yanfang , Yi Xin , Wang Jiayin 
Published: June 2022

Abstract
Estimating the status of homologous recombination deficiency (HRD) is of clinical interest because the homologous recombination-deficient cells are reported sensitive to poly-ADP ribose polymerase (PARP) inhibitors. As HRD status becomes a critical indicator, many approaches have been proposed to measure the HRD status, among which estimating HRD status from cancer sequencing data is the popular strategy, where the representative methods include HRDetect, SigMA, FoundationFocusCDx, MyChoiceHRD, etc. Although sequencing data is the same input of these bioinformatics tools, algorithms prefer different aspects. Some methods focus on germline variants in BRCA1/2 genes and somatic mutational signatures, while some others capture the genomic scars, including loss of heterozygosity (LOH), telomere allele imbalance (TAI) and large-scale state transition (LST). However, there are two major controversial points when applying these tools on clinical sequencing data. First, panel sequencing is the most popular sequencing plan in clinic, but gene panels usually carry only hundreds to a thousand genes. Thus, the panel sequencing can neither capture a large number of mutations to calculate mutational signatures, nor obtain large genomic scars, such as TAI and LST. Second, the associations between the mutations and HRD status is still unclear. Thus, scoring mutations and genomic scars is not reasonable. To solving these issues, we here proposed a machine learning-based method, called tmHRD, which estimates HRD status according to limited mutations and LOHs captured by clinical panel sequencing data. It consists of a semi-supervised learning (TRI) model and a multi-instance learning (MIL) model. The TRI model filters the false positives from mutation calls. Then, the filtered mutation calls from one patient is defined as a package, where each mutation call is an instance in the package. When training the MIL model, in each iteration, a package with known HRD status (label) is given to MIL model. MIL model calculates the correlations among instances and assigns an adjusted weight for each. Thus, the HRD status is only contributed by those mutations associated with. We tested tmHRD on several datasets obtained by the clinical trials we participated. Compared to the existing methods, tmHRD achieved better performance. The average recognition rate of tmHRD was approaching 90%, while the comparison methods show around 80%. The software package, tmHRD, is freely available at https://github.com/Sherwin-xjtu/TriMILhrd/ for academic usages only.
Citation Format: Xuwen Wang, Ying Xu, Yanfang Guan, Xin Yi, Jiayin Wang. tmHRD: Accurately estimating the homologous recombination deficiency status from clinical panel sequencing data [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 LB543.
Abstract LB567: Dramatic in vivo efficacy of the EZH2-inhibitor tazemetostat in PBRM1-mutated human chordoma xenograft
Authors: Passeri Thibault , Dahmani Ahmed , Masliah-Planchon Julien , Naguez Adnan , Michou Marine , El-Botty Rania , Vacher Sophie , Bouarich Rachida , Nicolas André , Polivka Marc , Franck Coralie , Schnitzler Anne , Némati Fariba , Roman-Roman Sergio , Bourdeaut Franck , Adle-Biassette Homa , Mammar Hamid , Froelich Sébastien , Bièche Ivan , Decaudin Didier 
Published: June 2022

Abstract
Background: Chordomas are considered as rare bone neoplasms characterized by a high level of recurrence and a poor long-term prognosis. Considering their chemo-radio-resistance, alternative treatment strategies are therefore strongly requested, but their development is limited by the paucity of relevant preclinical models. Mutations affecting genes of the SWI/SNF complex including PBMR1 are frequently found in chordomas, suggesting a potential therapeutic effect of epigenetic regulators in this indication.
Methods: Thirty-eight chordoma specimens derived from primary patients’ tumors were grafted into nude mice. Relationship between grafted tumors and clinical, biological and therapeutic features of corresponding patients were investigated. We subjected the established PDX models to histopathological and genetic examination; finally, a therapeutic program focused on the EZH2-inhibition was performed in one PDX model.
Results: Twelve PDX models were established and characterized on histological and biomolecular features. Patients whose tumors were able to grow into mice had a statistically significant lower progression-free survival than those whose tumors did not grow after in vivo transplantation (p=0.007). All PDXs maintained the same histopathological features as patients’ tumors. Homozygous deletions of CDKN2A/2B (58.3%) and PBRM1 (25%) variants were the most common genomic alterations found. In the tazemetostat treated PDX model harboring a PBRM1 variant, an overall survival of 100% was observed.
Conclusion: Our panel of chordoma PDXs represents a useful preclinical tool for both pharmacologic and biological assessments. The first demonstration of a high antitumor activity of tazemetostat in a PDX model harboring a PBRM1variant supports further evaluation of EZH2-inhibitors in this subgroup of chordomas.
Citation Format: Thibault Passeri, Ahmed Dahmani, Julien Masliah-Planchon, Adnan Naguez, Marine Michou, Rania El-Botty, Sophie Vacher, Rachida Bouarich, André Nicolas, Marc Polivka, Coralie Franck, Anne Schnitzler, Fariba Némati, Sergio Roman-Roman, Franck Bourdeaut, Homa Adle-Biassette, Hamid Mammar, Sébastien Froelich, Ivan Bièche, Didier Decaudin. Dramatic in vivo efficacy of the EZH2-inhibitor tazemetostat in PBRM1-mutated human chordoma xenograft [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 LB567.
Mitochondrial H
2
S Regulates BCAA Catabolism in Heart Failure
Authors: Li Zhen , Xia Huijing , Sharp Thomas E. , LaPenna Kyle B. , Elrod John W. , Casin Kevin M. , Liu Ken , Calvert John W. , Chau Vinh Q. , Salloum Fadi N. , Xu Shi , Xian Ming , Nagahara Noriyuki , Goodchild Traci T. , Lefer David J. 
Published: June 2022

Background:

Hydrogen sulfide (H
2
S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H
2
S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload–induced heart failure.

Methods:
Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency.

Results:

Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism with 3,6-dichlorobenzo1[b]thiophene-2-carboxylic acid (BT2) and administration of a potent H
2
S donor JK-1 ameliorates the detrimental effects of 3-MST deficiency in heart failure with reduced ejection fraction.

Conclusions:

Our data suggest that 3-MST derived mitochondrial H
2
S may play a regulatory role in branched-chain amino acid catabolism and mediate critical cardiovascular protection in heart failure.