bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 628: Liver macrophages promote breast cancer liver metastasis through migrating neutrophils and initiating NETosis
Authors: Li Heliang , Yang Linbin , Song Erwei 
Published: June 2023

Abstract
Neutrophils extracellular traps (NETs), which are DNA scaffolds in complex with granule proteins, could be detected in the pre-metastatic liver niches and were associated with a poor survival in breast cancer patients. However, the mechanisms of neutrophils infiltration and NETs formation in the pre-metastatic liver tissues remain poorly understood. Here, we dynamically characterized the liver micro-environment of normal and 4T1-bearing BALB/C mouse models with or without liver metastasis by the single cell RNA sequencing. Interestingly, we found that CXCL1 and CXCL2, derived from the liver macrophages, were dramatically elevated in pre-metastatic livers and induced the infiltration of peripheral neutrophils by CXCR2. Besides, liver macrophages were educated by cancer cells-derived cathepsin C to secrete the CXCL1 and CXCL2. Furthermore, we identified that the complement signals were over-activated in pre-metastatic livers and induced neutrophils to NETosis. Therapeutically, targeting CXCL1, CXCL2 and complement signals could inhibit the NET formation and effectively reduce breast cancer liver metastasis.
Citation Format: Heliang Li, Linbin Yang, Erwei Song. Liver macrophages promote breast cancer liver metastasis through migrating neutrophils and initiating NETosis [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 628.
Abstract 6304: Preclinical development of a next generation antibody drug conjugate (ADC) targeting B7-H3 for treatment of solid tumors
Authors: Xu Jian , Zong Qing , Wang Wei , Liu Qigang , Stann Sasha , Cai Jiaqiang 
Published: June 2023

Abstract
B7-H3 (CD276), an immune checkpoint member of the B7/CD28 family, is widely expressed in multiple cancers and is associated with poor prognosis. YL201 is a novel B7-H3-targeting antibody-drug conjugate (ADC) and built on MediLink’s tumor microenvironment activable linker-payload platform (TMALIN platform). This ADC is comprised of an anti-B7-H3 human monoclonal antibody conjugated to a novel topoisomerase 1 inhibitor via a protease-cleavable linker.
The novel linker-payload and site-specific conjugation of YL201 results in a homogeneous and more hydrophilic ADC. In addition, the binding specificity, affinity and avidity of antibodies show no impact after conjugation. In vitro, upon binding to B7-H3, the antigen-ADC complexes are internalized to lysosomal vesicles releasing the toxic payload, whose cytotoxic features drive cell cycle arrest, apoptosis, elevation of PARP/caspase 7 expression, as well as cell death and bystander effect. In preclinical studies, YL201 is effective in causing tumor regressions in both cell line- and patient-derived xenograft (CDX and PDX) mouse models at doses that are well tolerated. The in vivo pharmacokinetics in monkeys showed that YL201 is deemed as ‘highly stable’ in circulation. Safety evaluations demonstrated acceptable safety profile and no off-target toxicity in monkeys. These non-clinical data suggest the stability of linker in circulation but efficiently release the payload in tumors, and eventually, expanded the therapeutic window.
Taken together, preclinical data suggest that YL201 could be a promising treatment strategy for B7-H3 positive cancer patients.
Citation Format: Jian Xu, Qing Zong, Wei Wang, Qigang Liu, Sasha Stann, Jiaqiang Cai. Preclinical development of a next generation antibody drug conjugate (ADC) targeting B7-H3 for 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 6304.
Abstract 6306: Pharmacological deuteration of SCID mice using the water-isotopologue deuterium oxide (D2O) inhibits tumor growth in bioluminescent models of human malignant melanoma and pancreatic ductal adenocarcinoma
Authors: Jandova Jana , Galons Jean-Philippe , Dettman David L. , Wondrak Georg T. 
Published: June 2023

Abstract
Since its initial discovery as a natural isotopologue of dihydrogen oxide (1H2O), extensive research has focused on the biophysical, biochemical, and pharmacological effects of deuterated water [2H2O (D2O, also referred to as ‘heavy water’)]. Here, using diverse panels of cultured human malignant melanoma and pancreatic ductal adenocarcinoma (PDAC) cells we have profiled (i) D2O-induced phenotypic anti-proliferative and apoptogenic effects, (ii) redox- and proteotoxicity-directed stress response gene expression, and (iii) phosphoprotein-signaling related to endoplasmic reticulum (ER) and MAP-kinase stress response pathways. Differential RT-qPCR array analysis revealed early modulation of stress response gene expression elicited by D2O (90%; ≤6 h) confirmed by independent RT-qPCR analysis. Immunoblot-analysis revealed rapid (&lt; 6 h) onset of D2O-induced MAP-kinase signaling (p-JNK) together with ER stress response upregulation (p-eIF2α, ATF4, XBP1s, DDIT3/CHOP) attributable to deuteration-induced alteration of hydrogen bonding triggering proteotoxic stress. Next, we tested the chemotherapeutic efficacy of D2O-based drinking water supplementation in bioluminescent murine models of malignancy (A375-luc melanoma and BxPC-3-luc orthotopic PDAC xenografts in SCID mice). Time course of systemic deuteration (30% D2O in drinking water fed continuously for up to 21 days) was established using time-resolved whole-body proton magnetic resonance imaging (MRI) and isotope-ratio mass spectrometry (IR-MS)-based plasma (D/H)-analysis. In both models, D2O supplementation significantly suppressed tumor growth and metastasis with downregulated expression of PCNA/Ki67 while increasing tumor levels of DDIT3/CHOP, HO-1, and p-eIF2α. Taken together, these data demonstrate for the first time that pharmacological induction of systemic deuteration by oral administration of D2O, associated with induction of cellular ER stress, reduces tumor burden and metastasis in murine models of human malignant melanoma and PDAC.
Citation Format: Jana Jandova, Jean-Philippe Galons, David L. Dettman, Georg T. Wondrak. Pharmacological deuteration of SCID mice using the water-isotopologue deuterium oxide (D2O) inhibits tumor growth in bioluminescent models of human malignant melanoma and pancreatic ductal adenocarcinoma. [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 6306.
Abstract 6340: Preclinical development of a monoclonal antibody targeting CD24 as cancer immunotherapy
Authors: Tian Wenzhi , Li Song , Chen Dianze , Liu Dandan , Guo Huiqin , Yang Chunmei , Zhang Li , Zhang Wei , Tu Xiaoping , Peng Liang , Zhao Gui , Zhang Ruliang , Zhang Fan , Gan Frank X. 
Published: June 2023

Abstract
CD24 is a novel immune checkpoint that suppresses activation of macrophages, natural killer (NK) cells, T cells and B cells by binding to inhibitory receptor Siglec-10. CD24 is highly expressed on cancers of genitourinary (GU) and gastrointestinal (GI) systems, breast, and lung. High expression of CD24 is also known to be associated with poor prognosis for many types of cancers including breast, lung, GU and GI systems, bone, skin and brain. Mouse models of breast and lung cancer in literature revealed that CD24 attenuation in vivo leads to tumor inhibition and prolonged survival. To address the limited (~25%) overall response rate (ORR) of approved PD-1/PD-L1 antibodies for solid tumors, we developed IMM47, an IgG1 antibody that differentially targets phagocytosis and cytotoxicity onto CD24-expressing cancer cells. At doses between 3 mg/kg to 10mg/kg, IMM47 significantly reduced tumor volume in a MC38 mouse model of colon cancer. Mice treated with 10mg/kg IMM47 produced tumor-specific immune response that prevented growth of re-inoculation of colon cancer cells. Further mechanism of action studies showed that IMM47 selectively and differentially increased M1 spleen macrophages quantity to 7-10 folds higher in that induced by PBS control. In contrast, IMM47 only increased M2 spleen macrophages to less than 1.5 folds higher than induced by PBS control. Expression of MHC II in M1 macrophages was also increased in IMM47-treated mice, suggesting significant activation and antigen presentation by macrophages. Our data has also confirmed that IMM47 specifically binds to and induces ADCC (antibody-dependent cellular cytotoxicity),ADCP (antibody-dependent cellular phagocytosis), and CDC (complement-dependent cytotoxicity) against a variety of cancer cells. Taken together, our data show that targeting CD24 on tumor cells using our IMM47 antibody may serve as potent immunotherapy for multiple cancer indications.
Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang, Frank X. Gan. Preclinical development of a monoclonal antibody targeting CD24 as cancer immunotherapy. [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 6340.
Abstract 6344: Recombinant Immunotoxin exhibited targeted killing of Trop2 overexpressing tumour cells lines
Authors: Dogbey Dennis Makafui , Masuku Sizalobuhle , Barth Stefan 
Published: June 2023

Abstract
Introduction: The high prevalence of cervical cancer remains a global challenge particularly in developing countries where its therapy is principally by chemoradiation marked by severe toxicities. Antibody-based therapy targeting specific overexpressed surface antigen has proven as a promising strategy. Tumor-associated calcium signal transducer 2 (Trop2), also known as epithelial glycoprotein-1 antigen, is a membrane protein found in epithelial tissues involved in cellular signalling, migration, proliferation, and differentiation in normal cells. Its overexpression is validated in several tumor types including basal, squamous and adenocarcinomas of the cervix, breast, colon, and gastrointestinal tracts. Due to its differential overexpression, Trop2 is a viable therapeutic marker whereby a recombinant immunotoxin composed of a single chain variable antibody fragment (scFv) armed with Pseudomonas exotoxin A (Anti-Trop2-ETA) may be delivered for targeted killing of such tumors.
Methods: Plasmids encoding Anti-Trop2-ETA were designed in silico by fusion of anti-Trop2 single chain variable fragment (scFv) antibody to the N-terminus of Pseudomonas exotoxin A and then cloned into an pMT backbone. Expression was performed in BL21 E. Coli cells under osmotic stress and then Anti-Trop2-ETA was purified by IMAC via an N-terminus encoded polyhistidine tag. Purified fractions were structurally characterized by SDS PAGE gel and immunoblotting to confirm the presence of the Anti-Trop2-ETA protein to be used for treatment of tumor cell lines. Trop2 expression cervical cancer and breast tumor cell lines were confirmed, and cells were treated with Anti-Trop2-ETA.
Results: Dose dependent killing by Anti-Trop2-ETA was observed in the Trop2 expressing tumor cell lines. IC50 values were significantly lower for Trop2 expressing cells as compared to control cells lacking Trop2 expression.
Conclusion: Here, we demonstrated antigen specific killing of Trop2 overexpressing tumor cells in vitro. Targeted deployment of recombinant immunotoxin to specifically engage and kill Trop2 positive cells is a potential approach for cancer therapeutics. As such, the ability of the rIT to specifically target and kill Trop2 expressing tumors is an important initial finding towards the possibility of antigen-dependent elimination of Trop2 expressing cancer cells. Ongoing evaluations are aimed at antigen dependent biological activity as well as pharmacokinetics of the rIT in tumor bearing in vivo models.
Citation Format: Dennis Makafui Dogbey, Sizalobuhle Masuku, Stefan Barth. Recombinant Immunotoxin exhibited targeted killing of Trop2 overexpressing tumour cells lines [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 6344.
Abstract 6346: Discovery of HX011, a novel OX40 mAb, for potential cancer immunotherapy
Authors: Ke Hang , Zhang Faming , Li Jialin , Peng Feiyu , Chen Cen , Li Henry Qixiang 
Published: June 2023

Abstract
OX40, tumor necrosis factor receptor superfamily member 4, is an immune co-stimulatory receptor, together with its ligand OX40L, forming OX40-OX40L trimer-trimer complex between the surface of T-cells (OX40) and APCs/NKs (OX40L). OX40 expresses constitutively on Treg as well as on conventional Teff, particularly within TME. OX40/OX40L interactions directly triggers conventional T cell activation via NF-kB1 pathway and inhibits bcl-x and survivin to prevent apoptosis; and it also downregulates FoxP3/CTLA4, thus Treg function. OX40 agonistic antibodies have also been shown to activate tumor immunity and increase anti-tumor activity in preclinical models. Here we report that we identified/constructed a novel OX40-agonistic humanized IgG1 monoclonal antibody (mAb), HX011, with high affinity through hybridoma technology. HX011 was subsequently confirmed of the similar binding properties and functions as the original mouse mAb clone, 9C12: 1) binding to human OX40 (EC50 ~0.012 nM; 2) similar function binding in the reporter assay (EC50 ~6.6 nM); but 3) has little blockade of the OX40L binding to OX40. In another word, HX011 is similar to BMS-986178 for the first two assays, but contrastingly different for the third assay. Non-competing with OX40L may actually maximize T-cell activation, a potential advantage over a competing antibody. In vivo pharmacology modeling of HX011 in the humanized syngeneic CRC model, MC38, where syngeneic C57BL/6 mouse mice were knocked in with huOX40 (“HuGEMM-OX40”), demonstrated strong anti-tumor activity (TGI ~100% at 1 mg/kg, twice weekly). HX011 is being further investigated as a potential new immunotherapy for the treatment of cancers.
Citation Format: Hang Ke, Faming Zhang, Jialin Li, Feiyu Peng, Cen Chen, Henry Qixiang Li. Discovery of HX011, a novel OX40 mAb, for potential cancer immunotherapy [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 6346.
Abstract 6348: ABN202 (αEGFR-interferon-β mutein), a potent antibody-cytokine fusion protein for the treatment of EGFR-positive non-small cell lung cancer
Authors: Park Heegeon , Lee Saehyung , Park Hayeon , Hong Sunghyun , Kim Jaemun , Hong Sungyoul , Park Ji-hyun , Shin Young Kee , Choi Jun Young , Kim Na Young 
Published: June 2023

Abstract
ABN202 is an antibody-cytokine fusion protein consisting of interferon-β mutein (ABN102) molecularly fused to a anti-EGFR monoclonal antibody that recognizes the EGFR expressed on various types of cancer cells. In previous studies, we developed ABN102, a bio-better version of recombinant human interferon-β with hyperglycosylation via site-directed mutagenesis to improve stability, productivity, and pharmacokinetics properties. An addition of glycosylation at the N25 residue of ABN102 is expected to reduce the peripheral toxicity of ABN202, as it can shield the IFNAR2 binding interface. In this study, the binding ability and biological activity of ABN202 was evaluated in vitro models. ABN202 downregulates the EGFR protein expression and reduces EGFR phosphorylation by degrading target proteins via internalization in the EGFR-positive NSCLC cell line. In addition, we also determined the direct and indirect anti-cancer activity of ABN202 in preclinical models. Taken together, we suggest that ABN202 has potent anti-cancer activities, via direct cytotoxicity in EGFR-positive tumors and indirectly activating immune cells through Type I IFN signaling. we conclude ABN202 is a promising drug candidate for patients with EGFR-positive NSCLC.
Citation Format: Heegeon Park, Saehyung Lee, Hayeon Park, Sunghyun Hong, Jaemun Kim, Sungyoul Hong, Ji-hyun Park, Young Kee Shin, Jun Young Choi, Na Young Kim. ABN202 (αEGFR-interferon-β mutein), a potent antibody-cytokine fusion protein for the treatment of EGFR-positive non-small cell lung 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 6348.
Abstract 6366: NB002, a novel therapeutic antibody targeting unique epitope on TIM-3 presenting potent antitumor activity
Authors: Zhang Yu , Dong Jinyu , Wang Binbin , Ni Jie , Wang Dong , Shao Liegang , Xiong Meiguang , Wang Ting , McAllister Florencia , Dong Xin 
Published: June 2023

Abstract
Antibody-based Immune checkpoint inhibitor (ICI) therapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed death receptor-1 (PD-1) have significantly improved clinical outcomes in cancer treatment. Nonetheless, a large portion of the population has limited benefit from these ICI treatments due to lack of efficacy, resistance and intolerance. T-cell immunoglobulin and mucin domain containing-3 (TIM-3) has been proposed as a target for cancer immunotherapy. It is an inhibitory receptor modulating immune tolerance, and its expression has been broadly reported to be closely correlated to T cell exhaustion and pessimistic prognosis. Besides negatively modulating T cell status, TIM-3 is also expressed on natural killer (NK) cells, dendritic cells (DCs), macrophages and regulates immune responses bridging innate immunity and adaptive immunity. NB002 is a novel humanized Fc-engineered IgG1κ antibody, developed via NeologicsBio’s integrated target validation & antibody screening Tier-A platform. It has been characterized in a serial of function and efficacy studies and completed IND-enabling preclinical development. NB002 binds to human TIM3 with high affinity in the low nanomolar range and antagonize the TIM-3 pathway effectively in reporter cell and primary cell assays. NB002 increased the secretion of IFN-γ by activated PBMC cells and enhanced activation and killing activity of NK cells. Moreover, it exhibited a distinctive activity of restoring myeloid cells and enhancing antigen presentation and processing during anti-tumor immune responses, and superior efficacy in multiple humanized mouse models of cancer as monotherapy regimen. Importantly, X-ray crystallography demonstrated that NB002 recognized a unique epitope on TIM-3 and was confirmed by epitope binning assay and structural alignment. These data could potentially explain novel features of NB002, restoring both acquired and innate immunity which could lead cold tumor to hot tumor.In summary, these data showed that NB002 is a potent anti-TIM-3 antibody with pre-clinical properties. A phase 1 study is planned and patients with advanced metastatic solid tumors will be recruited.
Citation Format: Yu Zhang, Jinyu Dong, Binbin Wang, Jie Ni, Dong Wang, Liegang Shao, Meiguang Xiong, Ting Wang, Florencia McAllister, Xin Dong. NB002, a novel therapeutic antibody targeting unique epitope on TIM-3 presenting potent antitumor activity. [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 6366.
Abstract 6368: Preclinical pharmacology and safety studies of ZG005: an anti-PD-1/TIGIT bispecific mAb in a phase I clinical trial for advanced tumors
Authors: Zhu Bing , Dai Tongcheng , Liu Ruifeng , Suarez Alfonso , Liban Tyler , Zhang Bin , Karow Margaret , Sheng Jackie , Sheng Zelin , Lv Binhua 
Published: June 2023

Abstract
ZG005 is a humanized anti-PD-1/TIGIT bispecific antibody that effectively blocks the binding between PD-1 and TIGIT, on immune cells, with their specific ligands PD-L1 and PVR, on tumors. As a dual blockade of PD-1/TIGIT immune checkpoints, ZG005 exhibits sustained occupancy to both targets and inhibits their pathways specifically and simultaneously, leading to synergistic effects and boosting the ability of the immune system in killing tumor cells. With high binding affinities, ZG005 elicits the activation of T cells and NK cells resulting in increased release of cytokines and the depletion of Tregs, independent of ADCC activities. ZG005 utilizes the IgG4 isotype to avoid the potential negative impact of effector function and target-crosslinking that has been reported for anti-TIGIT therapeutics using IgG1 isotype. In vivo animal studies indicate that ZG005 has potent and dose-dependent anti-tumor efficacies in syngeneic models using CT26 and MC38 colon tumors in humanized PD-1/TIGIT dKIs mice. In these models, the whole blood and TIL analyses confirmed increases in CD8+ and NK cells but reduction of Treg cell levels after ZG005 treatments. The combination of ZG005 with chemotherapeutic-reagents, cisplatin and donafenib, enhanced their anti-tumor efficacies. Toxicity and safety pharmacology studies with weekly repeat doses for four weeks in cynomolgus monkeys, indicate that ZG005 is well tolerated. Over the dose range 20-180 mg/kg, there were no obvious toxic or adverse effects, and the HNSTD and NOAEL values were 180 mg/kg and 60 mg/kg, respectively. PK/TK analyses indicate a prolonged ZG005 receptor occupancy over 80%, consistent with in vitro binding results that are attribute to the S228P mutation in the IgG4 hinge region to prevent Fab exchange and enhance stability. The IND application of ZG005 has been approved by both FDA and NMPA, and the molecule is currently in phase I clinical trials for advanced solid tumors at escalated dosing of 0.3~20 mg/kg, Q3W, via i.v. administration.
Citation Format: Bing Zhu, Tongcheng Dai, Ruifeng Liu, Alfonso Suarez, Tyler Liban, Bin Zhang, Margaret Karow, Jackie Sheng, Zelin Sheng, Binhua Lv. Preclinical pharmacology and safety studies of ZG005: an anti-PD-1/TIGIT bispecific mAb in a phase I clinical trial for advanced 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 6368.