bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5524: AK127, a novel monoclonal antibody (mAb) targeting T cell immunoreceptor (TIGIT)
Authors: Huang Zhaoliang , Pang Xinghua , Zhong Tingting , Jin Chunshan , Chen Na , Xia Dennis , Zhang Peng , Wang Max , Xia Michelle , Li Baiyong 
Published: June 2022

Abstract
Introduction: Immune checkpoint blocking antibodies achieved great clinical success, yet a large fraction of cancer patients receive minimum benefit from current immunotherapies targeted PD-1 and CTLA-4. As a new multifunctional immune checkpoint molecule, TIGIT holds promise to become an important cancer immune therapy target. AK127 is a novel humanized immunoglobulin (Ig) G1 monoclonal antibody (mAb) targeting T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT). AK127 binds to TIGIT specifically and blocks the interaction of TIGIT with its ligands, thus relieves immune suppression and promotes anti-tumor immune response.
Method: The effect of AK127 on secretion of IL-2 in mixed culture of Jurkat-TIGIT and HT1080-aCD3scFv cells (ELISA) was determined in cellular assays. Binding kinetics of AK127 to C1q, FcγR were measured by Fortebio. ADCC, ADCP and CDC activities were determined in cellular assays. In preclinical in-vivo pharmacology studies, synergistic anti-tumor activity of AK127 and a bi-specific anti-PD1/CTLA4 antibody Cadonilimab (AK104) was investigated in BALB/c-hPD-1/hTIGIT transgenic mice with CT26.WT tumor model.
Result: AK127 blocked the immune inhibitory signal mediated by TIGIT, resulting in enhanced IL-2 secretion. AK127 exhibited binding to FcγIa, FcγRIIIa and C1q, and eliciting ADCC, ADCP and CDC. In animal models, both AK104 (0.5 mg/kg) and AK127 (4 mg/kg) significantly inhibited tumor growth. The combination of AK127 and AK104 produced a significantly enhanced anti-tumor effect than either monotherapy, demonstrating the synergistic anti-tumor activity of AK127 combined with AK104.
Conclusion: AK127 binds to human TIGIT with high affinity, competitively blocks the binding of TIGIT with its ligand CD155 and CD112, relieves immune suppression in both cellular and animal model systems, and promotes anti-tumor immune response.
Citation Format: Zhaoliang Huang, Xinghua Pang, Tingting Zhong, Chunshan Jin, Na Chen, Dennis Xia, Peng Zhang, Max Wang, Michelle Xia, Baiyong Li. AK127, a novel monoclonal antibody (mAb) targeting T cell immunoreceptor (TIGIT) [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 5524.
Abstract 5541: BGB-15025, a potent and selective HPK1 inhibitor, is efficacious as a single agent or in combination with PD-1 antibody in multiple tumor models
Authors: Liu Ye , Li Jing , Li Zhuo , Wang Qin , Zhou Xing , Liu Xiaoxin , Zhang Bo , Wang Xitao , Xu Sanjia , Sun Hanzi , Song Xiaomin , Yuan Xi , Wang Zhiwei , Liu Xuesong 
Published: June 2022

Abstract
Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-restricted serine/threonine protein kinase, has been reported to serve as a critical negative feedback regulator of T lymphocytes by phosphorylating the adaptor protein SLP76 in the TCR complex. The negative feedback role of HPK1 in TCR signaling makes it a promising target for immuno-oncology therapy. It has been recently demonstrated that the kinase activity of HPK1 is essential for its antitumor activity, and HPK1 inhibitors can be potentially combined with immune checkpoint inhibitor therapy (such as PD-1 antibody) for effective cancer treatment. Here, we report a potent and selective HPK1 inhibitor BGB-15025 which has been identified through in-house high throughput screening and structure-guided drug design. BGB-15025 potently inhibits HPK1 kinase activity in biochemical assay, with a 50% inhibitory concentration (IC50) of 1.04 nM under Km concentration of ATP. Consistently, BGB-15025 can potently reduce SLP76 phosphorylation and increase downstream ERK phosphorylation in a concentration dependent manner in T cells-based assay. As a consequence, BGB-15025 induces TCR activation and IL-2 production in T cells. Based on in-house profiling, BGB-15025 shows good selectivity profile among MAP4K family and does not affect ZAP70 phosphorylation up to 1 μM. Oral administration of BGB-15025 demonstrates dose-dependent pSLP76 inhibition in splenic T cells and induces serum IL-2 in mouse model. In efficacy studies, BGB-15025 exhibits anti-tumor activity in GL261 tumor model as single agent. Moreover, BGB-15025 demonstrated combination effect with anti-PD-1 antibody in CT26 and EMT-6 syngeneic tumor models. BGB-15025 is currently in phase I clinical trial to treat patients with advanced solid tumor, both as a single agent and in combination with anti PD-1 antibody tislelizumab.
Citation Format: Ye Liu, Jing Li, Zhuo Li, Qin Wang, Xing Zhou, Xiaoxin Liu, Bo Zhang, Xitao Wang, Sanjia Xu, Hanzi Sun, Xiaomin Song, Xi Yuan, Zhiwei Wang, Xuesong Liu. BGB-15025, a potent and selective HPK1 inhibitor, is efficacious as a single agent or in combination with PD-1 antibody in multiple tumor models [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 5541.
Abstract 5551: QLS31905, an anti-claudin 18.2/CD3 bispecific antibody for claudin 18.2-positive gastric cancer
Authors: Jiang Jiahua , Si Meimei , Luo Xiao , Wu Yun , Li Yongjun , Yan Xiaodan 
Published: June 2022

Abstract
Claudin 18.2 is a quadruple transmembrane protein with a complex structure and highly specific expression in gastric and pancreatic cancers. It is suggested that claudin 18.2 is an ideal target for cancer therapy. Anti-claudin 18.2 antibody IMAB362 has achieved remarkable success in the latest clinical trials. Multiple anti-claudin 18.2 monoclonal antibodies and chimeric antigen receptor T-cell therapy targeting claudin 18.2 have also entered phase I clinical trials. CD3 is a receptor that is present on the surface of T cells and is involved in the antigen recognition by T cells as well as in signal transduction. Anti-claudin 18.2/CD3 bispecific antibody can recruit T cells to tumor sites, activating T cells to kill tumor cells with high claudin 18.2 expression to improve efficacy. Here, we describe a new T cell-redirecting antibody (QLS31905) that is bispecific for claudin 18.2 and CD3. QLS31905 showed a potent in vitro cytotoxic activity against claudin 18.2-positive engineered cell lines HEK293-hCLDN18.2 and NCI-N87 CLDN18.2 as well as superior in vivo efficacy in humanized NCI-N87 CLDN18.2 model. Furthermore, QLS31905 was safe and well tolerated in a 4-week repeated dose (up to 10 mg/kg) toxicity study in cynomolgus monkeys. In vitro cytokine release was lower in the QLS31905 group than that in the AMG 910 (another anti-claudin18.2/CD3 bispecific antibody) group. Overall, these data suggested that QLS31905 has similar efficacy to AMG 910 and is safer. QLS31905 may be an effective and clinically valuable treatment for patients with claudin 18.2-positive gastric cancer.
Citation Format: Jiahua Jiang, Meimei Si, Xiao Luo, Yun Wu, Yongjun Li, Xiaodan Yan. QLS31905, an anti-claudin 18.2/CD3 bispecific antibody for claudin 18.2-positive gastric cancer [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 5551.
Abstract 5552: Novel set of OX40 targeted antibodies and VHHs include agonists and antagonists for future development
Authors: Cai Chenguang , Li Xiang , Hou Shin-Chen , Sun Guoqian , Li Ying , Yang Ting , Zhang Fengzhi , Sun Qi , Fu Shiying , Zhao Shuang , Lin You'you , Xue Feizheng 
Published: June 2022

Abstract
Immunotherapy is one of the most effective modern treatments for cancer. While immunotherapy operates through a broad class of mechanisms, modulating immune checkpoints have provided some of the most effective approaches, including inhibition of PD-1/PD-L1 pathway, CTLA-4, LAG-3, OX40, Tim-3, KIR and TIGIT to reverse tumor immune escape.OX40, also known as CD134 or TNFRSF4, is a membrane protein expressed in CD4+ and CD8+ T cells, neutrophils and NK cells. In the process of T cell activation, OX40 plays a synergistic stimulating function by binding with ligand OX40L. OX40 agonist immunotherapy has been previously shown to improve the survival rate of glioblastoma in mice, prevent tumor growth in ovarian cancer, increase the prognostic significance of CD8+ cell infiltration in colorectal cancer, and eliminate the inhibitory function of Foxp3+ Treg cells that constitutively Express OX40. On the contrary, blocking OX40 axis is a promising strategy to treat T cell hyperactivation in autoimmune diseases. As recently reported in the literature, a two-armed, random, double blinded phase 2b clinical trial demonstrated that telazorlimab, an antagonist OX40 antibody developed by Ichnos Sciences, met primary efficacy endpoints in treating atopic dermatitis.In this research, we developed a set of novel antibodies to OX40 using a hybridoma and VHH synthetic library; the set of antibodies includes both agonists and antagonists.We developed one hybridoma origin mAb into a human framework. Agonist activity was equal to MOXR0916 in NF- κB reporter-Jurkat assay, dependent on coupling by proteinA/cell-bound CD32b, non-competing with OX40L, and epitope mapped to domain 2+3.We identified dozens of binders from our synthetic single domain VH library. After construction into a IgG1Fc fusion form, 4 VHHs were obtained with significant agonistic activity, dependent on coupling by proteinA/cell bound CD32b. Another 5 VHHs were also obtained with significant antagonistic activity without coupling by proteinA/cell-bound CD32b. The 4 agonistic VHHs were confirmed with binding to domain 1+2, competitive to OX40L’s binding.These VHHs constructs represent a promising set of novel biologics to modulate OX40—as agonists or antagonists—and serve as the basis for development of potential new therapies in the clinic.
Citation Format: Chenguang Cai, Xiang Li, Shin-Chen Hou, Guoqian Sun, Ying Li, Ting Yang, Fengzhi Zhang, Qi Sun, Shiying Fu, Shuang Zhao, You'you Lin, Feizheng Xue. Novel set of OX40 targeted antibodies and VHHs include agonists and antagonists for future development [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 5552.
Abstract 5553: Anti-CD19-CD22 antibody drug conjugate to reduce tumor recurrence in B-cell hematologic cancers
Authors: Du Liang , Wan Tingting , Jin Yi , Yuan Jijun 
Published: June 2022

Abstract
With 1,279,000 new cases in 2020 and high incidence of relapse, hematologic cancers present significant opportunity for drug development. B-cell caners arise from various developmental stages of the B lymphocyte, and occur in several forms, including leukemia, lymphoma, and multiple myeloma. CD19 and CD22 are validated targets for B cell cancers, each with multiple drugs approved. However, single targeting therapies showed a poor median response likely due to loss of antigen expression upon treatment stress. CD19&CD22 dual targeting antibody drug conjugate can be a powerful killer of B-cell cancers, with more targeted patient populations due to the high expression of CD19, and good anti-tumor efficacy due to the high internalizing ability of CD22.To this end, we developed 7E11-13G9, which is a bispecific antibody designed for antibody-drug-conjugate for a larger market of B-cell hematological cancers.By the strong CD19 binding arm of 7E11 and the efficient CD22-mediated internalizing arm of 13G9, 7E11-13G9 BsAb kills more tumor cells with high potency and efficacy. In tumor cell killing assay, bispecific 7E11-13G9 showed significantly better anti-tumor efficacy than any of the benchmark antibodies, and even better than the combination of the anti-CD19 benchmark Loncastuximab with the anti-CD22 benchmark Inotuzumab. Significantly better anti-tumor effect and delayed tumor recurrence of CD19-CD22 bispecific compared with single target was demonstrated in Nalm6 acute lymphocyte leukemia model. 7E11-13G9 BsAb is stable and has good productivity in transient expression. Proof of concept study of antibody drug conjugate based on 7E11-13G9 was prepared, and showed great anti-tumor efficacy both in vitro and in vivo.
Citation Format: Liang Du, Tingting Wan, Yi Jin, Jijun Yuan. Anti-CD19-CD22 antibody drug conjugate to reduce tumor recurrence in B-cell hematologic cancers [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 5553.
Abstract 5572: T cell receptor modified with EDB-targeting ScFv and CD28 intracellular domain led to complete tumor regression in xenograft model
Authors: Zhang Zhijie , Qiu Wen , Liu Chang , Wang Muhan , Miao Yinghua , Ji Qingchao , Sun Rongchen , Yin Hongping , Yang Meijia 
Published: June 2022

Abstract
We explored use of chimeric antigen receptor T cell (CAR-T) for treatment of solid tumors, aiming at efficient killing of tumor cells while minimizing on-target off-tumor toxicities. We designed CAR targeting the extra domain B (EDB)-containing fibronectin, which is an oncofetal antigen widely expressed in tumor stroma and on the surface of cancer cells. Unlike membrane-spanning antigens, EDB-containing fibronectin is embedded in the extracellular matrix, and is enriched in new vasculatures and stromal tissues of tumor tissues. First, we made a second-generation EDB CAR (2G-EDB CAR) that killed EDB+ cells (U87MG, A549, and HUVEC) and showed tumor suppression in a U87MG xenograft tumor model. However, while in vitro the 2G-EDB CAR T cells were sufficiently cytotoxic, the in vivo inhibition of the tumor growth was moderate. Next we designed an EDB CAR that contained CD3ε to create 3ε-EDB CAR. We show that the 3ε-EDB CAR was incorporated into the T cell receptor (TCR) structure. The 3ε-EDB CAR completely displaced the native CD3ε in the TCR based on immune precipitation and Western analysis. The 3ε-EDB CAR was capable of inducing T cell activation and proliferation in the presence of EDB-fibronectin antigen. Further, the 3ε-EDB CAR T cells killed tumor cells containing EDB-fibronectin. In vivo, the 3ε-EDB CAR T cells demonstrated improved inhibition when compared to the 2G-EDB CAR T cells. To further enhance the EDB-targeting CAR, we added intracellular domain of CD28 to the 3ε-EDB CAR to create 3ε28-EDB CAR, and showed the 3ε28-EDB CAR was still incorporated into the TCR complex. The 3ε28-EDB CAR co-opted TCR complex and provided co-stimulatory signal upon binding of EDB antigens. Upon transduction of the 3ε28-EDB CAR into primary T cells, we observed upregulation of T cell activation markers CD25, CD69 and granzyme B in presence of the EDB antigen. We show that 3ε28-EDB CAR triggered the phosphorylation of CD3ζ, suggesting that EDB antigen stimulated co-opted TCR and signaled through the TCR-CD3 complex. T cells transduced with 3ε28-EDB CAR demonstrated stronger proliferation when activated by U87MG cells compared to 2G or 3ε-EDB CARs. Furthermore, 3ε28-EDB CAR T cells inhibited in vivo tumor growth in a dose-dependent manner, and most of the treated mice had no evidence of residual tumors. In conclusion, our results suggest that 3ε28-EDB CAR has great potential for treatment of solid tumors.
Citation Format: Zhijie Zhang, Wen Qiu, Chang Liu, Muhan Wang, Yinghua Miao, Qingchao Ji, Rongchen Sun, Hongping Yin, Meijia Yang. T cell receptor modified with EDB-targeting ScFv and CD28 intracellular domain led to complete tumor regression in xenograft model [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 5572.
Abstract 5587: STING and TLR 7/8 Agonist combination can improve immune checkpoint blockade therapy efficiency
Authors: Revuri Vishnu , Bhatnagar Shubhmita , Schultz John , Larson Peter , Ferguson David M. , Panyam Jayanth 
Published: June 2022

Abstract
Despite significant advancements in immune checkpoint blockade (ICB) therapy, only few patients respond to the treatment. Non-immunogenic cold tumors lack T-cell infiltration, which results in reduced ICB therapeutic efficiency. Immune adjuvants can reprogram the non-immunogenic cold tumor microenvironment (TME) to inflamed hot TME by activating antigen presenting cells and improving T-cell homing. Here, we investigate the potentials of 558 (a novel TLR 7/8 agonist) and ADU-S100 (stimulator of interferon gene (STING) agonist in clinical trials) combination on improving the activity of ICB. Human TLR-specific reporter cell assay using HEK-Blue™-hTLR7 and 8, confirmed the activation of both TLR 7 and TLR 8 with EC50 of 0.18 µM and 5.34 µM respectively, when treated with 558. In addition, treatment of human PBMCs with 558 increased the IFN-γ and TNF-α cytokine secretions. Moreover, the levels of IL-10, an anti-inflammatory cytokine were not increased upon treatment with 558. Although treatment of bone marrow derived dendritic cells (BMDC) with 558 resulted in CD40 expression, a reduced expression of CD80 and CD86, costimulatory molecules that are required for T-cell activation, was observed. Interestingly, 558 in combination with ADU-S100 not only increased the CD40 expression but also improved the expression of CD80 (4-fold) and CD86 on BMDCs. Furthermore, the levels of pro-inflammatory cytokines TNF-α and IL-6 was significantly increased when BMDCs were treated with 558 and ADU-S100 combination compared to the individual treatments. TME constitute M2 polarized macrophages that promote secretion of anti-inflammatory cytokines and favor tumor progression. Interestingly, 558 and ADU-S100 combination reduced the expression of CD206, a mannose receptor that is highly expressed on M2 macrophages and improved the expression of CD80 (25-fold) and CD86 (6-fold) compared to 558 treatments alone. These results confirmed the polarization of M2 macrophages to immunogenic M1 macrophages. Overall, these studies indicate promising potential of 558 and ADU-S100 combination in reprogramming the TME to aid in effective cancer treatments.
Citation Format: Vishnu Revuri, Shubhmita Bhatnagar, John Schultz, Peter Larson, David M. Ferguson, Jayanth Panyam. STING and TLR 7/8 Agonist combination can improve immune checkpoint blockade therapy efficiency [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 5587.
Abstract 5622: Preclinical evaluation of humanized PD1/GITR combination therapy using double humanized mouse
Authors: Yuan Dongdong , zhang Dongdong , Sun Hongyan , Zhang Mingkun , Dong Liyou , Ju Cunxiang , Li Shuai , Wang Huiyi , Zhao Jing , Gao Xiang 
Published: June 2022

Abstract
GITR (glucocorticoid-induced TNFR-related protein) is a member of tumor necrosis factor receptor superfamily, expressed on many kinds of cells including T cells, attracting attention as a co-stimulatory immune checkpoint molecule. GITRL, the ligand of GITR is mainly expressed on antigen presenting cells. GITR/GITRL interaction plays an important role on the development of immune response, which can serve as promising anti-tumor target. While more than twenty anti-GITR antibodies are at clinical stages, combination treatments of GITR agonist and PD-1 inhibitor may be a better choice. Thus, there is a need for pre-clinical mouse model to evaluate the anti-tumor effect of humanized PD1/GITR antibodies. Gempharmatech established PD1/GITR double humanized mouse line on a BALB/c background, in which the extracellular domain of mGITR was replaced with its human counterparts while the trans-membrane and cytoplasmic domain kept intact, as well as the same strategy of PD1. BALB/c-hPD1/hGITR mouse could successfully express similar levels of hGITR and hPD1 compared with BALB/c wild type mice. Moreover, no immune or developmental abnormalities were observed in the humanized mouse. Anti-GITR combination with anti-PD1 presented greater tumor growth inhibition than anti-PD1 or anti-GITR monotherapies in PD1/GITR double humanized mouse bearing CT26 tumors. In summary, BALB/c-hPD1/hGITR are valuable models for the pre-cilincal evaluation of candidate humanized PD1/GITR combination treatment or bispecific antibody therapies.
Citation Format: Dongdong Yuan, Dongdong zhang, Hongyan Sun, Mingkun Zhang, Liyou Dong, Cunxiang Ju, Shuai Li, Huiyi Wang, Jing Zhao, Xiang Gao. Preclinical evaluation of humanized PD1/GITR combination therapy using double humanized mouse [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 5622.
Abstract 5623: CD137 humanized mice for preclinical efficacy evaluation of therapeutic antibodies
Authors: Jiang Yunlong , Gu Tingting , Yu Weiwei , Sun Hongyan , Zhang Mingkun , Liang Juan , Li Shuai , Ju Cunxiang , Zhao Jing , Gao Xiang , Moore Mark W. 
Published: June 2022

Abstract
CD137 (41-BB, tumor necrosis factor receptor superfamily 9), expressed on activated T cells and NK cells, has gained increased attention as an anti-tumor target because of remarkable clinical efficacy using either a single agent or in combination with other immune checkpoint inhibitors. We constructed CD137 humanized mice based on two different backgrounds, C57BL6 and BALB/c mice, as well as dual-target and triple-target mice crossbred with PD1/PDL1 humanized mice to create an ideal model to study CD137 target drugs. The normal immune cell population in peripheral blood were not affected in CD137 humanized mice, and hCD137 was expressed on T cells after the stimulation with a anti CD3 antibody. We verified the efficacy of anti-CD137 drugs in BALB/c-hCD137 mice inoculated with different cancer cell lines (i.e. CT26, EMT6 and 4T1). The drug Urelumab showed a dramatic response in the hCD137 mice model inoculated with CT26 and EMT6 but not with 4T1 cell line. In a rechallenge study, no tumors grew in tumor-free mice previously treated with Urelumab, with effector memory T cells increased in peripheral blood, indicating Urelumab has a relatively long-lasting anti-tumor effect. The combination of Urelumab and anti-PD1 has a stronger tumor growth inhibition effect than that of anti-CD137 or anti-PD1 monotherapy on dual-target or triple target mice. These data show that the humanized CD137 mouse is a suitable model for evaluating the monotherapies or combination therapies targeting CD137.
Citation Format: Yunlong Jiang, Tingting Gu, Weiwei Yu, Hongyan Sun, Mingkun Zhang, Juan Liang, Shuai Li, Cunxiang Ju, Jing Zhao, Xiang Gao, Mark W. Moore. CD137 humanized mice for preclinical efficacy evaluation of therapeutic 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 5623.