bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4818: Fc-mediated mechanism of action for the novel EGFR-cMET bispecific antibody (JNJ-61186372) in non-small cell lung cancer
Authors: Vijayaraghavan Smruthi , Bushey Barbara , Lipfert Lorriane , Nanjunda Rupesh , Lacy Eilyn R. , Buckley Peter , Laquerre Sylvie , Lorenzi Matthew V. , Moores Sheri 
Published: August 2019

Abstract
JNJ-61186372 (JNJ-372) is an anti-EGFR and cMet bispecific antibody with an active Fc backbone (IgG1) designed to treat non-small cell lung cancer (NSCLC) disease. A first-in-human study is currently being conducted to assess the safety and preliminary efficacy of JNJ-372 in patients with advanced NSCLC. Early data suggests that JNJ-372 can induce partial responses in subjects with diverse populations of EGFR-mutated NSCLC, including Exon 20ins as well as TKI resistance mutations.
Our previous pre-clinical in vivo studies showed that the Fc inactive version (IgG2sigma) of the EGFR/cMet antibody was significantly impaired in its ability to inhibit tumor growth compared to the Fc active JNJ-372. The IgG2sigma variant also reduced the ability of the bispecific antibody to mediate downregulation of EGFR, cMet and downstream signaling components. This suggested that the interaction of the Fc arm with the Fc receptors on the innate immune cells play a crucial role in the mechanism of action of JNJ-372. While JNJ-372 has demonstrated antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) in vitro, the potential role of Fc interactions in downregulation of EGFR and cMet was not well understood.
We explored the different Fc-mediated immune effector functions of JNJ-372 and interrogated how they contribute to EGFR and cMet downregulation and overall efficacy. In NSCLC cell lines, JNJ-372 induced Fc-mediated dose-dependent ADCC and ADCP but not complement-dependent cytotoxicity. Further, the presence of isolated human immune cells (PBMC) significantly enhanced JNJ-372 mediated EGFR and cMet downregulation and dose-dependent tumor cell killing. Studies are in progress to better understand which immune cells and which Fc receptor interactions are essential for the drug efficacy through immune cell depletion and FcR blocking studies; such studies may help guide clinical biomarker development. This work elucidates a novel Fc-dependent mechanism of action for the EGFR-cMet bispecific antibody.
Citation Format: Smruthi Vijayaraghavan, Barbara Bushey, Lorriane Lipfert, Rupesh Nanjunda, Eilyn R. Lacy, Peter Buckley, Sylvie Laquerre, Matthew V. Lorenzi, Sheri Moores. Fc-mediated mechanism of action for the novel EGFR-cMET bispecific antibody (JNJ-61186372) in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4818.
Abstract 4821: Development of a potent Trop-2 antibody-drug conjugate, BAT8003, for the treatment of Trop-2 positive gastric tumors
Authors: Tang Weijia , Mei Xingxing , Ou Ziqiang , Gan Jirong , Li Shengfeng , Yu Jin-Chen 
Published: August 2019

Abstract
Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas while having low levels of expression on normal tissue. Overexpression of Trop-2 has been correlated with poor prognosis in several solid tumors. Trop-2 is overexpressed in ~60% of gastric cancer, which causes more than 500,000 mortalities every year in China. We have developed a Trop-2 antibody-drug conjugate (ADC), BAT8003, that utilizes an anti-Trop-2 IgG1 antibody, engineered for site-specific conjugation, a novel uncleavable linker, and a potent maytansine derivative as the payload. Site-specific conjugation allows for a more controllable drug-antibody ratio (DAR), resulting in a more homogenous product. BAT8003 also incorporates increased ADCC effects through afucosylation to further enhance potency. Here we show that BAT8003 is internalized in Trop-2 positive cells. It inhibits proliferation of a number of different Trop2-overexpressed tumor cells with IC50s of ~1 nM. In a gastric cancer (NCI-N87) mouse xenograft model, BAT8003 demonstrates strong inhibition activity on tumor growth at doses of 5 mg/kg and 15 mg/kg. A multiple dose toxicity study in monkey reveals that the highest non-severely toxic dose (HNSTD) of BAT8003 is 20 mg/kg when dose once every 3 weeks. The preclinical profile of BAT8003 warrants further clinical development for the treatment of gastric cancer as well as other Trop-2 over-expressing cancers.
Citation Format: Weijia Tang, Xingxing Mei, Ziqiang Ou, Jirong Gan, Shengfeng Li, Jin-Chen Yu. Development of a potent Trop-2 antibody-drug conjugate, BAT8003, for the treatment of Trop-2 positive gastric tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4821.
Abstract 4830: ABX9xx: A bispecific centyrin that synergizes to attenuate intracellular signaling in Met/EGFR positive tumors
Authors: Addis Russ , Kolakowski Robert , Kulkarni Swapnil , Gorsky Josh , Meyer Rebecca , ONeil Karyn 
Published: August 2019

Abstract
ABX9xx is a bispecific Centyrin targeting the Met-EGFR axis, an emerging cancer treatment paradigm. Centyrins are small, chemically simple proteins based on a human FN3 domain that can be engineered to have high affinity for a selected target and are easily linked to form multi-specific binders. The standard of care for patients with EGFR mutant non-small cell lung cancer (NSCLC) is treatment with small molecule tyrosine kinase inhibitors (TKI) including recently approved third generation molecules (ie. osimertinib). Despite initial promising responses with TKIs, most patients regress within 12-14 months due to resistance. A predominant resistance mechanism dependent on Met amplification and signaling has been described from both in vitro experiments and clinical data. Targeting Met and EGFR with a bispecific ligand blocking inhibitor that attenuates intracellular signaling may provide a significant efficacy advantage and reduced side effect profile compared to small molecule TKI combinations. Exploiting the potential for avidity on tumor tissue, a bispecific ligand blocking inhibitor of Met and EGFRis also anticipated to provide improved selectivity for tumor tissue that overexpress both receptors compared to normal tissue with lower receptor expression. To enable sustained exposure while maintaining small size for good tumor penetration, ABX9xx includes a domain comprising an albumin binding Centyrin. ABX9xx activity on Met, EGFR and downstream signaling proteins was confirmed on several lung cancer cell lines in vitro including those carrying clinically observed mutations in Met and EGFR. ABX9xx inhibited EGFR phosphorylation independent of EGFR mutational status with higher potency than osimertinib. In addition, ABX9xx inhibited Met phosphorylation with higher potency than Crizotinib, an ALK inhibitor with cross reactivity to Met, currently used to treat Met positive patients. The pharmacokinetic properties of ABX9xx in animal models suggest a suitable dosing paradigm in patients. Together the data provides a strong rationale for advancing ABX9xx into clinical development for NSCLC and other cancers where EGFR and MET are drivers of tumor progression.
Citation Format: Russ Addis, Robert Kolakowski, Swapnil Kulkarni, Josh Gorsky, Rebecca Meyer, Karyn ONeil. ABX9xx: A bispecific centyrin that synergizes to attenuate intracellular signaling in Met/EGFR positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4830.
Abstract 4831: Using reporter-based bioassays and engineered TNFalpha and VEGF+ target cells to measure Fc-mediated ADCC and CDC activity of anti-TNFá and anti-VEGF therapeutic antibodies
Authors: Garvin Denise , Grailer Jamison , Moravec Rich , Hartnett Jim , Heid Chris , Fan Frank , Cong Mei , Cheng Jey 
Published: August 2019

Abstract
Fc receptor-mediated effects contribute to the therapeutic response in terms of efficacy and safety of anti-TNF antibodies. Measurement of Fc-mediated antibody-mediated cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) during antibody drug discovery and development is not only important for antibodies that harness ADCC and/or CDC as their primary mechanism of action (e.g. rituximab, trastuzumab), but also for antibodies designed to target and block soluble ligands such as TNFα and VEGF. We previously reported the development of a cell-based reporter bioassay platform which has been used to measure ADCC and ADCP mediated through FcgRI, FcgRIIa and FcgRIIIa. These reporter bioassays exhibit the specificity, accuracy, precision, and robustness necessary for qualification according to ICH guidelines and have been used extensively to characterize and measure the potency of antibody-based biologics drugs that target cell surface immune receptors. In the current study, we sought to evaluate Fc-mediated ADCC and CDC activities of therapeutic antibodies designed to target and block soluble ligands including TNFa and VEGF. To measure ADCC activity of anti-TNFa and anti-VEGF blocking antibodies, we developed engineered target cells that express either membrane-bound TNFα or VEGF. When used as target cells with reporter-based effector cells expressing a relevant FcgR, ADCC activity of adalimumab (anti-TNFa) and bevacizumab (anti-VEGF) was detected in a specific and dose-dependent manner. Similarly, when used in a luminescence-based CDC assay, the engineered target cells elicited an appropriate FcgR-mediated response. The assay signals demonstrated IgG isotype specificity as IgG4 variants showed minimal activity in both ADCC and CDC assays. Our results demonstrate that the combined use of cell-based reporter bioassays with target cells engineered to express membrane-bound soluble ligands can provide a simple, specific, and quantitative platform to measure Fc-mediated effector functions of therapeutic antibodies targeting soluble ligands.
Citation Format: Denise Garvin, Jamison Grailer, Rich Moravec, Jim Hartnett, Chris Heid, Frank Fan, Mei Cong, Jey Cheng. Using reporter-based bioassays and engineered TNFalpha and VEGF+ target cells to measure Fc-mediated ADCC and CDC activity of anti-TNFá and anti-VEGF therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4831.
Abstract 4833: Antibody-drug conjugate targeting glypican-1 shows tumor growth inhibition in cholangiocarcinoma
Authors: Yokota Keiichiro , Serada Satoshi , Tsujii Shigehiro , Hiramatsu Kosuke , Namikawa Tsutomu , Murakami Ichiro , Hanazaki Kazuhiro , Naka Tetsuji 
Published: August 2019

Abstract
Cholangiocarcinoma is one of the most highly malignant cancers. Many patients need systemic chemotherapy for tumor development and recurrence, but their prognosis is poor. Therefore new treatment options are urgently required. We confirmed that the expression of glypican-1 (GPC1) was enhanced in cholangiocarcinoma. GPC1 is a cell surface membrane protein and has been reported as a poor prognostic factor in pancreatic cancer. In this study, we aimed to develop a new therapy for cholangiocarcinoma by the antibody-drug conjugate (ADC) targeting GPC1. By immunohistochemical analysis, enhanced expression of GPC1 was observed in clinical specimens of cholangiocarcinoma. KKU-055 and KKU-100 cells, which are cell lines of cholangiocarcinoma, had high expression of GPC1. In the KKU-055 xenograft model when we administered fluorescently-labeled GPC1 antibody to mice, it accumulated in tumor tissue. We developed a new anti-GPC1 monoclonal antibody (mAb) with highly internalizing activity. The anti-GPC1 mAb was conjugated with the cytotoxic agent monomethyl auristatin F (MMAF). GPC1-ADC showed potent antitumor effect toward KKU-055 and KKU-100 cells compared with the control ADC. In the KKU-055 xenograft model, GPC1-ADC had significant and potent tumor growth inhibition in a dose-dependent manner. In summary, our newly-developed GPC1-ADC showed significant tumor growth inhibition against GPC1-positive cholangiocarcinoma cell lines. Our preclinical data demonstrated that targeting GPC1 by ADC is a promising therapy for GPC1-positive cholangiocarcinoma.
Citation Format: Keiichiro Yokota, Satoshi Serada, Shigehiro Tsujii, Kosuke Hiramatsu, Tsutomu Namikawa, Ichiro Murakami, Kazuhiro Hanazaki, Tetsuji Naka. Antibody-drug conjugate targeting glypican-1 shows tumor growth inhibition in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4833.
Abstract 4838: Leflunomide inhibits the growth of LKB1-inactivated tumors in both xenograft and immunocompetent genetically engineered mouse models
Authors: Jin Rui , Liu Xiuju , Peng Wei , Fan Yijian , Liu Boxuan , Yang Shuanying , Xing Chun-gen , Gilbert-Ross Melissa , Marcus Adam , Zhou Wei 
Published: August 2019

Abstract
Introduction: LKB1 is the third mostly frequently mutated gene in lung adenocarcinoma, and is mutually exclusive with EGFR mutations. Furthermore, a recent clinical trial indicated that lung cancers with LKB1 mutations are unlikely to respond to immune checkpoint therapy. Therefore, there is an urgent need for novel therapies for LKB1-inactivated lung cancer. We previously demonstrated that leflunomide preferentially induces apoptosis in LKB1-null lung cancer cell lines in vitro. Here, we evaluated the effect of leflunomide in both a xenograft model and immune-competent genetically engineered mouse model (GEMM).
Methods: LKB1-null H460 xenograft mice were treated with leflunomide (35mg/kg/day) for 23 days through oral gavage and tumor volume was measured every the other day. KrasG12D/Lkb1-/-Luciferase GEMM mice were treated with leflunomide (30mg/kg/day) for 44 days and tumor burden was measured by bioluminescence imaging (BLI) score every week. At the end of experiments, tumors were dissected, weighed, and analyzed by immunohistochemistry.
Results: Although leflunomide is an FDA-approved agent to treat rheumatoid arthritis, its immune suppression function did not facilitate but inhibited the growth of KrasG12DLkb1-/- lung adenocarcinoma. This suppression was also observed in H460 xenografts, and leflunomide treatment did not alter animal weight in either model. Furthermore, distant cancer metastasis was not observed in leflunomide-treated GEMM. In residual tumors from the treated group, cleaved caspase-3 was not detectable but there was a significant decrease in Ki67 staining. This is consistent with our in vitro findings that leflunomide primarily inhibits cell proliferation through the promotion of G1 cell cycle arrest.
Conclusion: Our findings indicate that leflunomide may be a viable reagent for the treatment of LKB1-mutated lung adenocarcinoma.
Citation Format: Rui Jin, Xiuju Liu, Wei Peng, Yijian Fan, Boxuan Liu, Shuanying Yang, Chun-gen Xing, Melissa Gilbert-Ross, Adam Marcus, Wei Zhou. Leflunomide inhibits the growth of LKB1-inactivated tumors in both xenograft and immunocompetent genetically engineered mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4838.
Abstract 4841: Rapid screening of cyclotide-based libraries for the selection of potent E3 ligase antagonists
Authors: Camarero Julio A. 
Published: August 2019

Abstract
We report novel methods for the biosynthesis of natively-folded MCoTI-based cyclotides inside live E. coli cells using a split protein splicing unit. The cyclotide MCoTI-cylotides are potent trypsin inhibitors recently isolated from the seeds of Momordica cochinchinensis, a plant member of cucurbitaceae family. Biosynthesis of genetically encoded cyclotide-based libraries opens the possibility of using single cells as microfactories where the biosynthesis and screening of a particular inhibitor can take place in a single process within the same cellular cytoplasm. The cyclotide scaffold has a tremendous potential for the development of therapeutic leads based on their extraordinary stability and potential for grafting applications. We will show an example, where a large cyclotide-based genetically-encoded library was used to screen for low nanomolar antagonists for the Hdm2-HdmX RING-mediated E3 ligase activity. We will also present different strategies to improve the cellular uptake and pharmacokinetic profiles of bioactive cyclotides.
Citation Format: Julio A. Camarero. Rapid screening of cyclotide-based libraries for the selection of potent E3 ligase antagonists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4841.
Abstract 4847: Investigating the impact of astrocytes on targeted therapy of melanoma brain metastases
Authors: Parris Joshua , Basu Subhasree , Barnoud Thibaut , Zhao Yongkang , Somboonsong Peter , Chen Qing , Murphy Maureen 
Published: August 2019

Abstract
Metastatic melanoma is a devastating disease that leads to the development of brain metastases (MBMs) in 40-60% of patients. Upon diagnosis of brain metastases, patient overall survival is less than 6 months. Poor patient survival is believed to be due to resistance driven by the brain microenvironment. Collectively, these findings underscore the need for novel therapeutic strategies to improve the survival of patients with MBMs. Development of effective therapies relies on an understanding of the interaction between MBMs and different cell types within the brain microenvironment. Astrocytes are the most abundant cell type within the brain and interact with MBMs through direct and indirect mechanisms. Astrocyte interaction with MBMs alters MBM gene expression and promotes metastatic outgrowth and resistance to cytotoxic chemotherapies. Exactly how astrocytes alter MBM response to MAPK inhibition remains unclear. Using conditioned media from primary astrocytes, as well as co-culture of primary astrocytes with either the MBM cell line WM4265-2 or the primary melanoma cell line WM983B, we found that the interaction of melanoma cells with astrocytes increased melanoma sensitivity to MEK inhibition (MEKi). RNA sequencing of WM4265-2 and WM983B cell lines treated with the MEK inhibitor PD0325901 (PD901) showed significant up-regulation of the transcriptional regulator ID3, which is known to play a role in the resistance of melanoma to MAPK inhibition. Interestingly, astrocyte conditioned media prevented the upregulation of ID3. To validate this finding, we silenced ID3 in WM4265-2 and WM983B cell lines, and showed that knockdown of ID3 caused increased sensitivity to MEKi. These combined data support the premise that the increased response to PD901 in MBMs exposed to astrocytes is due to ID3 down-regulation. How ID3 modulates resistance to MAPK inhibition remains unclear. Elucidating the mechanism of ID3 mediated resistance to MEKi may uncover new avenues for improving the treatment of melanoma brain metastases.
Citation Format: Joshua Parris, Subhasree Basu, Thibaut Barnoud, Yongkang Zhao, Peter Somboonsong, Qing Chen, Maureen Murphy. Investigating the impact of astrocytes on targeted therapy of melanoma brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4847.
Abstract 4849: CAP-100: first-in-class anti-CCR7 antibody for CLL
Authors: Cuesta-Mateos Carlos , Muñoz-Calleja Cecilia , Loscertales Javier , Terron Fernando , Mol Wim 
Published: August 2019

Abstract
The homeostatic CC-chemokine receptor 7 (CCR7) is highly expressed in many hematological malignancies including chronic lymphocytic leukemia (CLL). CCR7 surface expression levels are much higher than those of CD20, and are correlated with poor prognosis. Upon engagement by its ligands (CCL19 and CCL21), CCR7 controls trafficking of CLL cells to locations where these chemokines are expressed, such as the lymph node (LN). In this protective microenvironment CCR7 ligands contribute to CLL cell survival and proliferation. Indeed, high CCR7-mediated in vitro migration of patient CLL cells correlates with LN involvement and adverse prognostic factors. Thus, strategies targeting CCR7 could provide an additional therapeutic approach for CLL.
Therefore, we have generated CAP-100, the first humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds to human CCR7 and neutralizes ligand-mediated signaling from both CCL19 and CCL21. The antibody effectively inhibited CLL cells migration and survival. Furthermore, in in vivo pre-clinical studies, CAP-100 was shown to inhibit entry of CCR7-expressing cells to LNs. The antibody showed potent cell killing activity against CLL cells while preserving normal blood cells. This Fc-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) clearly outperformed standard-of-care in CLL, such as rituximab. ADCC and migration inhibition were both independent of prognostic markers for high risk CLL, such as TP53 mutation including 17p deletion and relapse/refractoriness to various standard therapies, including BTK-inhibitors. Finally, when given as monotherapy in disseminated NHL xenograft tumors in SCID mice, CAP-100 exhibited tumor growth inhibition in established tumors and provided significant survival.
Collectively, our results demonstrate that CAP-100, the first-in-class anti-CCR7 mAb, is a potent antagonist with biological activity in CLL primary cells, including those from relapsed/refractory patients. Moreover, these results highlight the relevance of the CCR7-CCL19/CCL21 pathway as a therapeutic target in CLL. CAP-100’s unique propensity to block migration of CLL cells to the LN, in combination with its potent cell killing activity provides the biological rationale for use of CAP-100 in CLL, either as monotherapy or in combination with novel agents such as BTK-inhibitors. Clinical trials in CLL and other CCR7-expressing NHL will be initiated soon.
Citation Format: Carlos Cuesta-Mateos, Cecilia Muñoz-Calleja, Javier Loscertales, Fernando Terron, Wim Mol. CAP-100: first-in-class anti-CCR7 antibody for CLL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4849.