bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5618: Anti-FGFR4 antibody drug conjugate for immune therapy of rhabdomyosarcoma and hepatocellular carcinoma
Authors: Cheuk Adam , Shivaprasad Nitya , Skarzynski Martin , Baskar Sivasubramanian , Azorsa Peter , Khan Javed 
Published: August 2018

Abstract
Rhabdomyosarcoma (RMS), an aggressive soft tissue sarcoma originating from skeletal muscle in children and adolescent young adults. It is divided in two main histological subtypes including embryonal RMS driven by RAS pathway mutations and alveolar RMS driven by a chimeric fusion gene involving PAX3 or PAX7 with FOXO1. FGFR4 is a cell surface tyrosine kinase receptor that is a critical molecule in RMS biology. In RMS it is a direct target and strongly induced by PAX3-FOXO1 as well as PAX3, and PAX7. By immunohistochemistry we found high expression of FGFR4 in RMS cancers but low expression in normal human organs. Of note FGFR4 has been reported overexpressed in hepatocellular carcinoma (HCC). We therefore hypothesized that FGFR4 will provide a rational target for immune therapy in cancers with high expression. We generated fifteen binders against FGFR4 and characterized them further as candidates for immunotherapy. We found that 3A11, a mouse IgG antibody, bound to FGFR4 positive cell lines with an observed avidity of 1.9nM. By ELISA using the extra cellular domain of human FGFR1, FGFR2, FGFR3 or FGFR4, 3A11 showed dose dependent binding to FGFR4 only. 3A11 was also found internalized upon binding to FGFR4 positive cell lines. The VL and VH domain of 3A11 was cloned and chimeric 3A11 scFvFc (mouse Fv and Human IgG1 Fc) construct was made. The chimeric form of 3A11 antibody was successfully produced in vitro and retained its specificity. To investigate FGFR4-mediated cytotoxicity in RMS cell lines, we cultured RH30 (a RMS cell line expresses FGFR4) in the presence of the chimeric 3A11 and polyclonal anti-mouse 2°ADC conjugated to Duocarmycin DM for 72 hours. Dose-dependent cytotoxicity was observed in RH30, suggesting that chimeric form of 3A11 could deliver a cytotoxic payload to FGFR4 positive cells. We are currently developing antibody drug conjugate using the cytotoxic drug, pyrrolobenzodiazepine which will be tested in vitro and in vivo models of RMS. We have thus developed a chimeric antibody that may provide effective immune therapy for cancers with high FGFR4 expression including RMS and HCC
Citation Format: Adam Cheuk, Nitya Shivaprasad, Martin Skarzynski, Sivasubramanian Baskar, Peter Azorsa, Javed Khan. Anti-FGFR4 antibody drug conjugate for immune therapy of rhabdomyosarcoma and hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5618.
Abstract 5620: Multispecific antibodies targeting CD38 and PD-L1 show potent tumor cytotoxicity
Authors: Schooten Wim van 
Published: August 2018

Abstract
Multivalent antibodies targeting either CD38 alone or CD38 in conjunction with PD-L1 may yield therapeutics with superior biologic activities and provide benefit for treating malignancies expressing low levels of CD38 (DLCBL, daratumumab refractory MM, and NSCLC). Multivalent, multispecific antibodies kill CD38low cells through a variety of mechanisms including stronger and more specific engagement of CD38. Potent and directed immune checkpoint inhibition is realized by adding an anti-PD-L1 binding domain. Teneobio's discovery platform utilizes VH domains (UniDabs) of fully human heavy chain antibodies (UniAbs) to develop bi-, tri-, and tetravalent antibodies. Individual UniDabs targeting CD38 and PDL1 were identified using our unique sequence-based discovery platform and high-throughput lead evaluation pipeline (TeneoSeek). This robust screening workflow enables evaluation of a large diversity of natural fully human antibodies, targeting multiple epitopes on a single antigen and uncovering important sequence activity relationships. We have identified UniDabs that bind five different functional epitopes on human, cynomolgus and mouse CD38 including potent inhibitors of hydrolase and cyclase enzymatic functions. In addition, we generated a large panel of PD-L1 inhibitors that bind with high affinities human and cynomolgus PD-L1. Using different combinations and arrangements of UniDabs, a variety of multivalent antibodies were constructed and evaluated in in vitro models. Data from a range of assay types show that multivalent UniAbs targeting CD38 can be engineered to display superior tumor cell cytotoxicity through multiple mechanisms of action. Summary: Teneobio's discovery platform utilizes VH domains (UniDabs) of fully human heavy chain antibodies (UniAbs) to develop bi-, tri-, and tetravalent antibodies. Multivalent UniAbs targeting CD38 and PD-L1 can be engineered to display superior tumor cell cytotoxicity through multiple mechanisms of action.
Citation Format: Wim van Schooten. Multispecific antibodies targeting CD38 and PD-L1 show potent tumor cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5620.
Abstract 5623: Development of a CD47-blocking antibody as a cancer therapy
Authors: Oaks Joshua , Wang Ming , Zou Hui 
Published: August 2018

Abstract
Immune system avoidance by cancer cells is controlled through a variety of mechanisms such as CTLA-4 and PD-1/L1, which inhibit the T-cell mediated adaptive immune response to cancer. Similar mechanisms exist for evasion from innate immunity, for example, through CD47 overexpression. On healthy cells, CD47 serves as a “don't eat me” signal by the binding to the transmembrane SIRPα protein on phagocytic cells, and prevents the engulfment of “self” by macrophages. In several cancer types, tumor cells overexpress CD47 to elude the immune system. This property of CD47 makes it an attractive target for cancer treatment. Here we describe a humanized monoclonal antibody that is a potent disruptor of the CD47/SIRPα interaction and therefore presents itself as a potential therapeutic anti-CD47 antibody. This antibody binds robustly to recombinant extracellular domains (ECD) of human and cynomolgus CD47, and to full-length human and cynomolgus CD47 expressed on HEK293 cells. Functionally, it blocks the CD47/SIRPα interaction in an ELISA-based assay with an IC50 of single-digit nM. In a cell-based assay, effect on phagocytosis by this antibody was assessed. In addition, disruption of the TSP-1/CD47 interaction has been postulated to have positive outcomes in cancer therapy and the efficacy of this antibody on inhibiting this interaction is also investigated. Finally, the effect of the antibody on Raji human Burkitt's lymphoma xenograft growth in mice will be presented. A concern with anti-CD47 therapy is the undesired targeting of red blood cells (RBCs). This antibody does not induce marked hemagglutination, suggesting a limited impact on RBCs. Taken together, our data suggest that we have developed a novel, humanized anti-CD47 antibody that can restore immune system targeting of cancer cells without inducing significant RBC agglutination.
Citation Format: Joshua Oaks, Ming Wang, Hui Zou. Development of a CD47-blocking antibody as a cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5623.
Abstract 5624: Development of novel bispecific immune modulating antibodies
Authors: Vitale Laura A. , Thomas Lawrence J. , He Li-Zhen , O'Neill Thomas , Widger Jenifer , Crocker Andrea , Testa James , Sundarapandiyan Karuna , Forsberg Eric , Boyer James , Storey James , Goldstein Joel , Marsh Henry C. , Keler Tibor 
Published: August 2018

Abstract
The initial success with checkpoint blocking antibodies has evolved into a tremendous effort in combination therapy to further improve outcome in responsive cancers and to overcome resistance. There is strong rationale for this approach, as the cancer-immunity cycle has many points for intervention, and the immune system has developed multiple pathways to the same end. The use of bispecific antibodies provides opportunities to engage two pathways simultaneously that can result in greater efficacy, improved safety profile, and simplified development compared to separately administered antibodies. To generate bispecific antibodies that blocked the PD-1 signaling pathway, we developed and characterized fully human PD-L1 specific antibodies generated using human Ig transgenic mice. A lead antibody was chosen for its potent activity in functional assays and good manufacturing properties. Our initial bispecific construct couples our CD27 agonist antibody with the PD-L1 antibody (αCD27xαPD-L1) as we have previously shown that this combination led to improved therapeutic activity in the BCL1 disseminated lymphoma model. We found that the αCD27xαPD-L1 was more potent in CD27 costimulation assays such as NFkB activation, and T cell cytokine production compared to the parental antibodies. Similarly, αCD27xαPD-L1 was more efficacious in vivo as measured by Ag-specific T cell IFN-γ production and antitumor activity. Importantly, the bispecific antibody was more effective than the combination of anti-CD27 and anti-PD-L1 antibodies in the BCL1 lymphoma model. The enhanced efficacy was attributed to more efficient cross-linking of the bispecific antibody/CD27 receptor, resulting in stronger T cell activation. In addition, we observed that CD27 signaling increased PD-L1 expression on both tumor and immune cells, which may further enhance the activity of the bispecific antibody. The use of bispecific antibodies can improve the efficacy and profile of immunotherapeutic monoclonal antibodies by combining complementary functionalities and enhancing target cross-linking in the relevant tissues. We are currently exploring this approach with multiple antibodies from our pipeline.
Citation Format: Laura A. Vitale, Lawrence J. Thomas, Li-Zhen He, Thomas O'Neill, Jenifer Widger, Andrea Crocker, James Testa, Karuna Sundarapandiyan, Eric Forsberg, James Boyer, James Storey, Joel Goldstein, Henry C. Marsh, Tibor Keler. Development of novel bispecific immune modulating antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5624.
Abstract 5628: Measurement of Fc-mediated ADCC and CDC activity of anti-TNFA and anti-VEGF therapeutic antibodies using reporter-based bioassays and engineered TNFA+ and VEGF+ target cells
Authors: Garvin Denise , Grailer Jamison , Moravec Rich , Hartnett Jim , Ott Vanessa , Fan Frank , Cong Mei , Cheng Zhi-jie Jey 
Published: August 2018

Abstract
Fc-mediated effector functions are critical to the efficacy and safety of therapeutic 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 TNFA 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 FcΓRI, FcΓRIIa and FcΓRIIIa. 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 TNFA or VEGF. When used as target cells with reporter-based effector cells expressing a relevant FcΓR, 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 FcΓR-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, Vanessa Ott, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Measurement of Fc-mediated ADCC and CDC activity of anti-TNFA and anti-VEGF therapeutic antibodies using reporter-based bioassays and engineered TNFA+ and VEGF+ target cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5628.
Abstract 563: Identification of a novel biomarker to predict pathologic complete response for neoadjuvant chemoradiotherapy in locally advanced rectal cancer
Authors: Kim Jong Gwang , Lee In Hee , Lee Soo Jung , Chae Yee Soo , Kang Byung Woog 
Published: August 2018

Abstract
Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Good pathologic response to CRT is associated with better outcome. However, there is a lack of effective methods to select rectal cancer patients who would or would not have a benefit from CRT. Therefore, we aimed to perform whole-exome sequencing (WES) for rectal cancer to identify the novel genetic variations predicting CRT benefit in LARC. Two independent sets were used to evaluate the genetic differences between the good response group and poor response group to CRT. Fifteen patients who achieved pathologic complete response were divided into the good response group and 15 patients with pathologic stage III were classified as poor response group. Among these 30 patients, WES was examined. To validate discovery set, additional samples (n=67) were genotyped for candidate variants using TaqMan SNP genotyping assays or Sanger sequencing. Overall, the current study included a total of 97 LARC patients who were treated with neoadjuvant CRT followed by curative surgery at Kyungpook National University Medical Center. We found 5 candidate variants significantly associated with pathologic complete response (BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, RAET1L rs912565) using WES. In the dominant model, patients with GC/CC genotype of DLC1 rs3816748 (p=0.032), AC/CC genotype of DNAH14 rs3105571 (p=0.009) and TT genotype of RAET1 rs912565 (p&lt;0.0001) showed higher rate of pCR compared to those of other genotype patients. In the recessive model, the BCL2L10 rs2231292 (p=0.036) and ITIH5 rs3824658 (p=0.003) were significantly associated with pathologic CR. Four SNPs (DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, RAET1L rs912565) found to be significantly correlated with pCR in codominant model. However, none of the SNPs was associated with the relapse-free survival or overall survival. The present results suggest that the genetic variation of the BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565 genes can be used as biomarkers predicting CRT response for patients with LARC.
Citation Format: Jong Gwang Kim, In Hee Lee, Soo Jung Lee, Yee Soo Chae, Byung Woog Kang. Identification of a novel biomarker to predict pathologic complete response for neoadjuvant chemoradiotherapy in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 563.
Abstract 5638: A tetanus-way of improving synthetic long peptide tumor vaccination
Authors: Drijfhout Jan Wouter , Fletcher Erika , Leja-Jarblad Justyna , Kerzeli Iliana , Cordfunke Robert , Tornqvist Gunilla , Lindqvist Frida , Hultqvist Greta , Valentijn Rob , Ladjervardi Sam , Haggman Michael , Ullenhag Gustav , Mangsbo Sara 
Published: August 2018

Abstract
We have previously identified a natural B cell epitope derived from tetanus toxin named Minimal Tetanus Toxin Epitope (MTTE)[1]. Most healthy individuals have IgG1 antibodies to this peptide sequence but no IgM antibodies. We have assessed the possibility to apply this MTTE sequence in drug development with the intention to create immune complexes and use them as vehicles to carry antigen-material into dendritic cells. Thru a conjugation method three MTTE sequences and a longer synthetic peptide stretch harboring T cell epitopes are linked together. As immune complexes are efficient carriers of antigen material and can promote cross-presentation the aim is to use these conjugates for therapeutic purposes in diseases where a strong cellular immune response should be induced.
To further evaluate the MTTE peptide conjugates in drug development we have investigated how a diphtheria, tetanus, pertussis (DTP) vaccination induces antibody titers against the linear tetanus sequence. Herein we have studied the MTTE location in the tertiary structure of the protein, how cancer patients respond with antibody titers against MTTE along with a subsequent T cell response and in vivo anti-tumor responses (mice). In addition we have studied safety in terms of cytokine release assessment pre and post a DTP vaccination. We found that the MTTE sequence is part of an alpha-helix that is externally oriented and thereby accessible for peptide binding. We found that not helper epitope is part of the MTTE sequence and that healthy individuals as well as cancer patients can mount IgG titers against the epitope, this also result in more efficient induction of recall responses post a DTP booster than pre boost. Mice seropositive to the MTTE sequence can mount anti-tumor responses, while this is not seen in seronegative animals. In addition, a cytokine release assessment using a modified chandler loop model with intact complement does not display a broad immediate cytokine release pre or post a DTP booster. We conclude that it is efficacious and safe to make use of a peptide conjugate in a drug development project with the aim to use it as a vaccine strategy.
[1] Mangsbo et al. In press. Molecular Immunology 2017
Citation Format: Jan Wouter Drijfhout, Erika Fletcher, Justyna Leja-Jarblad, Iliana Kerzeli, Robert Cordfunke, Gunilla Tornqvist, Frida Lindqvist, Greta Hultqvist, Rob Valentijn, Sam Ladjervardi, Michael Haggman, Gustav Ullenhag, Sara Mangsbo. A tetanus-way of improving synthetic long peptide tumor vaccination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5638.
Abstract 5649: Multi-omics data indicate that primary and lymph node oral cancer cells-derived extracellular vesicles carry cargo molecules with a specific aggressive pattern
Authors: Busso-Lopes Ariane F. , Carnielli Carolina M. , Winck Flávia , Riaño-Pachón Diego M. , Oliveira Ana K. , Costa Rute A. , Rivera César , Caldana Camila , Fox Jay W. , Leme Adriana F. Paes 
Published: August 2018

Abstract
Oral squamous cell carcinoma (OSCC) exhibits high incidence and morbidity, representing 300,000 new cases and 145,000 deaths per year. Moreover, the 5-year survival rate is 50% and this is directly associated with regional lymph node metastases. To explore how the extracellular vesicles (EVs) play a significant role on OSCC lymph node metastasis, we characterized the EVs released by tumor primary site cells and their paired lymph node metastasis cells using nanoparticle tracking analysis, high-resolution microscopy (Cryo-EM), EVs uptake by HUVEC, BJ-5ta and gingival primary fibroblasts recipient cells and the proteins, lipids, metabolites and miRNAs contents. Both cells-derived EVs showed a similar size, morphology, and the presence of annexin-2 and flotillin-1 surface markers. Interesting, only gingival primary recipient cells were more likely to uptake primary OSCC-derived EVs compared with lymph node-derived EVs. This effect is probably associated with the differential abundance of 490 proteins, 316 miRNAs, 63 lipids and 17 metabolites between the oral cancer cells-derived EVs. Markedly, multilevel omic data integration indicates that metabolic processes were over-represented mainly in primary OSCC-derived EVs, suggesting that these EVs carry specific cargo molecules associated with a more aggressive pattern compared with lymph node OSCC-derived EVs.
Financial support: FAPESP (Process number 2016/50005-7).
Citation Format: Ariane F. Busso-Lopes, Carolina M. Carnielli, Flávia Winck, Diego M. Riaño-Pachón, Ana K. Oliveira, Rute A. Costa, César Rivera, Camila Caldana, Jay W. Fox, Adriana F. Paes Leme. Multi-omics data indicate that primary and lymph node oral cancer cells-derived extracellular vesicles carry cargo molecules with a specific aggressive pattern [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5649.