bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 639: Antibody-mediated blockade of phosphatidylserine combined with radiation improves survival and tumor eradication in a rat model of non-small cell lung cancer
Authors: Belzile Olivier , Zhang Zhang , Huang Xianming , Saha Debabrata , Brekken Rolf A. 
Published: May 2015

Abstract
Stereotactic body radiation therapy (SBRT) uses image guidance to deliver very high doses of radiation, in no more than 5 fractions, to tumors. SBRT has shown remarkable benefit in patients with peripheral lung tumors but can cause severe toxicity to central organs when the tumor is proximally located if full potency doses are used (18 Gy x 3 fractions, for example). Bavituximab, a therapeutic monoclonal antibody that is headed to Phase III clinical trials, recognizes the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on both tumor blood vessels and tumor cells subjected to SBRT. We hypothesized that treatment with the antibody 2aG4 (a murine version of bavituximab) would synergize with SBRT and allow tolerable doses of radiation to be used to treat centrally-located NSCLC without sacrificing efficacy. Nude rats bearing established orthotopic A549-luc NSCLC were treated with 3x12 Gy of radiation alone or combined with 2aG4 (4mg/kg) injected twice per week. Tumor growth was followed by bioluminescence. Rats treated with radiation and 2aG4 had a 100% survival rate 106 days after implantation and tumors were completely eradicated in 44% of these animals. In contrast, rats treated with radiation had a survival rate of 17% while only 11% of untreated rats survived. A toxicity study was conducted in which 3x12 Gy of radiation was delivered to central organs of tumor-free rats. This treatment does not appear to cause severe toxicity. These results suggest that bavituximab with radiation may result in improved clinical outcome in patients with centrally-located Non-Small Cell Lung Cancer (NSCLC).
Citation Format: Olivier Belzile, Zhang Zhang, Xianming Huang, Debabrata Saha, Rolf A. Brekken. Antibody-mediated blockade of phosphatidylserine combined with radiation improves survival and tumor eradication in a rat model of non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 639. doi:10.1158/1538-7445.AM2014-639
Abstract 64: A p53 activating mutation drives metastatic high-grade serous ovarian cancer arising from the ovary in mice
Authors: Kim Jaeyeon , Coffey Donna M. , Ma Lang , Matzuk Martin M. 
Published: May 2015

Abstract
The tumor suppressor p53 is the most frequently mutated gene in high-grade serous ovarian cancer, or high-grade serous carcinoma (HGSC) − the most common and deadliest ovarian cancer. Yet it remains unknown whether p53 mutation can drive HGSC. To address this, we have incorporated a p53 activating mutation, p53R172H, into conditional Dicer-Pten double-knockout (DKO) mice, generating triple-mutant (TKO) mice. Like DKO mice, these TKO mice develop fallopian-tube-originated HGSCs, aggressively metastasizing inside the abdominal cavity, inducing ascites, and killing the mice. Then, unlike DKO mice, when both fallopian tubes are surgically removed from TKO mice, TKO ovaries alone are capable of developing HGSCs, which also metastasize to the abdominal cavity, including the omentum, diaphragm, and mesentery. This finding indicates that p53 mutation can drive HGSC in the ovary. To further examine the ability of p53 mutation to drive ovarian HGSC, we have generated p53R172H-Pten double-mutant mice (DMu), a control line for TKO mice. Intriguingly, 30% of the DMu mice (12/40 mice) develop metastatic HGSCs in the ovary, which spread to the abdominal cavity before killing the mice, just like TKO mice with fallopian tubes removed. Unlike TKO and DKO mice, however, DMu mice show no sign of tumor in the fallopian tube. Our new mouse models of ovarian cancer therefore show that p53 mutation indeed can initiate and drive metastatic HGSCs arising from the ovary. Clinically, our study suggests that besides the fallopian tube, the ovary can serve as a source of high-grade serous ovarian cancer. (Grant support: Ovarian Cancer Research Fund (OCRF); Marsha Rivkin Ovarian Cancer Challenge Grant; F32 NCI National Research Service Award (NRSA); K99/R00 NCI Pathway to Independence Award)
Citation Format: Jaeyeon Kim, Donna M. Coffey, Lang Ma, Martin M. Matzuk. A p53 activating mutation drives metastatic high-grade serous ovarian cancer arising from the ovary in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 64. doi:10.1158/1538-7445.AM2014-64
Abstract 647: CD20-specific Engineered Toxin Body demonstrates direct cell kill of multiple B-cell Non-Hodgkin's lymphoma types
Authors: Rajagopalan Sangeetha , Wirth Rachel , Erdman Jennifer , Grant Kari , Brieschke Brigitte , Flores Rodney , Null William , Liu Jen-Sing , Willert Erin K. , Higgins Jack P. 
Published: May 2015

Abstract
The B-cell membrane protein CD20 is expressed by both benign and neoplastic lymphocytes. It has been a superb target for immunotherapies targeting B-cell derived diseases. There are several anti-CD20 antibodies which have been developed for B-cell lymphoma therapy. The most successful example of this targeted approach is rituximab, which is approved for front and second line therapy of Non-Hodgkin lymphoma (NHL). However, rituximab has limited direct cell-kill effects, acting primarily through indirect immune responses induced by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC). While CD20-targeted radiotherapeutics have shown promise, their administrative challenges have curtailed their clinical utility. Thus, a therapeutic approach with direct cell-kill activity against CD20-expressing cells would be clinically useful. We have developed an engineered toxin body (ETB) comprising a CD20 scFv and a modified Shiga-like Toxin A (MT-3724) capable of specifically recognizing and killing CD20 expressing cells. MT-3724 is selectively cytotoxic against B-cell NHL cell lines and against NHL cells obtained from patients. It demonstrated potent cytotoxicity against Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma with IC (50) values ranging from 1.4 nM to 12 nM. Through immunofluorescent tracking, MT-3724 internalizes within one hour after binding to CD20 (+) B cells. To our knowledge, this is the first example of efficient internalization of an immunotoxin via CD20. Consistent with the in vitro activity, MT-3724 demonstrated anti-tumor efficacy in mice-bearing NHL cell line xenografts. These results show that MT-3724 is a promising targeted therapeutic agent against CD20 positive B-cell lymphomas and is currently under further development.
Citation Format: Sangeetha Rajagopalan, Rachel Wirth, Jennifer Erdman, Kari Grant, Brigitte Brieschke, Rodney Flores, William Null, Jen-Sing Liu, Erin K. Willert, Jack P. Higgins. CD20-specific Engineered Toxin Body demonstrates direct cell kill of multiple B-cell Non-Hodgkin's lymphoma types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 647. doi:10.1158/1538-7445.AM2014-647
Abstract 648: Semi-synthetic peptibodies are a novel personalized therapeutic with activity against lymphoma in vitro and in vivo
Authors: Torchia James , Ng Patrick , Chen Homer , Weiskopf Kipp , Levy Ronald 
Published: May 2015

Abstract
The complementarity determining region, or idiotype, of the surface immunoglobulin receptor is a true tumor-specific marker on B-cell lymphomas unique to each patient. Antibodies against idiotype can induce complete regression of lymphoma in patients, but since this requires the generation of a custom monoclonal antibody for each patient, it has not been practical.
We have developed a method for targeting idiotype using a novel construct that we refer to as a “semi-synthetic peptibody”. It consists of a synthetic peptide ligand for idiotype that is covalently linked to the amino terminus of a recombinant IgG Fc domain. Peptide ligands for idiotype can be identified by high throughput screens of random peptide libraries and produced inexpensively by solid-phase synthesis. Linkage of these idiotype ligands to the Fc domain enhances their pharmacokinetics and augments their anti-tumor effect by activating innate immune effectors. Since each patient-specific synthetic peptide can be chemically linked to a common IgG Fc domain, this modular design yields a custom therapeutic that may be more practical to produce than a unique biologic monoclonal antibody.
We demonstrate that semi-synthetic peptibodies bind specifically to the idiotype of tumor cells and induce apoptosis by crosslinking surface immunoglobulin. Additionally, they trigger antibody dependent cellular cytotoxicity, antibody mediated phagocytosis, and complement-mediated lysis of opsonized lymphoma cells in vitro. They possess a favorable pharmacokinetic profile and are sufficient to clear tumor in SCID mice challenged intravenously with a luciferase-labeled human lymphoma cell line. Tumor clearance in vitro and in vivo mediated by peptibody was superior to that achievable with an anti-idiotype monoclonal antibody.
Thus, semi-synthetic anti-idiotype peptibodies demonstrate multimodal activity against lymphoma cells in vitro and clear human lymphoma in a disseminated xenograft model. This modular, semi-synthetic design may enable a personalized and targeted therapy that is feasible to produce for patients with B-cell lymphoma.
Citation Format: James Torchia, Patrick Ng, Homer Chen, Kipp Weiskopf, Ronald Levy. Semi-synthetic peptibodies are a novel personalized therapeutic with activity against lymphoma in vitro and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 648. doi:10.1158/1538-7445.AM2014-648
Abstract 649: Development and preclinical characterization of an Fc-optimized CD133 antibody for improved induction of NK cell reactivity against myeloid leukemia
Authors: Koerner Samuel , Leibold Julia , Grosse-Hovest Ludger , Bühring Hans-Jörg , Salih Helmut R. , Jung Gundram 
Published: May 2015

Abstract
NK cells are cytotoxic lymphocytes that play a major role in anti-tumor immunity and largely contribute to the efficacy of allogenic stem cell transplantation (SCT) in leukemia. Another clinically important feature of NK cells is their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) upon application of anti-tumor antibodies (mAb) such as Rituximab. Modifications of the human IgG1 Fc-part of anti-tumor antibodies may lead to markedly improved capability to recruit Fc-receptor bearing effector cells. Here we report on the development and preclinical characterization of an Fc-optimized mAb directed towards CD133, a molecule expressed on a wide variety of malignant cell types. Initially we evaluated binding of three different mouse anti-human CD133 mAbs (clones AC133, W6B3 and 293C3) to 20 AML and 6 CML samples to identify a clone with optimal binding characteristics. Binding of AC133 and W6B3 to the leukemic cells in 11/20 AML and 5/6 CML samples was comparable. In contrast, binding of 293C3 was observed in 18/20 AML cases and 5/6 CML cases. This indicates that 293C3 recognizes a particular epitope, which is expressed in a high proportion of AML cases. Therefore mAb 293C3 was selected for generation of chimeric mAbs with either a wildtype Fc part (293C3-WT) or a variant containing distinct modifications (S239D/I332E) to enhance its affinity to the Fc receptor CD16 (293C3-SDIE). The binding specificity of 293C3-WT and 293C3-SDIE was validated in analyses with CD133 transfectants and the respective mock controls. In cytotoxicity assays and analyses of NK cell degranulation, 293C3-WT clearly induced NK cell ADCC against primary leukemia cells. However, ADCC activity of the Fc-optimized mAb 293C3-SDIE markedly exceeded that of its counterpart containing the wild type Fc part. Considering the expression of CD133 on healthy hematopoietic progenitor cells, we presently evaluate potential toxicity of the antibodies towards these cells and other healthy tissue. We envisage that 293C3-SDIE might be an attractive immunotherapeutic reagent for the elimination of minimal residual disease in CD133 expressing leukemia, particularly in the context of allogenic SCT.
Citation Format: Samuel Koerner, Julia Leibold, Ludger Grosse-Hovest, Hans-Jörg Bühring, Helmut R. Salih, Gundram Jung. Development and preclinical characterization of an Fc-optimized CD133 antibody for improved induction of NK cell reactivity against myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 649. doi:10.1158/1538-7445.AM2014-649
Abstract 65: Ink4a/Arf locus drives gastric tumorigenesis through induction of parietal cell loss
Authors: Seishima Ryo , Wada Takeyuki , Hasegawa Hirotoshi , Ishii Yoshiyuki , Okabayashi Koji , Tsuruta Masashi , Kitagawa Yuko , Saya Hideyuki , Nagano Osamu 
Published: May 2015

Abstract
Background: Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. Spasmolytic polypeptide-expressing metaplasia (SPEM) is one of the preneoplastic lesions in the stomach and is triggered by the loss of parietal cells that secrete gastric acid. The Ink4a/Arf locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p19(ARF) in mice. However, little is known regarding the role of these proteins encoded by the INK4a/ARF locus in gastric tumorigenesis.Methods: To evaluate the functional role of Ink4a/Arf locus, we crossed mouse gastric cancer modelK19-Wnt1/C2mE mice with Ink4a/Arf (-/-) mouse and generated Ink4a/Arf (-/-) K19-Wnt1/C2mE mice and evaluated the effect of deletion of Ink4a/Arf locus on the parietal cell loss and formation of SPEM and gastric tumor. Results: In K19-Wnt1/C2mE mice, accumulation of reactive oxygen species (ROS) and the increase of p19 expression were observed in gastric epithelium along with the parietal cells loss leading to SPEM development. However, the parietal cells loss followed by formation of SPEM and gastric tumor were drastically suppressed in Ink4a/Arf (-/-) K19-Wnt1/C2mE mice. Furthermore, treatment of tamoxifen, an inducer of parietal cells loss, in Ink4a/Arf (-/-) mice revealed that deletion of Ink4a/Arf locus suppresses parietal cells loss in mice. Conclusion: These results suggest that activation of p19(ARF) tumor suppressor protein by ROS accumulation paradoxically play a key role in the parietal cells loss leading to gastric tumorigenesis.
Citation Format: Ryo Seishima, Takeyuki Wada, Hirotoshi Hasegawa, Yoshiyuki Ishii, Koji Okabayashi, Masashi Tsuruta, Yuko Kitagawa, Hideyuki Saya, Osamu Nagano. Ink4a/Arf locus drives gastric tumorigenesis through induction of parietal cell loss. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 65. doi:10.1158/1538-7445.AM2014-65
Abstract 651: Ex vivo and in vivo characterization of IPH4102, a humanized anti-KIR3DL2 antibody for the treatment of cutaneous T-cell lymphomas
Authors: Marie-Cardine Anne , Viaud Nicolas , Dujardin Arnaud , Joly Rachel , Gauthier Laurent , Bonnafous Cecile , Blery Mathieu , Paturel Carine , Bensussan Armand , Bagot Martine , Sicard Helene 
Published: May 2015

Abstract
KIR3DL2 belongs to the killer immunoglobulin (Ig)-like receptors (KIRs) family and is composed of three extracellular Ig-like domains. KIR3DL2 is naturally expressed on some NK cells and minor subpopulations of CD8+ and CD4+ T cells. Physiologically, KIRD3L2 is an inhibitory receptor for human leukocyte antigen (HLA) class I molécules regulating NK cell activation. Interestingly, KIR3DL2 is also expressed on several subtypes of T lymphomas/leukemias, and in particular on Advanced cutaneous T cell lymphomas (CTCL), making it a unique therapeutic target in cancer. From a wide collection of anti-KIR3DL2 monoclonal antibodies (mAbs) with distinct properties related to several epitopes, we have selected IPH4102 as the lead therapeutic candidate. IPH4102 is a humanized IgG1 that selectively kills KIR3DL2-positive cells in vitro, mainly through antibody-dependent cell cytotoxicity (ADCC). IPH4102 also improves survival of mice engrafted with KIR3DL2-positive tumors. More importantly, IPH4102 exerts remarkable anti-tumor activity against primary KIR3DL2-positive tumor cells ex vivo: using blood taken from Sézary Syndrome patients as experimental model, we demonstrated the efficient killing of primary leukemic cells by autologous NK cells engaged by IPH4102. IPH4102 IND-enabling studies are ongoing. In parallel, other anti-KIR3DL2 mAbs were also developed as unique and sensitive tools for the detection by immunohistochemistry of KIR3DL2 on tumor biopsies. Owing to its efficacy profile and to the highly restricted expression pattern of its target KIR3DL2, IPH4102 stands as a very promising therapeutic option for the treatment of advanced cutaneous T cell lymphomas.
Citation Format: Anne Marie-Cardine, Nicolas Viaud, Arnaud Dujardin, Rachel Joly, Laurent Gauthier, Cecile Bonnafous, Mathieu Blery, Carine Paturel, Armand Bensussan, Martine Bagot, Helene Sicard. Ex vivo and in vivo characterization of IPH4102, a humanized anti-KIR3DL2 antibody for the treatment of cutaneous T-cell lymphomas . [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 651. doi:10.1158/1538-7445.AM2014-651
Abstract 658: A bispecific HER2 targeting FynomAb with superior anti-tumor activity and novel mode of action
Authors: Schade Babette , Brack Simon , Attinger-Toller Isabella , Klupsch Kristina , Woods Richard , Hachemi Helen , Bey Ulrike von der , Koönig-Friedrich Susann , Bertschinger Julian , Grabulovski Dragan 
Published: May 2015

Abstract
Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2 targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-HER2 resistance.
Fynomers are small 7 kDa globular proteins derived from the SH3 domain of the human Fyn kinase (Fyn SH3) that can be engineered to bind with antibody-like affinity and specificity to virtually any target of choice. Fynomers can be fused to N-terminal and/or C-terminal ends of antibodies to generate multispecific therapeutics (FynomAbs) with tailored architectures. FynomAbs can be produced using standard antibody technology (GMP production yield of 3.3 g/L at 1000 L scale achieved), and show IgG-like biophysical properties and pharmacokinetic profiles.
Based on the approved antibody pertuzumab we have created a panel of bispecific FynomAbs which target two epitopes on HER2. The activity of the HER2 targeting FynomAbs was found to depend on the FynomAb architecture, i.e. the spatial arrangement of the binding sites of antibody and the Fynomer.
The most potent of these FynomAbs, termed COVA208, demonstrated superior tumor cell growth inhibition in vitro compared to pertuzumab and trastuzumab. COVA208 was characterized in detail and showed an increased ability to induce rapid HER2-internalization and apoptosis in vitro. Moreover, it elicited a stronger inhibition of downstream HER2 signaling which was accompanied by a reduction of HER2, HER3 and EGFR levels in vitro and in vivo. The therapeutic potential of COVA208 has been demonstrated in vivo in four different HER2 mouse models, where COVA208 exhibited excellent anti-tumor activity. Importantly, COVA208 demonstrated superior activity in vivo compared to trastuzumab and pertuzumab.
The bispecific FynomAb COVA208 has the potential to enhance the clinical efficacy and expand the scope of HER2-directed therapies, and delineates a paradigm for designing a new class of antibody-based therapeutics for other receptor targets.
Citation Format: Babette Schade, Simon Brack, Isabella Attinger-Toller, Kristina Klupsch, Richard Woods, Helen Hachemi, Ulrike von der Bey, Susann Koönig-Friedrich, Julian Bertschinger, Dragan Grabulovski. A bispecific HER2 targeting FynomAb with superior anti-tumor activity and novel mode of action. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 658. doi:10.1158/1538-7445.AM2014-658