bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2426: Anti-Glypican3 antibody for treatment of human liver cancer
Authors: Ishiguro Takahiro , Kinoshita Yasuko , Sugimoto Masamichi , Miyazaki Yoko , Kato Atsuhiko , Nakano Kiyotaka , Takai Hirotake , Tsunoda Hiroyuki , Sugo Izumi , Ohizumi Iwao , Aburatani Hiroyuki , Hamakubo Takao , Kodama Tatsuhiko , Tsuchiya Masayuki , Okabe Hisafumi Yamada 
Published: February 2011

Abstract
Glypican-3 (GPC3) is a member of the glypican family of heparan sulfate proteoglycans, which are linked to the cell surface through a glycosyl phosphatidyl inositol anchor. GPC3 has been reported to be highly expressed in the majority (70-100%) of HCC, and considered to play a role in the tumorigenesis of HCC. Although the molecular mechanism by which GPC3 functions in tumorigenesis has not been fully elucidated, the high prevalence in HCC has led to considerable interest in GPC3 as a diagnostic marker and therapeutic target.
In this study, we obtained a monoclonal antibody (mAb) against the COOH-terminal part of GPC3, which induced antibody-dependent cellular cytotoxicity (ADCC). The mAb, designated mGC33, exhibited marked tumor growth inhibition of s.c. transplanted Hep G2 and HuH-7 xenografts that expressed GPC3 but did not inhibit growth of the SK-HEP-1 that was negative for GPC3. mGC33 was efficacious even in an orthotopic model; it markedly reduced the blood alpha-fetoprotein levels of mice intrahepatically transplanted with Hep G2 cells. To develop an antibody-based immunotherapy, we generated humanized GC33 (hGC33) by complementarily determining region (CDR) grafting. hGC33 was as efficacious as mGC33 against the Hep G2 xenograft, but hGC33 lacking carbohydrate moieties caused neither ADCC nor tumor growth inhibition. Depletion of CD56+ cells from human peripheral blood mononuclear cells markedly abrogated the ADCC caused by hGC33. The results show that the antitumor activity of hGC33 is mainly attributable to ADCC, and in human, natural killer cell-mediated ADCC is one possible mechanism of the antitumor effects by GC33. We also evaluated the antitumor activity of hGC33 combined with standard chemotherapy agent sorafenib. hGC33 and sorafenib combination was more potent in inhibiting tumor growth than sorafenib alone in the s.c. transplanted Hep G2 xenograft model. Administration of sorafenib alone did not change the GPC3 expression level in xenograft tumor. These suggest that this combination regimen may be clinically useful as an anti-liver cancer therapy.
In careful examination of the safety of hGC33 in nonclinical studies, specific adverse findings on GPC3 expressed tissue or organs were not observed after repeated administration. Therefore hGC33 will provide a novel treatment option for liver cancer patients with GPC3-positive tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2426.
Abstract 2428: PPMX-2017: Antibody against CDH3 with potent efficacy against lung cancer
Authors: Zhang Lilin , Ishii Keisuke , Kayukawa Yoko , Yagami Shuing , Kouda Katsushi , Katsumi Keiko , Sakamoto Aya , Satoh Hirokazu , Onishi Hiroshi , Nomura Fumiko , Kotaka Romi , Matsuura Tadashi , Sudo Yukio , Aburatani Hiroyuki 
Published: February 2011

Abstract
Cadherin 3/P-cadherin (CDH3) is a member of cadherin family proteins involved in the cell-cell adhesion. Based on a genome-wide cDNA microarray analysis of pancreatic cancer, we found that CDH3 is overexpressed in pancreatic cancer. We also confirmed by our immunohistochemistry study that CDH3 protein was expressed highly in pancreatic, lung, colon and other types of cancer tissues but not in normal tissues. Since CDH3 is a transmembrane glycoprotein and overexpressed in cancer tissues, it is an attractive therapeutic target for various kinds of cancer. In this present study, we generated a series of monoclonal antibodies against CDH3 and evaluated their anti-tumor effect both in vitro and in vivo. PPMX2017, an antibody from the series, is an anti-human CDH3 specific mouse IgG2a antibody. The in vitro studies demonstrated that PPMX2017 elicited strong antibody dependent cellular cytotoxicity (ADCC) activity on CDH3-positive cancer cell lines (lung cancer: NCI-H358 and A431, pancreatic cancer: KLM1 and Bxpc3.). Furthermore, PPMX2017 showed a significant antitumor effect in a therapeutic xenograft model of lung cancer where NCI-H358 cell-generated tumors grew to 70∼90 mm3 before administration of this antibody. PPMX2017 suppressed tumor growth by 60∼80% compared with control IgG in a dose range of 0.3mg∼5mg/kg. These findings show that CDH3 is a potential target for cancer therapy and PPMX2017 is a candidate for the development of antibody therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2428.
Abstract 2433: Eradication of established pancreatic tumors in mice by engagement of extra-tumoral human T cells with BiTE antibody MT110
Authors: Friedrich Matthias , Drache Daniela , Amann Maria , Filusch Susanne , Voelkel Markus , Thomas Oliver , Baeuerle Patrick A. , Rattel Benno 
Published: February 2011

Abstract
MT110 is a T cell-engaging, EpCAM/CD3-bispecific BiTE antibody that is currently being tested in a dose-escalating clinical phase 1 study in gastrointestinal and lung cancer patients. MT110 has shown high potency of redirected lysis in cell-based assays at picomolar concentrations.
Previous studies with MT110 have shown that subcutaneous (s.c.) pancreatic tumor formation can be delayed in NOD/SCID mice when human tumor cells are mixed prior to inoculation with human peripheral blood mononuclear cells (PBMC) at a ratio of 1:2. Likewise, MT110 is able to eradicate s.c.-implanted human metastatic tissue (&lt;80 mm3) freshly dissected from ovarian cancer patients. In this model, the only source of effector cells were tumor-resident T cells from the respective patient sample.
Here we have further explored in a new NOD/SCID mouse model the anti-tumor activity of MT110 on established s.c. tumors derived from the human pancreas cancer cell line Aspc1. Effector cells, human peripheral T cells, were expanded ex vivo in the presence of T cell mitogens. NOD/SCID mice were reconstituted with human T cells by intraperitoneal (i.p.) injection once the tumors had reached at least 150 mm3. Following adoptive transfer, human T cells were detected in the peripheral blood of mice for up to 6 days. Tumor-bearing mice were treated for 28 days with 350 µg MT110/kg (approx. 3 µg MT110/mouse) by either daily i.v. bolus injection or continuous i.p. infusion using Alzet osmotic pumps.
With the onset of MT110 treatment by either route, Aspc1 tumors of approx. 300 mm3 started to shrink. After two weeks, tumors in all MT110-treated mice were less than
50 mm3, and 3 out of animals 11animals were completely free of tumor. In contrast, all tumors in vehicle control mice had reached an average size of 500 mm3 during this period. At the end of the study after 8 weeks and 2.5 weeks after last dosing, 3 out of 11 animals remained tumor-free. Among the remaining eight tumor-bearing animals, all showed tumor regression 38-40 days after start of the study. Our data show that established tumors grown can be eradicated by BiTE antibody MT110 by engaging initially extra-tumoral human T cells. This indicates that cancer therapy with MT110 and other BiTE antibodies in development may not solely rely on tumor-resident T cells. Moreover, MT110 may have activity against pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2433.
Abstract 2436: AGS-16M8F is a novel antibody drug conjugate (ADC) for treating renal and liver cancers
Authors: Gudas Jean M. , Torgov Michael , An Zili , Jia Xiao- Chi , Morrison Karen J. , Morrison Robert K. , Yang Peng , Raitano Arthur B. , Kanner Steven B. , Jakobovits Aya 
Published: February 2011

Abstract
AGS-16 is a novel transmembrane antigen discovered by Agensys using transcription profiling and is expressed in kidney, liver and other cancers. A fully human IgG2k monoclonal antibody that binds to AGS-16 with high affinity was conjugated to the anti-microtubulin drug monomethyl auristatin F (MMAF) via a noncleavable maleimidocaproyl (mc) linker to yield the antibody drug conjugate, AGS-16M8F. AGS-16M8F was evaluated for binding affinity, species cross reactivity and cell cytotoxicity in vitro. Its’ anti-tumor activity was investigated using multiple established patient-derived and cell line models of renal clear cell carcinomas. The pharmacokinetics (PK) of AGS-16M8F was evaluated in mice. In addition, the expression of AGS-16 protein in patient kidney and liver cancer specimens was confirmed using IHC. AGS-16M8F bound with high affinity (Kd = 0.3 nM) to both human and cynomolgus monkey AGS-16 orthologs. Following cell surface binding, AGS-16M8F was internalized and trafficked to lysosomes leading to catabolism and release of active drug metabolite. AGS-16M8F mediated potent cell cytotoxicity in vitro and led to significant and prolonged growth inhibition or complete eradication of multiple established renal cancer xenograft models, including those grown orthotopically. Pharmacokinetic analysis of AGS-16M8F in mice demonstrated ADC stability. IHC analysis confirmed that AGS-16 was highly expressed in over 80% of renal clear cell cancers and 33% of hepatocellular carcinomas. When considered together these data indicate that AGS-16M8F is a promising therapeutic ADC for the treatment of renal and other AGS-16 expressing cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2436.
Abstract 2439: Cross-linker evaluation in the design of antibody-SN-38 conjugates for cancer therapy
Authors: Moon Sung-Ju , Tat Fatma , Sheerin Agatha , Zalath Maria , Arrojo Roberto , Cardillo Thomas M. , Govindan Serengulam V. , Goldenberg David M. 
Published: February 2011

Abstract
Antibody (MAb) conjugates of the potent topoisomerase I inhibitor, SN-38, prepared using the bifunctional derivative, ‘CL2-SN-38’ (maleimido-[x]-Phe-Lys-PABOCO-20-O-SN-38), were previously shown to produce significant and selective therapeutic efficacies of human tumor xenografts in nude mice. With a view to examining alternative linkers for possible improvement, we prepared a variant, namely maleimido-[x]-Lys-PABOCO-20-O-SN-38 (‘CL2A-SN-38’), and two other derivatives with cross-linker attachment at the 10-position of SN-38 instead of the 20-position: maleimido-[x]-Phe-Lys-N(Me)-(CH2)2-N(Me)-CO-10-O-SN-38 (‘CL2D-SN-38’) and maleimido-[x]-Phe-Lys-PABOCO-N(Me)-(CH2)2-N(Me)-CO-10-O-SN-38 (‘CL2E-SN-38’). In these, PAB is p-aminobenzyl moiety and ‘x’ contains a short PEG group to increase solubility. Conjugates of the humanized anti-CEACAM5 MAb, hMN-14 (labetuzumab), were prepared by reacting the maleimide-appended SN-38 derivatives with mildly reduced hMN-14. The SN-38/MAb molar substitutions were in the range of 5.9 to 6.3. In vitro studies showed a similarity in the stabilities, in mouse serum, of CL2 and CL2A-based linkers, but an order of magnitude greater stability for conjugates with linker at the 10-position; however, CL2D-SN-38 linker was inert to dipeptide cleavage by cathepsin B at the lysosomal pH of ∼ 5. The latter finding was also reflected in the loss of cytotoxicity due to hMN-14-CL2D-SN-38 conjugate in the LS174T colon cancer cell line in vitro. All conjugates were also evaluated in an exploratory preclinical therapy experiment in nude mice with aggressive s.c. LS174T human colon cancer xenografts. Conjugates were administered i.p. in groups of tumor-bearing animals (n = 10) at a schedule of 0.39 mg/kg of SN-38 equivalent twice weekly × 2 weeks. Untreated animals received saline. Mean tumor volumes (cm3) of animals in various treatment groups, on day 18, were: 0.073 ± 0.035 for the hMN-14-CL2-SN-38 positive control group; 0.055 ± 0.032 for the hMN-14-CL2A-SN-38 group; 0.518 ± 0.239 for the hMN-14-CL2D-SN-38 group; 0.490 ± 0.224 for the hMN-14-CL2E-SN-38 group; and 1.09 ± 0.88 for the untreated group. Median survival times (days) were 54.5, 55, 30, 25, and 26.5 for these groups, respectively. These results showed that a cleavable peptide was not necessary in the SN-38 conjugate design, as hMN-14-CL2A-SN-38 was equivalent to hMN-14-CL2-SN-38 in efficacy, and that hMN-14-CL2E-SN-38 was surprisingly much less efficacious than the CL2 and CL2A-based conjugates despite its higher relative stability.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2439.
Abstract 2440: CD47 is a prognostic factor and an antibody target that synergizes with rituximab to eradicate non-Hodgkin lymphoma
Authors: Chao Mark P. , Alizadeh Ash A. , Tang Chad Z. , Myklebust June H. , Varghese Bindu , Jan Max , Cha Adriel C. , Tan Brent T. , Park Christopher Y. , Levy Ronald , Weissman Irving L. , Majeti Ravindra 
Published: February 2011

Abstract
Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative, and must be combined with cytotoxic chemotherapy for clinical benefit. Here we identify CD47 as an attractive monoclonal antibody target in NHL. A major function of CD47 is to inhibit phagocytosis, through binding its receptor, SIRP-alpha, on phagocytes. We hypothesize that NHL cells over-express CD47 to evade immune phagocytosis and that blockade of CD47 signaling by a monoclonal antibody can eliminate NHL cells by enabling phagocytic engulfment. Here we investigate the therapeutic potential of an anti-CD47 antibody alone and in combination with rituximab for the treatment of NHL. We predict that the combination of anti-CD47 antibody and rituximab through utilization of two independent antibody mechanisms will result in synergistic phagocytosis and elimination of NHL cells.
We found that CD47 protein is highly expressed on primary human NHL cells compared to normal B cell counterparts. Higher CD47 gene expression predicted an inferior outcome in several cohorts of NHL patients, providing independent prognostic value. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells but not normal cell counterparts in vitro while the combination of anti-CD47 antibody and rituximab resulted in synergistic phagocytosis of NHL cells. In vivo, anti-CD47 antibody treatment of human NHL-engrafted mice reduced lymphoma burden and prolonged survival compared to IgG control treatment. Furthermore, anti-CD47 antibody treatment in combination with rituximab led to elimination of lymphoma and cure of NHL-engrafted mice compared to either antibody treatment as a single agent. The above in vivo results were observed in both a disseminated and localized human NHL cell line mouse model as well as in primary human lymphoma xenotransplants. These antibodies synergized through a novel mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers. Together, these data provide the rationale for utilizing an anti-CD47 antibody either alone or in combination with rituximab in treating human NHL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2440.
Abstract 2443: Tetraspanin CD151 as a target for antibody-based cancer therapy
Authors: HAEUW Jean-François F. 
Published: February 2011

Abstract
The tetraspanin CD151 is known to be functionally linked to cancer metastasis. In human, increased expression of CD151 is indicative of a poor prognosis in different cancer types. Whereas its precise mechanism of action remains obscure, CD151 was shown to regulate cell motility and adhesion through association with laminin-binding integrins such as α3β1 or α6β4, and more recently the communication between endothelial and tumor cells. Overexpression of CD151 in tumor cells enhances cell migration, cell invasion and experimental metastasis. Silencing of CD151 with specific siRNA was shown to delay tumour formation in vivo in a mouse model of breast cancer. Several anti-CD151 monoclonal antibodies (Mabs) were shown to display anti-metastatic activity in vivo. Inhibition of metastasis was not attributed to any effect of these Mabs on tumor cell growth but was essentially linked to inhibition of cell motility. However, a more direct effect could be expected. For these reasons, we generated different anti-CD151 Mabs via immunisation with transfectant cells and evaluated their anti-tumor activity in xenograft and orthotopic mouse models to further investigate the role of CD151 in cancer progression in vivo. Interestingly, anti-CD151 Mabs inhibited potently primary tumor growth in different xenograft models including prostate, lung and breast cancer models. These results demonstrate that CD151 could be of importance for controlling tumor cell proliferation. In addition, as anticipated, we showed that anti-CD151 Mabs were also able to inhibit metastasis in vivo in an orthotopic A549 lung cancer model with well characterized lung metastases. The mechanism of action of these Mabs on tumor cells is under investigation and preliminary in vitro data will be presented. Altogether, our results strongly suggest that CD151 could function at multiple cancer stages, including not only metastasis cascade steps but also earlier steps of primary tumor growth, reinforcing thus the interest of this innovative target in oncology. Mabs targeting CD151 may be of significant interest for cancer biotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2443.
Abstract 2445: Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models
Authors: Siders William M. , Shields Jacqueline , Garron Carrie , Hu Yanping , Boutin Paula , Shankara Srinivas , Weber William , Roberts Bruce , Kaplan Johanne M. 
Published: February 2011

Abstract
Alemtuzumab (Campath) is a recombinant humanized IgG1 monoclonal antibody directed against CD52, an antigen expressed at high levels on the surface of normal and malignant B and T lymphocytes. Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but the exact mechanism by which the antibody depletes malignant lymphocytes in vivo is not clearly defined. To address this issue, the anti-tumor activity of alemtuzumab was studied in disseminated and subcutaneous xenograft tumor models. The density of CD52 target antigen on the surface of tumor cells appeared to be an important factor as an overall correlation was observed between the anti-tumor activity of alemtuzumab and levels of CD52 expression. Deglycosylation of alemtuzumab resulted in a loss of complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro and was found to abolish anti-tumor activity in vivo. Individual inactivation of these effector mechanisms in tumor-bearing mice indicated that the protective activity of alemtuzumab in vivo was primarily dependent on ADCC mediated by neutrophils and to a lesser extent NK cells, as evidenced by the loss of tumor growth inhibition caused by removal of these populations with antibodies to Gr-1 or asialo-GM-1, respectively. In contrast, inactivation of complement by treatment with cobra venom factor or depletion of macrophages using clodronate liposomes had no significant impact on the anti-tumor activity of alemtuzumab in vivo. Increasing the number of circulating neutrophils by treatment with G-CSF enhanced the anti-tumor activity of the antibody thus providing further evidence for the involvement of neutrophils as effector cells in the activity of alemtuzumab.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2445.
Abstract 2446: Biodistribution of antibody drug conjugates by LC-MS
Authors: Srinivasan Mohan , Thevanayagam Lourdes , Chakraborty Indrani , Bell Alasdair , Deshpande Shrikant , Pan Chin , Cardarelli Pina M. , Gangwar Sanjeev , Chong Colin , Cortez Orville , Klitzing David , Jiang Jerry , Greenbaum Meghan , Phillips James 
Published: February 2011

Abstract
Introduction: A method to study biodistribution of adduct forming antibody drug conjugates (ADCs) by LC-MS
Description: ADCs are increasingly used to deliver cytotoxic payloads to tumor cells. While the targeted approach has vastly improved the toxicity profiles of these drugs, it is still important to understand the bio-distribution and the enhanced tumor localization this approach offers. Radio-labeled methods are still the most reliable approach to study the bio-distribution, but may not be able to differentiate between the drug that is present in the tissue from those that have formed covalent adducts upon non-specific internalization. Here, we describe a mass-spectrometric methods to identify these covalent adducts these cytotoxic agents form and how such methods could be utilized to map the bio-distribution in xenograft models.
Data: The antibody drug conjugate is highly localized in the tumor with a %ID/gm value of almost 40 within 24 hours of dosing and no non-specific accumulation in other organs observed.
Conclusions: A simple and robust LC-MS based method has been developed to understand the bio-distribution of antibody-drug conjugates by detecting and quantifying the actual and final chemical state of the toxin in the targeted cell. This method could be used to evaluate the (1) PK of antibody-drug conjugates (2) make lead selections at advanced preclinical stages of antibody-drug development (3) understand the ADME properties of the chosen antibody-drug conjugate
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2446.