bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4393: ASG-5ME is a novel antibody drug conjugate (ADC) for treating prostate cancers
Authors: Gudas Jean M. , An Zili , Morrison Robert Kendall , Morrison Karen J. , Jia Xiao-Chi , Raitano Arthur B. , Duniho Steven , Smith Leia , Hayes Dawn , Senter Peter , Benjamin Dennis , Jakobovits Aya 
Published: February 2011

Abstract
AGS-5 is a novel transmembrane antigen discovered by Agensys using transcriptional profiling that is highly expressed in a variety of epithelial tumors. A fully human IgG2k monoclonal antibody that binds to AGS-5 with high affinity was conjugated with the anti-microtubulin drug, monomethyl auristatin E (MMAE), via a conditionally labile valine-citrulline (vc) maleimidocaproyl linker to yield an average drug: antibody ratio of 3.7. Following cell surface binding, ASG-5ME is internalized and trafficked through the endocytic pathway, where proteolytic cleavage releases free active drug that subsequently binds and disrupts microtubules. We evaluated the expression of AGS-5 protein in a large number of prostate patient tumors using IHC. ASG-5ME was evaluated for its cell cytoxicity in vitro, and its anti-tumor activity was investigated on different established xenograft tumors, using both patient-derived and cell line models of prostate cancer. The pharmacokinetics of ASG-5ME in mice was also evaluated. Our studies indicated AGS-5 protein was expressed in more than 95% of primary prostate cancer specimens and distant metastases, and on more than 90% and 80% of pancreatic and gastric cancer specimens, respectively. ASG-5ME, bound with high affinity (Kd = 0.5 nM) to both human and cynomolgus monkey AGS-5 and mediated potent dose dependent cell cytotoxicity in vitro. ASG-5ME showed significant long term tumor regression and eradication of multiple established prostate cancer xenografts, including those grown orthotopically. Phamacokinetic (PK) analysis of ASG-5ME in mice indicated that the ADC was stabile with long T1/2 of ∼12 days. When considered together these data indicate that ASG-5ME is a promising therapeutic ADC for the treatment of prostate and other AGS-5 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 4393.
Abstract 4398: Maytansinoid release from thioether linked antibody maytansine conjugates (AMCs) under oxidative conditions: Implication for formulation and for ex vivo sample analysis in pharmacokinetic studies
Authors: Fishkin Nathan , Maloney Erin , Chari Ravi , Singh Rajeeva 
Published: February 2011

Abstract
Several antibody—maytansinoid conjugates (AMCs) are in various stages of clinical testing, with the most advanced being trastuzumab-DM1 (T-DM1) in Phase III testing. In T-DM1, the maytansinoid, DM1, is linked to the trastuzumab antibody via a non-reducible (“non-cleavable”) thioether bond using the SMCC (N-succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate) linker. It has been reported that T-DM1 shows evidence of maytansinoid loss in circulation over time based on ex vivo analysis (Liepold, AACR 2009 abstract #2914), and it has been assumed that a slow retro-Michael reaction is the cause of some linker cleavage.
In the present study, however, we demonstrate that a more likely source of observed maytansinoid release is a reaction generated ex vivo. In our study, we used a model synthetic compound, DM1-MCC, which has the DM1 maytansinoid linked via a thioether bond like that in T-DM1, and also a thioether-linked AMC. When incubated in human plasma ex vivo, these were found to release maytansinoid sulfonate (DM1-SO3-) under physiological conditions (37°C, pH 7.4) at a slow rate. The formation of an initial sulphenic acid intermediate (RSOH) during β-elimination was confirmed with trapping experiments using dimedone (5,5-dimethyl-1,3-cyclohexanedione). Oxidatively-stressed AMCs and a model substrate with a more hindered thioether made with the maytansinoid DM4 showed a 3-fold increase in rate of sulfoxide formation, but an 8-fold lower rate of β-elimination compared to unhindered thioethers. DM1-MCC and thioether-linked AMCs were incubated at 37°C with thiol-trapping agents, such as 2,2′-dipyridyldisulfide. No release of DM1-thiol was detected under these conditions. In contrast, greater than 20% of conjugated maytansinoid was cleaved from a thioether-linked AMC under oxidative stress conditions (10−6 M H2O2 1 hr, 4°C dialysis, then incubation 18 h at pH 7.4, 37 °C).
The present observations suggest that ex vivo thioether oxidation may lead to maytansinoid release from conjugates. This sulfoxide elimination is noted at 37 °C under aqueous conditions and is likely facilitated by the mildly acidic β-hydrogen on the maleimide (pKa ∼ 25). Oxidation of thioethers (such as methionine) is common during protein extraction and concentration, and the present studies underscore the importance of reducing autooxidation of thioether-linked AMCs with regard to sample handling during pharmacokinetic analyses and conjugate formulation.
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 4398.
Abstract 4400: A novel bispecific antibody with high-affinity to DOTA-metal haptens for pretargeted radioimmunotherapy
Authors: Orcutt Kelly Davis , Frangioni John V. , Wittrup K Dane 
Published: February 2011

Abstract
In an effort to reduce background and at the same time maintain hapten retention in the tumor for pretargeted radioimmunotherapy (PRIT) applications, we recently engineered a high-affinity single chain variable fragment (scFv) to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) metal chelates. This scFv displays ∼100 pM affinity to Lu and Y chelates of DOTA, ∼1 nM affinity to In chelates of DOTA-aminobenzene (DOTABn), and ∼10 nM affinity to In chelates of DOTA. A bispecific antibody (bsAb) construct was then engineered as a fusion of this scFv to the C-terminus of an IgG light chain.
We present a three-step method for PRIT using the IgG-scFv bsAb, a dextran-based clearing agent, and radiolabeled DOTA. Biodistribution and tumor uptake were evaluated in mice with LS174T carcinoembryonic antigen (CEA)-positive tumors using this anti-CEA bsAb and 177Lu-DOTA, 111In-DOTABn, or 111In-DOTA after pretargeting with the bsAb at time t = −25 h, and clearing of residual bsAb with a dextran-based compound at t = −1 h. The bsAb exhibited tumor uptake of 19 ± 3 %ID/g at 24 h post injection resulting in approximately 10^5 DOTA binding sites per cell. The PRIT approach resulted in 177Lu-DOTA tumor uptake of ∼14 %ID/g at 24 h and 48 h, tumor to kidney ratios of ∼20 at 24 h and 48 h and tumor to blood ratios greater than 300 at 24 h and 48 h.
The PRIT system was used to analyze in vivo the effect of small molecule affinity on tumor uptake. 177Lu-DOTA with an affinity of ∼100 pM for the bsAb resulted in 9-fold higher tumor uptake at 24 h than 111In-DOTABn (∼1 nM), and 28-fold higher tumor uptake than 111In-DOTA (∼10 nM). In addition, haptens with higher affinity resulted in higher tumor to kidney and tumor to blood ratios.
We present here a PRIT approach with the highest yet reported 48 h tumor to blood and tumor to kidney ratios for CEA targeting. In addition, we report for the first time a systematic study of the effect of small molecule affinity on tumor uptake with affinities spanning a range of two orders of magnitude.24 h biodistribution of DOTA haptens with varying affinities Affinity for bsAb24 h tumor uptake24 h tumor/kidney ratio24 h tumor/blood ratio177Lu-DOTA∼100 pM13.8 ± 2.1 %ID/g18.0 ± 2.2324 ± 56111In-DOTABn∼1 nM1.6 ± 0.3 %ID/g5.6 ± 1.774 ± 4111In-DOTA∼10 nM0.5 ± 0.1 %ID/g1.2 ± 0.4not measurable
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 4400.
Abstract 4401: Antibody-mediated targeting of the uPA proteolytic activity neutralizes uPA functions in vivo
Authors: Lund Ida K. , Jögi Annika , Rønø Birgitte , Rasch Morten G. , Lund Leif R. , Almholt Kasper , Gårdsvoll Henrik , Behrendt Niels , Rømer John , Høyer-Hansen Gunilla 
Published: February 2011

Abstract
Urokinase-type plasminogen activator (uPA) plays a central role in tissue remodeling processes, during both normal physiological conditions and cancer progression. Most of our understanding of the role of uPA in vivo is derived from studies using gene-targeted uPA-deficient mice. To enable in vivo studies on the acute and specific interference with uPA functionality in adult mice, we have now developed murine monoclonal antibodies (mAbs) directed against murine uPA by immunization of uPA-deficient mice with the recombinant protein. Guided by ELISA, Western blotting, SPR and enzyme kinetic analyses, we have selected two highly potent and inhibitory anti-uPA mAbs (mU1 and mU3). Both mAbs recognize epitopes located on the B-chain of uPA that encompasses the catalytic site. In activity assays in vitro, mU1 blocked uPA-catalyzed plasminogen activation as well as plasmin-mediated pro-uPA activation, whereas mU3 only was directed against the first of these reactions.
We provide evidence that acute disruption of uPA activity in the adult mouse was effective with mU1, but not mU3, because only mU1 rescued mice treated with a uPA-activable anthrax pro-toxin. Moreover, systemic administration of mU1 (i) delayed wound healing in tissue-type plasminogen activator (tPA)-deficient mice, and (ii) impaired uPA-mediated hepatic fibrinolysis in tPA-deficient mice, resulting in a phenotype mimicking that of uPA;tPA double-deficient mice. Importantly, these results demonstrate the specific antagonist-directed targeting of mouse uPA at the enzyme activity level in normal physiological processes in vivo. Preliminary results indicate that wild-type mice, which have been transplanted with murine Lewis lung carcinoma cells, display significant reduction in primary tumour growth, when treated with mU1 as compared to placebo-treated (i.e. PBS-treated) littermates. We thus suggest that mU1 is an excellent mAb candidate for therapeutic intervention studies in mouse cancer models.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 4401.
Abstract 4407: Neutralizing monoclonal antibody to periostin (PN) inhibits ovarian tumor metastatic growth in animal models
Authors: Zhu Min , Saxton Romaine E. , Ramos Lillian , Chang David D. , Karlan Beth Y. , Gasson Judith C. , Slamon Dennis J. 
Published: February 2011

Abstract
Periostin (PN), an extracellular matrix protein, is reported to be overexpressed in a variety of human cancers and its functions appear to be linked to tumor angiogenesis and metastasis. Our previous results show that engineered PN overexpression promotes ovarian tumor growth and dissemination in vivo. In the present study, we developed a neutralizing monoclonal antibody to PN, named MZ-1, and have investigated its effects on human ovarian tumor cell metastasis and progression. MZ-1 markedly reduced tumor metastatic growth in orthotopic ovarian tumor models derived from two PN-expressing ovarian cancer cell lines A2780 and TOV-112D. These in vivo antitumor effects of MZ-1 were attributed to its specific inhibition of anchorage-independent growth and survival of PN-expressing cells, as well as its neutralization on PN-induced migration. The data suggests that blocking PN expression may be a novel approach for treatment of ovarian 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 4407.
Abstract 441: Temporal profiling of a breast cancer cell line MCF-7 in response to reoxygenation
Authors: Chen Kuo Chin , Tsai Mong Hsun , Chuang Eric Y. , Hsiao Chuhsing Kate , Lai Liang Chuan 
Published: February 2011

Abstract
Oxygen fluctuation resulting from hyper-proliferation of tumor cells, abnormal metabolism and disorganized tumor neovasculature characterizes the microenvironment of many cancers, which influences tumor development and angiogenesis. Furthermore, this condition increases chemo-resistance and radio-resistance of tumor cells, and also associates with increased invasion and metastatic potential accompanied with a poor prognosis. Hypoxia/ reoxygenation induce oxidative stress, which leads to DNA damage and genomic instability. It is known that multiple cellular responses were activated in order to survive under this microenvironment, but little is known about the dynamic response upon reoxygenation. To investigate the dynamic response of signalling pathways in tumor adaptation, a breast cancer cell line MCF-7 was cultured under 0.5% oxygen condition 24 hours followed by reoxygenation, and was harvested at various time points during reoxygenation. Genome-wide microarray results revealed that 274 genes were differentially expressed during reoxygenation; 47.4% of them were up-regulated and 52.3% down-regulated. Furthermore, pathway analysis, including canonical pathway and gene network, were performed using Ingenuity Pathway Analysis. Selected genes of interest were validated by quantitative real-time PCR, such as hexokinase 2 (HK2) and cyclin D3 (CCND3). Survival analysis using clonogenic assay showed little effect of reoxygenation on MCF-7 cells, but proliferation was inhibited upon reoxygenation. Our result showed dynamic changes of MCF-7 gene expression and molecular pathways unpon reoxygenation, which shed some light on understanding of tumor adaptation.
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 441.
Abstract 4413: STX140 is an orally bioavailable microtubule targeting agent with no associated peripheral neuropathy and potent anti-metastasis efficacy in vivo
Authors: Newman Simon P. , Foster Paul A. , Day Joanna M. , Leese Mathew P. , Potter Barry VL , Reed Michael J. , Purohit Atul 
Published: February 2011

Abstract
There is a continued need for orally bioavailable anti-cancer compounds that exhibit good efficacy and with a more favourable toxicity profile than current ‘traditional’ cytotoxics. The microtubule disruptor, STX140 has previously been shown to have excellent oral bioavailability and significantly reduce tumor growth in vivo. These data presented here show STX140 to: lack significant neuropathy in a validated in vivo behavioural model and to significantly reduce metastasis in a highly aggressive orthotopic model of breast cancer.
To assess the potential for neurotoxicity animals were dosed with, vehicle (0.5% methlycellulose), STX140 (20 mg/kg p.o. 5/7 × 4) or Taxol (15 mg/kg i.v weekly x 4). Thermal hyperalgesia, as assessed by paw withdrawal latency, was measured every 3-4 days using Hargreaves Plantar equipment. The 4T1 murine tumor cell line was used to establish orthotopic tumors in the mammary fad pads of nude mice. After 28 days dosing, as above, tumor size, number of lung and liver metastasises were recorded. Additionally relative levels of circulating tumor cells (CTCs) were assessed by quantifying the number of viable tumor cell colonies grown from 30 µL of blood taken by cardiac puncture at day 28.
In the thermal hyperalgesia model of neuropathy Taxol caused a significant decrease in paw withdrawal latency from day 14 till the end of study, in contrast there were no significant changes in withdrawal times in either the vehicle or STX140 dosed groups. In the 4T1 xenograft study both Taxol and STX140 reduced, tumor volume, extent of lung metastasis and number of viable CTCs in the blood relative to vehicle. In a separate study STX140 but not Taxol caused a significant improvement in survival.
These studies highlight the excellent efficacy of the orally bioavailable anti-cancer agent STX140 in a highly aggressive model of breast cancer. STX140 may offer a major additional advantage over existing drugs as the most common dose limiting toxicity of neuropathy, is negated / minimised.
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 4413.
Abstract 4417: Uptake of the new paclitaxel-derivative (ANG1005) by the low-density lipoprotein receptor-related protein1 (LRP1) is related to the aggressive phenotype of glioblastoma cells
Authors: Bertrand Yanick , Currie Jean-Christophe , Demeule Michel , Régina Anthony , Stanimirovic Danica , Castaigne Jean-Paul , Béliveau Richard 
Published: February 2011

Abstract
The most common primary brain tumour is glioblastoma multiforme (GBM). Despite latest cancer researches to improve the outcome of patients with GBM, this highly aggressive tumour remains one of the most difficult tumors to treat. Angiochem's Engineered Peptide Compounds (EPiC) provides a non-invasive and flexible platform for small and large molecules to treat brain diseases. Based on these properties, we have created a portfolio of new drug entities composed of siRNA, peptides and mAbs, The most advanced, ANG1005, is a new taxane derivative currently completing two Phase ½ clinical trials for the treatment of primary and secondary brain tumors. This EPiC drug is comprised of one Angiopep-2 peptide conjugated to three molecules of paclitaxel. Recently, Angiopep-2 has been shown to use the low-density lipoprotein related protein 1 (LRP1) has a gateway across the blood-brain barrier. Interestingly, LRP1 seems to be required in many tumours for the aggressive behaviour and is overexpressed in GBM. Here, we show an increase uptake of Angiopep-2 in implanted brain tumour using in vivo imaging when compared to the contralateral normal brain region. In these tumors, ANG1005 could be detected by LC/MS/MS analysis and immunohistochemistry. We next characterized Angiopep-2 and ANG1005 uptake in human U87 glioblastoma cell line. The transfection of U87 cells with siRNA LRP1 decreased the uptake of both Angiopep-2 and ANG1005 indicating that LRP1 is involved in their internalization in glioblastoma cells. Furthermore, we measured an increase in the uptake of both Angiopep-2 and ANG1005 in glioblastoma (U87) cells under three experimental conditions that mimic the aggressive cancer cell microenvironment: acidic pH, serum deprivation and hypoxia. Interestingly, under these conditions LRP1 expression was also increased. The increase of ANG1005 uptake and LRP1 expression indicates that the aggressive cancer microenvironment phenotype favors the entry of this anticancer drug into glioblastoma cells. Overall these results demonstrate that the EPiC drug ANG1005 can be an effective therapeutic strategy to target brain cancer cells and aggressive tumors such as GBM.
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 4417.
Abstract 4420: ABI-013: A novel nanoparticle albumin-bound (nab) docetaxel analog with superior antitumor activity over docetaxel
Authors: D'Cruz Osmond , Piacente Marit , Trieu Vuong , Tao Chunlin , Desai Neil 
Published: February 2011

Abstract
Background: Docetaxel-based chemotherapy is currently used to treat patients with a variety of tumors. A critical challenge has been to improve its chemotherapeutic levels without systemic toxicity. We developed ABI-013, a novel analog of docetaxel (Taxotere®) as a solvent (polysorbate 80/ethanol)-free, nanoparticle albumin-bound 70-nm (nab) form with improved stability in vivo as a tumor-targeting chemotherapeutic agent. In this study, we evaluated the comparative antitumor activity of ABI-013 versus Taxotere® in human tumor xenografts.
Methods: Subcutaneous human breast (MDA-MB-231), colon (HT29 and HCT-116), and lung (H358) tumors were grown in athymic nude mice and treated intravenously (IV) with ABI-013 (15, 30, 60, 90, 120 or 150 mg/kg) or Taxotere (MTD of 15 mg/kg) on a q4dx3 schedule. Evaluations of anti-tumor activity were based on the number of partial and complete regressions, the median number of days for tumors in each group to reach one tumor mass doubling (T-C) or the percentage tumor growth inhibition (%TGI).
Results: Significant dose-dependent TGI was observed with complete or partial tumor regressions in all xenograft models treated with ABI-013. In the MDA-MB-231 breast tumor model, ABI-013 effectively delayed the tumor growth with T-C values of 83.1, 80.7, and &gt;84.8 days at dosages of 120, 90, and 60 mg/kg, respectively, with &gt;96% TGI compared to vehicle control (P &lt; 0.0001 vs. saline). In contrast, Taxotere delayed the tumor growth with a T-C value of 49.5 days and decreased tumor growth by 88% (P &lt; 0.0001 vs. saline). In the HT 29 colon tumor model, Taxotere revealed dose-limiting toxicity with a 27% body weight loss (BWL) despite 86 to 91% TGI (P &lt; 0.01 vs. saline). In contrast, ABI-013 (90 mg/kg) caused complete tumor regression with a maximum BWL of 19% (P &lt; 0.0001 vs. saline). Treatment with Taxotere delayed the growth of HCT-116 colon tumor with a T-C value of 14.9 days with a maximum BWL of 21%. In contrast, complete tumor regression was achieved in 40% of ABI-013-treated mice. In the H358 human non-small cell lung cancer model, unlike Taxotere, ABI-013 (60 mg/kg) caused partial tumor regression with minimal toxicity.
Conclusion: ABI-013, a solvent-free nanoparticle albumin-bound 70-nm particle form of a novel docetaxel analog, had superior antitumor activity in human breast, colorectal, and lung cancer xenograft models compared with equitoxic doses of solvent-based formulation of docetaxel. The nab form of the novel docetaxel analog shows promise in cancer therapy.
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 4420.