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  • 1
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    Abstract LB-43: M402, a novel heparin sulphate mimetic, synergizes with gemcitabine to improve survival and reduce metastasis and epithelial-to-mesenchymal transition (EMT) in a genetically engineered mouse model for pancreatic cancer
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. LB-43-LB-43
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. LB-43-LB-43
    Abstract: Introduction: Heparan sulphate proteoglycans (HSPGs) play a central role in tumor progression and metastasis by presenting and modulating growth factors, cytokines, and other soluble factors. A novel heparin sulphate mimetic (M402), engineered from heparin to have low anti-coagulant activity, has shown promising anti-tumor efficacy in several pre-clinical tumor models. This study was designed to probe the efficacy and mechanism of action of M402 in a genetically engineered mouse (GEM) model for pancreatic cancer. Methods: Mice that spontaneously develop pancreatic cancer (LSL-KRASG12D/+; Trp53 LSL-R172H/flox; pdx-CRE) were treated with twice weekly i.p. doses of saline or gemcitabine (50 mg/kg) starting at Day 30, or with saline or M402 (40 mg/kg/day) administered by a subcutaneous osmotic minipump from Day 30-90, or with a combination of gemcitabine plus M402. Results: Treatment with M402 alone did not prolong survival and gemcitabine alone showed only a modest improvement in survival; however the combination of M402 and gemcitabine significantly improved survival. Moreover, mice treated with the combination of M402 and gemcitabine showed a substantially lower incidence of metastasis. RT-qPCR analysis revealed that M402 treated mice had significantly lower levels of TGF-alpha mRNA than the saline control group, which is corroborated by a corresponding decrease in tumor cell proliferation. Immunohistochemical analysis revealed that M402 treated mice developed reduced areas of epithelial-to-mesenchymal transition (EMT), as defined by negative staining for E-Cadherin, strongly positive staining for vimentin and positive nuclear staining for SNAIL. As there is a direct link between EGFR activation and the nuclear localisation of SNAIL we propose that M402 affects gemcitabine sensitivity and metastasis formation by reducing the expression of TGF-alpha. Discussion: M402 increased the anti-tumor efficacy of gemcitabine in a GEM model for pancreatic cancer resulting in increased survival and, interestingly, decreased incidence of metastasis. One potential mechanism is that the observed reduction in EMT may be due to the reduced expression of TGF-alpha, a cognate ligand for EGFR. These data suggest that the EGFR pathway is active in KRAS mutant tumors. Overall, these results provide a rationale for investigating the clinical use of M402 in combination with gemcitabine in the treatment of human pancreatic cancer. 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 LB-43.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-LB-43
    RVK:
    XA 36000
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 2
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    Abstract 3113: M402, a novel heparan sulfate mimetic, modulates the desmoplastic response in an orthotopic pancreatic cancer model in mice
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3113-3113
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3113-3113
    Abstract: Pancreatic ductal adenocarcinoma (PDAC), currently the fourth leading cause of cancer-related deaths in the US, is one of the most lethal cancers due in part to its resistance to or poor delivery of existing chemotherapeutics (such as gemcitabine). One of the hallmarks of this deadly disease is extensive desmoplasia in the surrounding tumor microenvironment. Recent advances in pancreatic cancer research implicate the involvement of several heparin-binding growth factors that control tumor-stroma interactions (including sonic hedgehog (shh), HB-EGF, TGFs, PDGF and HGF). We have rationally designed a heparan sulfate mimetic, M402, that has previously been shown in animal studies to reduce metastatic seeding through disruption of multiple heparin-binding growth factor-mediated pathways. We hypothesized that M402, alone or in combination with gemcitabine, could potentially modulate tumor-stroma interactions in an orthotopic pancreatic cancer model (Capan-2 cell line) which displays moderate desmoplasia in vivo. Capan-2 human adenocarcinoma cells (∼1×106 cells) were injected into the pancreases of immunodeficient mice (Nu/Nu CD-1, female, 8 weeks old). M402 (40 mg/kg/day) or saline treatment commenced on day 4 (via osmotic pump). Gemcitabine (30-60 mg/kg, twice weekly, IP) treatment commenced between weeks 3-6. At the termination of each study (week 8), gross anatomical observations were made of the primary pancreatic tumor and metastatic lesions in the surrounding tissues including the spleen, intestines and liver. The primary pancreatic tumor was weighed and further processed for immunohistochemistry and mRNA expression of fibrotic matrix markers (fibronectin and COLI) and shh signaling (shh and Gli1). Gemcitabine was increasingly less effective when started at later time points, but still reduced the primary tumor weight by 60-70% (30-45 mg/kg) when treatment was started at week 5. M402 was also effective as monotherapy. The addition of M402 to gemcitabine showed only marginally more activity on primary tumor burden; however, metastasis, invasion, and surrounding fibrotic lesions appeared more impacted by the combination treatment than either agent alone. Immunohistochemical and qPCR analyses showed reduced shh and Gli1 with M402 and gemcitabine combination treatment. These results show that M402 can modulate tumor-stroma interactions involved in the desmoplastic response in a murine model of pancreatic cancer. These results provide a rationale for the clinical investigation of M402 as a potential anti-desmoplastic agent in pancreatic cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstrac t nr 3113. doi:10.1158/1538-7445.AM2011-3113
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3113
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 3
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    Nipocalimab’s Selective Targeting of FcRn and IgG Clearance Preserves Key Immune Functions
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Neurology Vol. 99, No. 23 ( 2022-12-5), p. S5-S6
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 99, No. 23 ( 2022-12-5), p. S5-S6
    Abstract: To characterize the effect of nipocalimab, a fully human, effectorless IgG1 anti-neonatal Fc receptor (FcRn) monoclonal antibody on immune function. Background Nipocalimab binds to FcRn with high affinity which prevents IgG recycling, leading to reduced serum levels of total IgGs, including pathogenic IgG autoantibodies. Rapid, sustained lowering of IgG was observed in the phase 2 VIVACITY study in generalized myasthenia gravis (gMG) and in phase 1 healthy volunteers. In gMG patients, nipocalimab induced rapid and sustained lowering of anti-AChR autoantibodies and MG-ADL scores, but no serious adverse events including clinically significant infections. Design/Methods Nipocalimab was evaluated extensively in vitro and in nonhuman primate-based chronic toxicology studies to evaluate selectivity, tolerability, safety and immunopharmacology. Safety, tolerability and immune-focused assessments in clinical phase 1 and Phase 2 MG studies were also completed (NCT02828046, NCT03772587). Results Nipocalimab binds specifically in vitro to FcRn without activation of effector function or inhibition of antigen presentation. In nonhuman primates administered up to 300 mg/kg nipocalimab QW for up to 6 months, sustained lowering of IgG was observed without adverse effects. Immunotoxicology identified no effect on immune cell phenotypes; CD8 T cell, NK or innate cell functions; T-dependent neoantigen IgM responses. Neoantigen IgG production was observed, but with lowered peak IgG titers consistent with the anticipated increase in IgG clearance with nipocalimab. In clinical studies, nipocalimab demonstrated a reproducible selective decrease in total serum IgG, including all subclasses of IgG, with no effect on IgM, IgA, IgE, CH50, C3, C4, inflammatory cytokines or acute phase proteins including, C-reactive protein (CRP). Conclusions These data suggest that nipocalimab can selectively lower IgG and IgG autoantibodies while preserving cellular immunity, complete IgM response and IgG production after neoantigen challenge. Overall, nipocalimab's selective effect on IgG recycling provides a mechanistic rationale for potentially decreased infection risk despite substantial IgG lowering.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/01.wnl.0000903080.38659.15
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 4
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    Abstract 302: Characterization of effects of M402 on EMT in pancreatic ductal adenocarcinoma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 302-302
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 302-302
    Abstract: Background: Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. The current treatment for resectable disease consists of surgery and adjuvant gemcitabine therapy. However, for more than 80 percent of the patients with PDA surgery is not an option. For these patients palliative chemotherapy using gemcitabine, or most recently FOLFIRINOX, is considered standard of care. Even with palliative chemotherapy the median overall survival for patients with metastatic PDA is dismal and improved therapeutic strategies are a clear unmet medical need. Heparins may be of interest for the treatment of PDA. They play an important role in tumor progression and metastasis by binding at heparin binding domains, thereby preventing growth factor gradients created along proteoglycan heparan sulfates and thus disrupting signaling. We used a novel heparan sulfate mimetic, M402, which binds to multiple growth factors, adhesion molecules, and chemokines. We previously showed that M402 decreases both epithelial-to-mesynchymal transition and chemotherapy resistance in PDA. Here we further evaluated the underlying mechanisms of M402 in EMT. Results: We studied the effects of M402 on PDA using a genetically engineered mouse model (GEMM) for PDA (LSL-KRASG12D/+; Trp53 LSL-R172H/flox; pdx-CRE), which recapitulates human PDA. Combination therapy of M402 with gemcitabine significantly prolonged the average survival of the mice when compared to mice treated with gemcitabine monotherapy (87 days versus 78 days) and significantly reduced metastasis and local invasion into the small intestine. These data suggest an effect of M402 on invasiveness and EMT. Gemcitabine treatment increased EMT as determined by staining for E-cadherin and Fsp1 double positive cells. In contrast, M402 treatment resulted in a decrease in E-cadherin and Fsp1 double positive cells in pancreatic tumors. We next sought to determine whether M402 affects cancer cells or stromal cells. In vitro experiments show that cell lines derived from our model respond to M402 by decreasing their invasive behavior in 3D culture and scratch assays. Moreover, we found that M402 augments the gemcitabine effect in vitro. These data suggest that M402 affects both EMT and gemcitabine response. Further identification by whole transcriptome microarray analysis of treated tumors hints towards a role of M402 in affecting multiple signaling pathways involved in the regulation of EMT. These data will undoubtedly lead to better insight into the mechanism of action of M402 and will increase our understanding of the pathways PDA cells use to evade the effects of chemotherapy. M402 is currently being investigated in a phase 1/2 M402 gemcitabine combination study to assess if these findings can be translated into a clinical benefit in pancreatic cancer patients. Conclusion: These data suggest that M402 reduces acquired chemotherapy resistance in a GEMM for PDA by decreasing EMT. Citation Format: Ilse Oosterom, Birgit C. Schultes, Chia Lin Chu, Zoya Galcheva-Gargova, Elma Kurtagic, He Zhou, Jay Duffner, Emile E. Voest, David A. Tuveson, Martijn Lolkema. Characterization of effects of M402 on EMT in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 302. doi:10.1158/1538-7445.AM2013-302
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-302
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 5
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    Abstract 561: Discovery of a potential best-in-class anti-CD38 therapeutic utilizing Fc multimerization
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 561-561
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 561-561
    Abstract: CD38 targeting antibodies are at different phases of clinical development, with daratumumab already approved as monotherapy and in combination with standards of care in multiple myeloma (MM). Anti-CD38 monoclonal antibodies (mAbs) induce tumor cell depletion in part by Fc-dependent effector mechanisms such as antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC). However, not all MM patients achieve minimal residual disease (MRD)-negativity and similar clinical response. In addition, some patients on daratumumab develop resistance due to reduced cell surface CD38 and high levels of complement inhibitors (CD55 and CD59). We have leveraged Fc multimerization technology (Ortiz et al Sci Transl Med. 2016; 8: 365) to generate an optimized platform (SIF; selective immunomodulator of Fc receptors) that utilizes the valency effect of Fc multimerization to enhance binding to the Fcγ receptors and complement. We combined the Fab-region of CD38 targeting mAb to SIF platform to generate an anti-CD38 SIFbody to enhance immune and complement mediated cytotoxicity against tumor cells. In several human tumor cell line-based cytotoxic assays using primary human effector cells (NK cells and macrophages) and complement, the anti-CD38 SIFbody demonstrates up to 10-fold increase in efficacy and ≥16-fold increase in potency compared to daratumumab and the surrogate therapeutic anti-CD38 mAb (TAK-079). In isolated whole human blood incubated with tumor cells, the anti-CD38 SIFbody demonstrated 40-100 fold increase in potency and 2-3 fold increase in efficacy. In bone marrow cells isolated from MM patients with & gt;80% plasma cells anti-CD38 SIFbody showed better potency and a 3-5 fold increased efficacy (with 100% plasma cell elimination) than daratumumab, suggesting the SIFbody may be more suitable molecule for achieving greater MRD-negativity rates in MM patients. Daratumumab fails to induce CDC against tumor cell lines with low CD38 and high CD55 and CD59, however the SIFbody achieves 100% efficacy in such settings, suggesting this molecule may be effective in patients who are developing resistance to treatment. In single dose pharmacodynamic and tolerability studies in cynomolgus monkeys SIFbody demonstrated up to 5-fold increase in B cell depletion from peripheral blood compared to TAK-079 across all dose ranges (0.3, 1, & 3 mg/kg) tested without any adverse events. Therefore, by leveraging our Fc multimerization technology we have generated a differentiated potential best-in-class anti-CD38 therapeutic. Citation Format: Amit Choudhury, Daniel F. Ortiz, Shannon Argueta, Kevin Garofalo, Jonathan C. Lansing, Utsav Jetley, Danice Wilkins, Carlos Bosques, Edward Cochran, Naveen Bhatnagar, Jay Duffner, Abhinav Gupta, Stan Lee, Karunya Srinivasan, Viraj Parge, Radouane Zouaoui, Jason Wang, Anthony M. Manning. Discovery of a potential best-in-class anti-CD38 therapeutic utilizing Fc multimerization [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 561.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-561
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
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    Abstract 1524: M402, a novel heparan sulfate mimetic, inhibits pancreatic tumor growth and desmoplasia potentially via sonic hedgehog signaling in an orthotopic mouse model
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1524-1524
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1524-1524
    Abstract: One of the hallmarks of pancreatic ductal adenocarcinoma (PDAC) is extensive desmoplasia in the surrounding tumor microenvironment that prevents delivery of chemotherapeutics (such as gemcitabine). Dysregulation of sonic hedgehog (SHH, a heparin-binding morphogen), has been implicated in pancreatic cancer tumorigenesis. We have rationally designed a heparan sulfate mimetic, M402, that has previously been shown in animal studies to reduce metastatic seeding through disruption of several key heparin-binding growth factors (including FGF2, VEGF, SDF-1α and P-Selectin). We hypothesized that M402, alone or in combination with gemcitabine, could potentially modulate tumor-stroma interactions in an orthotopic pancreatic cancer model (Capan-2 cell line) which secretes SHH and displays a desmoplastic response in vivo. Capan-2 human adenocarcinoma cells (∼1x106 cells) were injected into the pancreata of immunodeficient mice (Nu/Nu CD-1). M402 (10-40 mg/kg/day) or saline treatment commenced on Day 4 or 32. Gemcitabine (30-60 mg/kg, twice weekly, IP) treatment commenced between Weeks 3-6. At the termination of each study (Week 8), gross anatomical observations were made of the primary pancreatic tumor and metastatic lesions in the surrounding tissues including the spleen, intestines and liver. Gemcitabine was increasingly less effective when started at later time points, but still reduced the primary tumor weight by 60-70% (at 30-45 mg/kg) when treatment was started at week 5. While the addition of M402 to gemcitabine showed some additive effect on primary tumor burden, metastasis, invasion, and surrounding fibrotic lesions appeared particularly impacted by the combination treatment. M402 was also effective as monotherapy showing a dose-dependent reduction in primary tumor weight and fibrotic lesions. Immunohistochemical and qPCR analyses showed reduced fibrosis and SHH signaling with M402 and gemcitabine combination treatment. These results demonstrate that M402 can modulate tumor-stroma interactions involved in the desmoplastic response in a murine model of pancreatic cancer and provide a rationale for the clinical investigation of M402 as a potential anti-desmoplastic agent in pancreatic cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1524. doi:1538-7445.AM2012-1524
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1524
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 7
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    Abstract 2269: M402 - A novel heparan sulfate proteoglycan mimetic targeting tumor-host interactions
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2269-2269
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2269-2269
    Abstract: Heparan sulfate proteoglycans (HSPGs) play important roles in tumorigenesis by mediating tumor-stromal interactions through the presentation of growth factors, cytokines, and chemokines critical for tumor progression, survival and metastasis. M402 is a rationally engineered, non-cytotoxic HSPG mimetic, designed to disrupt tumor-host interactions. M402 binds and inhibits multiple factors including VEGF, FGF2, SDF-1α, and P-selectin. A single 20 mg/kg subcutaneous (s.c.) dose of M402 effectively reduced seeding of B16F10 murine melanoma cells to the lung in a syngeneic experimental metastasis model. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis of orthotopically implanted 4T1 murine mammary carcinoma in this model. M402 treatment also normalized circulating levels of GR1+ immature myeloid cells and platelet counts in 4T1 metastatic tumor bearing mice. Fluorescently-labeled M402 exhibited selective accumulation in the primary tumor. Immunohistological analyses of primary tumor presented a decrease in microvessel density in M402-treated animals, suggesting anti-angiogenesis may be one of the mechanisms involved in vivo. Importantly, M402, as monotherapy or in combination with chemotherapeutics, also revealed significant survival benefits in this aggressive tumor model. These data demonstrate that targeting HSPG biology may provide a useful approach to attenuate multiple pathways involved in tumor progression and metastasis. 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 2269.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-2269
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 8
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    M402, a heparan sulfate mimetic and novel candidate for the treatment of pancreatic cancer.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 4056-4056
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 4056-4056
    Abstract: 4056 Background: Recent advances in pancreatic cancer research implicate the involvement of several heparin-binding growth factors (such as HGF, HB-EGF, PDGF, hedgehogs, and TGFs) that control tumor-stroma interactions. We have rationally designed a heparan sulfate mimetic, M402, which has been previously shown to affect tumor progression and metastasis through disruption of multiple pathways. We hypothesized that M402 could modulate tumor-stroma interactions and enhance the efficacy of gemcitabine, and evaluated its efficacy in two preclinical models. Methods: A genetically engineered mouse model (GEMM; KrasLSL G12D p53LSL R172H ) featuring spontaneous pancreatic tumor formation and metastasis assessed M402’s effect on tumorigenesis and metastasis. The orthotopic Capan-2 model in nude mice evaluated the effect of M402 on desmoplasia, a fibrotic response that hinders effective delivery of chemotherapeutics, via inhibition of sonic hedgehog (SHH) signaling in fibroblasts and stellate cells. In both models, M402 was studied as monotherapy and with gemcitabine. Results: In the GEMM, M402 significantly prolonged survival in combination with gemcitabine while each monotherapy showed modest efficacy. M402, alone and in combination, also reduced metastases and local invasion and inhibited epithelial-to-mesenchymal transition. In the Capan-2 model, gemcitabine was increasingly less effective as desmoplasia progressed over time. The addition of M402 to gemcitabine increased its efficacy with respect to primary tumor burden. Metastasis, invasion, and surrounding fibrotic lesions appeared particularly impacted by the combination treatment. M402 was also effective as monotherapy with dose-dependency, which correlated with reduced SHH signaling. Conclusions: M402 can modulate tumor-stroma interactions involved in the metastatic and desmoplastic pathways in two pancreatic cancer models supporting the translation of these findings into a clinical study. A first-in-human study is planned that will evaluate the safety, pharmacokinetics, efficacy, and biomarker profiles of escalating M402 doses in combination with gemcitabine in patients with metastatic pancreatic cancer.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.4056
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 9
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    M281, an Anti‐FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First‐in‐Human Study
    Wiley ; 2019
    In:  Clinical Pharmacology & Therapeutics Vol. 105, No. 4 ( 2019-04), p. 1031-1039
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 105, No. 4 ( 2019-04), p. 1031-1039
    Abstract: M281 is a fully human, anti‐neonatal Fc receptor (FcRn) antibody that inhibits FcRn‐mediated immunoglobulin G (IgG) recycling to decrease pathogenic IgG while preserving IgG production. A randomized, double‐blind, placebo‐controlled, first‐in‐human study with 50 normal healthy volunteers was designed to probe safety and the physiological maximum for reduction of IgG. Intravenous infusion of single ascending doses up to 60 mg/kg induced dose‐dependent serum IgG reductions, which were similar across all IgG subclasses. Multiple weekly doses of 15 or 30 mg/kg achieved mean IgG reductions of ≈85% from baseline and maintained IgG reductions ≥75% from baseline for up to 24 days. M281 was well tolerated, with no serious or severe adverse events ( AE s), few moderate AE s, and a low incidence of infection‐related AE s similar to placebo treatment. The tolerability and consistency of M281 pharmacokinetics and pharmacodynamics support further evaluation of M281 in diseases mediated by pathogenic IgG.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.2019.105.issue-4
    DOI: 10.1002/cpt.1276
    RVK:
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    Language: English
    Publisher: Wiley
    Publication Date: 2019
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  • 10
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    M281: A Therapeutic Anti-FcRn Blocking Antibody for Rapid Clearance of IgG and IgG Autoantibodies in Immune Cytopenias and Other Auto/Allo-Immune Disease
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 3472-3472
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3472-3472
    Abstract: Introduction IgG antibodies are the primary pathogenic agent in a number of auto- or allo-immune diseases. Efficacious therapies which decrease systemic levels of pathogenic antibodies include treatment with IVIG therapeutic plasmapheresis or immunoabsorption. Here, a novel strategy was evaluated to induce IgG clearance in diseases driven by IgG autoantibodies by blockade of FcRn-mediated IgG recycling. Methods M281 was developed as a high affinity, effectorless IgG1anti-FcRn monoclonal antibody. M281 effect on IgG recycling was evaluated in human umbilical vein endothelial cells in vitro. In vivo studies in transgenic human FCGRT/mouse FCGRT null mice and cynomolgus monkey were performed to characterize the pharmacokinetics, biodistribution, target occupancy, specificity of M281 and its efficacy in mouse models of thrombocytopenia and arthritis. Results M281 demonstrates specific dose-dependent, albumin-sparing IgG clearance in human FCGRT transgenic/mouse FCGRT null mice and in cynomolgus monkeys. M281 inhibits IgG recycling in endothelial cells in vitro and IgG clearance in vivo. Pharmacokinetics, target occupancy, pharmacodynamics and biodistribution indicate typical recombinant antibody biodistribution with rapid, dose dependent target inhibition and systemic clearance. M281 also demonstrated efficacy in mouse idiopathic thrombocytopenia purpura and collagen antibody-induced arthritis models of disease. Conclusions These findings support the evaluation of M281 as a strategy for the rapid and reversible suppression of pathogenic autoantibodies or alloantibodies in the setting of immune cytopenias, acquired inhibitors, thrombotic states and other disorders. Disclosures Ling: Momenta Pharmaceuticals: Employment, Equity Ownership. Roy:Momenta Pharmaceuticals: Employment, Equity Ownership. Daly:Momenta Pharmaceuticals: Employment, Equity Ownership. Cochran:Momenta Pharmaceuticals: Employment, Equity Ownership. Tyler:Momenta Pharmaceuticals: Employment, Equity Ownership. Markowitz:Momenta Pharmaceuticals: Employment, Equity Ownership. Bulik:Momenta Pharmaceuticals: Employment, Equity Ownership. Choudhury:Momenta Pharmaceuticals: Employment, Equity Ownership. Meador:Momenta Pharmaceuticals: Employment, Equity Ownership. Parge:Momenta Pharmaceuticals: Employment. Mekala:Momenta Pharmaceuticals: Employment, Equity Ownership. Sipsey:Momenta Pharmaceuticals: Employment, Equity Ownership. Gurnani:Momenta Pharmaceuticals: Employment, Equity Ownership. Duffner:Momenta Pharmaceuticals: Employment, Equity Ownership. Lee:Momenta Pharmaceuticals: Employment, Equity Ownership. Washburn:Momenta Pharmaceuticals: Employment, Equity Ownership. Meccariello:Momenta Pharmaceuticals: Employment, Equity Ownership. Schaeck:Momenta Pharmaceuticals: Employment, Equity Ownership. Wang:Momenta Pharmaceuticals: Employment, Equity Ownership. Schultes:Momenta Pharmaceuticals: Employment, Equity Ownership. Hillson:Momenta Pharmaceuticals: Employment, Equity Ownership. Avery:Momenta Pharmaceuticals: Employment, Equity Ownership. Kaundinya:Momenta Pharmaceuticals: Employment, Equity Ownership. Manning:Momenta Pharmaceuticals: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.3472.3472
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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