10 results on '"Surekha S. Akella"'
Search Results
2. Supplementary Materials and Methods from ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models
- Author
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Susan E. Morgan-Lappe, Jijie Gu, Louie Naumovski, Sherry L. Ralston, Wenqing Gao, Surekha S. Akella, Catherine Zhang, Sarah R. Mudd, Fang Jiang, Sanjay C. Panchal, Enrico L. DiGiammarino, Lucia J. Eaton, Kelly D. Foster-Duke, Deanna L. Haasch, Dominic J. Ambrosi, Jonathan A. Hickson, and Yingchun Li
- Abstract
This file describes the binding assay details of surface plasmon resonance technology, ligand and receptor binding competition assays, western blot detection of DLL4 protein down-regulation, and the methods to measure total circulating soluble DLL4 and VEGF in cynomolgus monkey plasma.
- Published
- 2023
3. Data from ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models
- Author
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Susan E. Morgan-Lappe, Jijie Gu, Louie Naumovski, Sherry L. Ralston, Wenqing Gao, Surekha S. Akella, Catherine Zhang, Sarah R. Mudd, Fang Jiang, Sanjay C. Panchal, Enrico L. DiGiammarino, Lucia J. Eaton, Kelly D. Foster-Duke, Deanna L. Haasch, Dominic J. Ambrosi, Jonathan A. Hickson, and Yingchun Li
- Abstract
Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment–related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study. Mol Cancer Ther; 17(5); 1039–50. ©2018 AACR.
- Published
- 2023
4. ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models
- Author
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Susan E. Morgan-Lappe, Wenqing Gao, Enrico L. Digiammarino, Yingchun Li, Surekha S. Akella, Sanjay C. Panchal, Jonathan Hickson, Sarah R. Mudd, Louie Naumovski, Jijie Gu, Ralston Sherry L, Dominic J. Ambrosi, Catherine Zhang, Kelly Foster-Duke, Lucia Eaton, Fang Jiang, and Deanna L. Haasch
- Subjects
Vascular Endothelial Growth Factor A ,0301 basic medicine ,Cancer Research ,Angiogenesis ,medicine.medical_treatment ,Cell ,Immunoglobulins ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Immunologic Factors ,Chemotherapy ,biology ,business.industry ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Macaca fascicularis ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,biology.protein ,Cancer research ,Drug Screening Assays, Antitumor ,Antibody ,Glioblastoma ,business ,HT29 Cells - Abstract
Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment–related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study. Mol Cancer Ther; 17(5); 1039–50. ©2018 AACR.
- Published
- 2018
5. Abstract 867: ABT-165 is a first-in-class therapeutic Dual Variable Domain Immunoglobulin (DVD-IgTM) that targets DLL4 and VEGF for the treatment of cancer
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Yingchun Li, Wenqing Gao, Fang Jiang, Lucia Eaton, Surekha S. Akella, Deanna L. Haasch, Jonathan A. Hickson, Jijie Gu, Ralston Sherry L, Kelly Foster-Duke, Dominic J. Ambrosi, and Susan Morgan-Lappe
- Subjects
Cancer Research ,Chemotherapy ,Bevacizumab ,biology ,business.industry ,medicine.medical_treatment ,Notch signaling pathway ,Cancer ,medicine.disease ,Blockade ,Immune system ,Oncology ,Cancer stem cell ,biology.protein ,Cancer research ,Medicine ,Antibody ,business ,medicine.drug - Abstract
The first generation anti-angiogenic drugs designed to block the VEGF/VEGFR pathway lend modest clinical benefit for cancer patients. Other than VEGF, DLL4 is the only known angiogenic factor with a haploinsufficiency phenotype, underscoring its essential role in vascular function. Indeed, both the VEGF/VEGFR and the DLL4/Notch signaling axes are known to cooperate during pathological angiogenesis. DLL4 is also implicated in VEGF-independent pathways, cancer stem cell survival, and immune suppression that could collectively contribute to tumor cell resistance. Given both intrinsic and acquired patient resistance mechanisms exist, targeting the DLL4/Notch pathway represents a unique opportunity for a combination strategy to improve upon current VEGF/VEGFR pathway inhibitor therapies. To this end, ABT-165 was developed as a first-in-class dual specific biologic using AbbVie's proprietary dual-variable domain immunoglobulin (DVD-IgTM) technology. ABT-165 is capable of simultaneously binding to DLL4 and VEGF with nanomolar affinities and blocking the cognate ligand-receptor interactions that result in the potent inhibition of DLL4-mediated Notch1 activation and VEGF-stimulated endothelial cell proliferation. ABT-165 is functionally superior in vitro compared to the combination of parental anti-VEGF and anti-DLL4 antibodies. In human tumor xenograft models, ABT-165 induced significant inhibition of tumor growth and survival benefit compared to single anti-DLL4 or anti-VEGF antibody treatments at equivalent doses. Mechanistically, this enhancement of anti-tumor efficacy is due in part to the disruption of new tumor vasculature coupled with blockade of vessel perfusion. Furthermore, ABT-165 in combination with cytotoxic chemotherapy agents induced tumor regression, which outperformed bevacizumab plus chemotherapy in both human breast and colon xenograft models. ABT-165 displays non-linear, dose-dependent pharmacokinetic profiles in mice and cynomolgus monkeys, with an apparent terminal half-life > 5 days in both species at a target saturation dose. In a GLP monkey toxicity study, ABT-165 at doses up to 200 mg/kg was well-tolerated with non-adverse treatment-related histopathology findings limited to the liver and thymus. In contrast, adverse and non-adverse findings were observed in the hearts of rats and monkeys, respectively, with an in-house proprietary anti-DLL4 antibody. Given that coupling of anti-DLL4 with anti-VEGF activities into a DVD-Ig may lend improved safety and/or efficacy profiles compared to antibodies, ABT-165 was advanced into a Phase 1 clinical trial. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Yingchun Li, Jonathan Hickson, Dominic Ambrosi, Deanna Haasch, Kelly Foster-Duke, Lucia Eaton, Fang Jiang, Surekha Akella, Wenqing Gao, Sherry Ralston, Jijie Gu, Susan Morgan-Lappe. ABT-165 is a first-in-class therapeutic Dual Variable Domain Immunoglobulin (DVD-IgTM) that targets DLL4 and VEGF for the treatment of cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 867.
- Published
- 2016
6. Developmental ontogeny of NAD+ kinase in the rat conceptus
- Author
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Craig Harris and Surekha S. Akella
- Subjects
Male ,medicine.medical_specialty ,Pyridines ,Biology ,Toxicology ,Kidney ,Cofactor ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Biosynthesis ,Pregnancy ,Placenta ,Internal medicine ,medicine ,Conceptus ,Animals ,Lung ,Pharmacology ,chemistry.chemical_classification ,Kinase ,Myocardium ,Heart ,Embryo, Mammalian ,NAD ,Rats ,Phosphotransferases (Alcohol Group Acceptor) ,medicine.anatomical_structure ,Endocrinology ,Enzyme ,chemistry ,Toxicity ,biology.protein ,Female ,NAD+ kinase ,NADP - Abstract
The ubiquitous NAD+ kinase (NADK) is the only known enzyme to catalyze formation of NADP+ from NAD+. The capacity to maintain an adequate supply of NADP(H) has important implications for development because of its requirement as a cofactor and electron donor in biosynthesis and detoxication reactions. Modulation of NADK may directly influence NADP(H) concentrations and cell sensitivity to embryotoxicants. Measurable activities of NADK were not detected in gestational day (GD) 10 rat conceptuses. By GD 11, specific activities of 1.8 and 7.0 pmol NADP+/min/microg protein were measured in embryos and visceral yolk sacs (VYSs), respectively. The VYS specific activities decreased thereafter to 0.5 pmol NADP+/min/microg protein by GD 18. Specific activities of NADK in placenta increased from 1.3 pmol NADP+/min/microg protein on GD 11 to 32.7 pmol NADP+/min/microg protein on GD 15. Specific activities in the liver increased from 1.7 pmol NADP+/min/microg protein on GD 15 to 51.1 pmol NADP+/min/microg protein on GD 21. NADK specific activities were also determined in other developmentally relevant tissues such as the heart and the brain. In the heart, NADK activity was at its lowest just before birth while in the brain it peaked at 5.4 pmol NADP+/min/microg protein just prior to birth. In the lung, activity increased from 0.9 pmol NADP+/min/microg protein on GD 17 to 5.9 pmol NADP+/min/microg protein on GD 21. However, activities dropped in the kidney from 2.0 pmol NADP+/min/microg protein on GD 17 to 1.1 pmol NADP+/min/microg protein on GD 21. These results demonstrate dramatic temporal and spatial variations in NADK activity. Tissue variations in NADK activities may reflect alterations in functional needs for cofactors during differentiation and a cooperation between tissues to optimize detoxification capacity. This is particularly important when chemical exposure during pregnancy disrupts pyridine nucleotide redox status and the conceptus must rely on NADK to provide additional NADP(H).
- Published
- 2001
7. Pyridine nucleotide flux and glutathione oxidation in the cultured rat conceptus
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Craig Harris and Surekha S. Akella
- Subjects
Glutathione reductase ,Toxicology ,medicine.disease_cause ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Organ Culture Techniques ,tert-Butylhydroperoxide ,Pregnancy ,medicine ,Conceptus ,Animals ,Yolk sac ,Chromatography, High Pressure Liquid ,Yolk Sac ,chemistry.chemical_classification ,Diamide ,Proteins ,Glutathione ,DNA ,Embryo, Mammalian ,NAD ,Oxidants ,Molecular biology ,Rats ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Protein Biosynthesis ,Thiol ,Female ,NAD+ kinase ,Oxidation-Reduction ,Homeostasis ,Oxidative stress ,NADP - Abstract
It is proposed that protection of the developing embryo from chemical and environmental insults that produces oxidative stress requires a proper glutathione (GSH) and pyridine nucleotide status in both the embryo and extra-embryonic membranes. Modulation of pyridine nucleotide flux [NAD(H) and NAD(P)H] in the visceral yolk sac (VYS) by the thiol oxidants diamide and tert-butyl hydroperoxide (tBH) was studied in real time using microfiberoptic sensors in GD 10 rat conceptuses. Consecutive 5-min exposures to 125- and 250-microM diamide resulted in a fluorescence decrease of 14 and 32 Arbitrary Fluorescence Units (AFU). An additional consecutive exposure to 500-microM diamide caused an attenuated decrease followed by a rebound increase of 22 AFU. Consecutive 5-min exposures to tBH at 250 and 500 microM produced fluorescence decreases similar to that of 500 microM diamide, but the decreases were attenuated at 1000 microM. However, there was variability in the rebound increase. A 5-min exposure to tBH (500 microM) alone caused a fluorescence decrease of 14 AFU followed by a rebound increase of 8 AFU. The rate of fluorescence decrease was attenuated by 50% with pretreatment with the glutathione reductase (GSSG-Rd) inhibitor, BCNU (1,3, bis(2 chloroethyl)-1-nitrosourea), indicating that the decrease in surface fluorescence was probably attributable to a decrease in NADPH. Decreases in fluorescence, observed from the surface of the VYS, correlated with decreases in GSH/GSSG ratios in the embryos and the VYS. After exposure to tBH, GSH levels in conceptuses decreased at the end of 5 and 15 min, with a corresponding increase in oxidized glutathione (GSSG) at the end of 3, 5, and 15 min. Our results demonstrate that the increased production of GSSG on exposure to thiol oxidants correlates with a decrease in the reduced pyridine nucleotide, implying the presence of an active GSSG-Rd pathway in the conceptus during organogenesis, and implicating an important role of the pyridine nucleotides in the restoration of GSH homeostasis in the developing rat conceptus during organogenesis.
- Published
- 1999
8. Challenges and gaps in immunosafety evaluation of therapeutics: An IQ DruSafe survey.
- Author
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Collinge M, Neff-LaFord H, Akella S, Fogal B, Fraser K, Jabbour J, Harper K, Maier CC, Malherbe L, Marshall N, Rao GK, Raman K, Skaggs H, Weber F, and Fuller CL
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- Humans, Animals, Surveys and Questionnaires, Cytokines immunology, Risk Assessment, Drug Evaluation, Preclinical methods, Toxicity Tests methods, Immunologic Factors adverse effects, Immunologic Factors toxicity
- Abstract
Immunotoxicology/immunosafety science is rapidly evolving, with novel modalities and immuno-oncology among the primary drivers of new tools and technologies. The Immunosafety Working Group of IQ/DruSafe sought to better understand some of the key challenges in immunosafety evaluation, gaps in the science, and current limitations in methods and data interpretation. A survey was developed to provide a baseline understanding of the needs and challenges faced in immunosafety assessments, the tools currently being applied across the industry, and the impact of feedback received from regulatory agencies. This survey also focused on current practices and challenges in conducting the T-cell-dependent antibody response (TDAR) and the cytokine release assay (CRA). Respondents indicated that ICH S8 guidance was insufficient for the current needs of the industry portfolio of immunomodulators and novel modalities and should be updated. Other challenges/gaps identified included translation of nonclinical immunosafety assessments to the clinic, and lack of relevant nonclinical species and models in some cases. Key areas of emerging science that will add future value to immunotoxicity assessments include development of additional in vitro and microphysiological system models, as well as application of humanized mouse models. Efforts are ongoing in individual companies and consortia to address some of these gaps and emerging science., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
- Full Text
- View/download PDF
9. Pregnancy Experience: Nonclinical Studies and Pregnancy Outcomes in the Daclizumab Clinical Study Program.
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Gold R, Stefoski D, Selmaj K, Havrdova E, Hurst C, Holman J, Tornesi B, Akella S, and McCroskery P
- Abstract
Introduction: Multiple sclerosis (MS) is more common in women and can occur during childbearing years; thus, information on outcomes following exposure to MS therapy during pregnancy is important. No formal studies of daclizumab have been conducted in pregnant women. Here, we report available nonclinical and clinical data on pregnancy outcomes from the daclizumab clinical study program., Methods: Reproductive and developmental toxicity studies were conducted in cynomolgus monkeys. Reports of pregnancies that occurred during the daclizumab clinical study program through March 9, 2015 were collated and summarized. In the event of pregnancy, daclizumab was discontinued and safety monitoring continued., Results: Studies in cynomolgus monkeys showed no daclizumab-related effects on maternal well-being, embryo-fetal development, indirect fertility end points, and pre- and postnatal development and growth. Across the clinical study program, 38 pregnancies were reported in 36 daclizumab-exposed women (on treatment ≤6 months from last dose); 20 resulted in live births and four (11%) in spontaneous abortions or miscarriages. One congenital heart defect (complex transposition of great vessels) occurred in one live birth (considered unrelated to daclizumab); daclizumab had been discontinued and intramuscular interferon beta-1a and lisinopril were used at conception. Eight women had an elective termination, two had an ectopic pregnancy, and two were lost to follow-up; two pregnancy outcomes are pending. Six additional pregnancies occurred in five women >6 months after their last daclizumab dose; in one additional pregnancy, exposure was unknown., Conclusion: Spontaneous abortion rate in daclizumab-exposed women was consistent with early pregnancy loss in the general population (12%-26%). Data on pregnancies exposed to daclizumab do not suggest an increased risk of adverse fetal or maternal outcomes, although the numbers are too small for definitive conclusions. CLINICALTRIALS., Gov Identifiers: NCT00390221, NCT01064401, NCT01462318, NCT00870740, NCT01051349, and NCT01797965., Funding: Biogen and AbbVie Biotherapeutics Inc.
- Published
- 2016
- Full Text
- View/download PDF
10. Microscopic background changes in brains of cynomolgus monkeys.
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Butt MT, Whitney KM, Davis W, Akella S, Parker S, and Foley GL
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- Animals, Brain pathology, Case-Control Studies, Female, Gliosis pathology, Male, Microscopy, Reference Values, Retrospective Studies, Brain cytology, Macaca fascicularis anatomy & histology, Toxicity Tests methods
- Abstract
Brain sections from control cynomolgus monkeys (Macaca fascicularis) used in toxicology studies were evaluated retrospectively in order to better understand spontaneous background changes in this species. Hematoxylin and eosin-stained slides from 76 animals (38 males and 38 females) of 9 studies were examined. Eleven animals (9 males and 2 females) were each observed to have 1 to 3 findings within the brain sections examined, for a total of 19 findings. No findings were noted in the spinal cord. The most common finding was focal to multifocal perivascular infiltration of mononuclear cells, affecting the parenchyma, the meninges, or the choroid plexus. Additionally, focal gliosis was observed in 6 animals and a single focus of hemosiderin deposition (coincident with focal gliosis and mononuclear cell infiltrate) was noted in 1 animal. Most of the glial foci were composed of cells consistent with microglial cells, with or without admixed lymphocytes. All findings were of slight or minimal severity, lacked an apparent cause, and were considered incidental and of negligible biologic significance. An awareness of the spontaneous incidence of these background findings may facilitate the discernment of toxicologically relevant effects when these findings are observed., (© 2014 by The Author(s).)
- Published
- 2015
- Full Text
- View/download PDF
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