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Carter D.,Pai Life Sciences, Inc. | Carter D.,Compliment Corporation | Lieber A.,University of Washington
FEBS Letters | Year: 2014

The complement system is composed of soluble factors in plasma that enhance or "complement" immune-mediated killing through innate and adaptive mechanisms. Activation of complement causes recruitment of immune cells; opsonization of coated cells; and direct killing of affected cells through a membrane attack complex (MAC). Tumor cells up-regulate complement inhibitory factors - one of several strategies to evade the immune system. In many cases as the tumor progresses, dramatic increases in complement inhibitory factors are found on these cells. This review focuses on the classic complement pathway and the role of major complement inhibitory factors in cancer immune evasion as well as on how current protein engineering efforts are being employed to increase complement fixing or to reverse complement resistance leading to better therapeutic outcomes in oncology. Strategies discussed include engineering of antibodies to enhance complement fixation, antibodies that neutralize complement inhibitory proteins as well as engineered constructs that specifically target inhibition of the complement system. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Source

Fox C.B.,Infectious Disease Research Institute IDRI | Sivananthan S.J.,Infectious Disease Research Institute IDRI | Duthie M.S.,Infectious Disease Research Institute IDRI | Vergara J.,Infectious Disease Research Institute IDRI | And 6 more authors.
Journal of Nanobiotechnology | Year: 2014

Background: Recent reports that TLR4 and TLR7 ligands can synergistically trigger Th1 biased immune responses suggest that an adjuvant that contains both ligands would be an excellent candidate for co-administration with vaccine antigens for which heavily Th1 biased responses are desired. Ligands of each of these TLRs generally have disparate biochemical properties, however, and straightforward co-formulation may represent an obstacle.Results: We show here that the TLR7 ligand, imiquimod, and the TLR4 ligand, GLA, synergistically trigger responses in human whole blood. We combined these ligands in an anionic liposomal formulation where the TLR7 ligand is in the interior of the liposome and the TLR4 ligand intercalates into the lipid bilayer. The new liposomal formulations are stable for at least a year and have an attractive average particle size of around 140 nm allowing sterile filtration. The synergistic adjuvant biases away from Th2 responses, as seen by significantly reduced IL-5 and enhanced interferon gamma production upon antigen-specific stimulation of cells from immunized mice, than any of the liposomal formulations with only one TLR agonist. Qualitative alterations in antibody responses in mice demonstrate that the adjuvant enhances Th1 adaptive immune responses above any adjuvant containing only a single TLR ligand as well.Conclusion: We now have a manufacturable, synergistic TLR4/TLR7 adjuvant that is made with excipients and agonists that are pharmaceutically acceptable and will have a straightforward path into human clinical trials. © 2014 Fox et al.; licensee BioMed Central Ltd. Source

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 208.64K | Year: 2016

DESCRIPTION provided by applicant A problem with hematopoietic stem cell HSC transplantation is the risk of primary or secondary graft failure As an example in patients with hematologic malignancies who underwent their first myeloablative allogeneic hematopoietic cell transplantation primary graft failure is One year overall survival after re transplantation due to primary graft failure without relapse is as low as Risk factors for primary graft failue are insufficient numbers of transplanted HSCs and the necessity to reduce the intensity of chemotherapy and radiation conditioning due to the poor physical condition of patients to be treated Reduced intensity conditioning is also required for HSC transplantation in certain non malignant diseases such as Fanconi anemia We are about to initiate clinical trials on a combination therapy of rituximab and our recombinant affinity enhanced protein Ad K that depletes the complement inhibitory protein CD from the cell surface and thereby enhances in vivo antibody therapy in cancers Unexpectedly we have found that this protein may have a significant ex vivo use Ad K alone when added to human CD cells dramatically enhances their ability to engraft in myelo ablated animals This has important implications for HSC transplantation This project will move this HSC engraftment enhancement candidate towards clinical testing in humans The public health implications of improving clinical outcomes in therapies that require engraftment are significant Specific areas that would benefit from the results of the studies proposed here include humanized mouse models that receive human HSCs HSC gene therapy and diseases that are treated by HSC transplantation Among these are malignant diseases leukemia lymphoma gliomas neuroblastomas and other solid tumors myelodysplastic syndromes genetic diseases and inborn errors of metabolism The specific aims of the proposal include To understand the mechanism of Ad K mediated engraftment enhancement To optimize the approach and achieve engraftment with lower HSC numbers To test the engraftment enhancer in more challenging transplantation settings In phase we will extend the findings to non human primates and begin translational activities leading to a pre IND meeting to support clinical trials on this ex vivo enhancer Since we have already begun cGMP manufacture of our lead candidate for combination cancer therapy with rituximab clinical translation of the findings in this proposal should be straightforward The commercial potential for this product is clear and there is a great benefit to HSC transplant patients if our early animal model results are verified in humans PUBLIC HEALTH RELEVANCE Engraftment of cells is an important problem both with established transplantation protocols as well as those that will be required for new stem cell transplantation approaches The new engraftment enhancer described in this proposal will improve current therapies and the success of new treatments worldwide

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.16M | Year: 2016

DESCRIPTION provided by applicant Schistosomiasis is a major neglected tropical disease of public health concern to a billion people with million currently infected and million at risk to acquire the infection the majority of these in Africa The disease has a high impact on affected peopleandapos s lives with disability adjusted life years at million years which ran this malady ahead of malaria Current control strategies have been geared toward repeated treatment with a drug discovered in the s and standards for monitoring administration and progress have been inconsistent and inadequate Reliance on the drug therapy approach alone is a poor strategy since this approach has had little impact on the reduction of disease transmission and there is always the inherent threat of drug resistance being developed by the parasite A prophylactic schistosomiasis vaccine that provides at least protection would play an important role in dramatically reducing the impact of this disease Vaccine generated immune responses could lead to reduced worm burdens and lower egg production and ultimately result in lowered transmission This application is an extension of our systematic and methodical approach towards developing a vaccine for schistosomiasis Over the last twenty years we have applied this strategy towards developing Sm p into a viable vaccine candidate At present to our knowledge Sm p is the sole schistosome vaccine candidate that has been tested for prevention interruption of transmission and in therapy Our candidate vaccine has three protective effects worm reduction egg reduction and protection against acute disease Funding this application will help our continuing efforts to develop Sm p through cGMP manufacture for future human clinical trials ultimately resulting in an approved vaccine PUBLIC HEALTH RELEVANCE A low cost effective vaccine for schistosomiasis would greatly aid in the fight against this debilitating disease By producing a new candidate vaccine compliant with federal regulations for human clinical trials we intend to progress toward a commercial product leading to an improvement in global health

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 191.16K | Year: 2014

Project Summary Tumors survive cancer therapy in part by blocking the entrance and permeation of drugs into the cancer. We have developed a therapeutic, JO-1 , that selectively opens up tumors, which dramatically enhances penetration. This results in markedly increased concentrations of cancer drugs in the tumor, which becomes a sink , thereby reducing drug levels in the rest of the body. JO-1 may allow doctors to treat patients with cancer drugs at increased doses, which directly correlates with enhancedtherapeutic effects. At the same time, it could reduce or eliminate the side effects of cancer therapy and address one of the major needs of the current state-of-the- art: Developing therapies that are both more effective and less toxic. Importantly, JO-1can be used to improve clinical outcomes with cancer drugs that are already on the market as well as the next generation of cancer drugs. The goal of this proposal is to develop and test a new Targeted / Enhancing Conjugate ( TEC ) of a tumor-targeting t

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