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Ledon N.,Center for Molecular Immunology | Casaco A.,Center for Molecular Immunology | Beausoleil I.,Center for Molecular Immunology
Placenta | Year: 2011

Although pharmaco/toxicological studies have always been conducted in pharmacologically relevant species in which the test material is pharmacologically active, the very specificity of many biopharmaceuticals could present challenges in the identification of a relevant species for pharmaco/toxicological studies. Alternative approaches may improve the predictive value of preclinical assessments of species-specific biopharmaceuticals. This could lead to improved decision-making, reduce the number of experimental animals by eliminating non-relevant studies, and decrease the time and cost involved in the drug development process. As an alternative to utilizing traditional animal models, this study investigated the activity of human EGF and the anti-EGF receptor monoclonal antibodies nimotuzumab and cetuximab using the placenta microsomal fraction of different experimental animals. Ligand-receptor binding curves were obtained from the different experimental animal models, and binding constants were calculated based on the Scatchard plots. The constants for human and monkey EGF receptor expressed on the placental extract showed a Ka < 10-8 M, while rabbits, mice and rats showed a Ka > 10-8 M. The K a values obtained from animal placentas show that Macaca fascicularis and Cercopitecus aethiops monkeys are relevant species for studying the pharmaco/toxicological properties of nimotuzumab and cetuximab. © 2011 Elsevier Ltd. All rights reserved.


News Article | October 27, 2016
Site: www.chromatographytechniques.com

Aside from the cigars, one of the most anticipated imports to come from the thaw in U.S.-Cuban relations is a promising lung cancer vaccine that has been decades in development in the Communist island nation. The CIMAvax-EGF vaccine will now undergo a clinical trial overseen by the U.S. Food and Drug Administration – the next step toward bringing it to American patients. The joint announcement was made Wednesday by the Roswell Park Cancer Institute, the Center for Molecular Immunology (CIM) in Cuba, and the State of New York. “The goals of this clinical trial – to speed and enrich the best ideas for defeating cancer – align perfectly with the White House’s bold Cancer Moonshot effort,” said Candace Johnson, president and CEO of Roswell Park. “The promise of our collaborative research, the affinity that grew between Roswell Park and CIM and the pace at which our collaboration has grown are testaments to the fact that these are the right steps at the right time.” “This is a day we have been working toward for many years,” added Agustin Lage, the director of CIM, the Cuban counterpart on the work. The Phase I/II clinical trial will begin next month, take about three years, and enroll anywhere between 60 to 90 patients. Roswell Park, in Buffalo, N.Y., will be the sole location of the trials. The vaccine has been in development for 25 years in Cuba, where lung cancer is one of the leading causes of death. The results so far show that patients’ lives were extended from seven to an average of 18 months with the vaccine treatment. Some studies have already shown promise in CimaVax, as it has cut back the EGF needed for the cancer to progress. It has done this with minimal side effects, according to some experts. Survival dramatically improved in those patients with advanced Stage 3 and Stage 4 tumors, according to a Cuban study conducted in 2007. However, the vaccine has only been administered to a few thousand people worldwide – and it is still far from FDA approval. The group Cancer Research UK urged patience in looking to CimaVax, in a statement released last year. “This research is promising but this is a small trial and we will need more trial results before we know exactly how well the vaccine works for people with lung cancer. A phase 3 trial is currently in progress in Cuba,” they said in a statement. President Barack Obama announced the U.S. was “extending a hand of friendship” to Cuba in December 2014. The cooperation between Cuban and American doctors began with an April 2015 trade mission, headed by Gov. Andrew Cuomo of New York. Since then, the U.S. has restored up to 110 daily flights to Havana. Cuomo said this week that the new trials were part of a “success story” in Buffalo. “With Roswell Park at the forefront of world-renowned medical research, we are this much closer to making a breakthrough that will combat cancer and save lives,” the governor said. If the vaccine ultimately does improve survival rates, it could be a huge breakthrough for American health. Each year, an estimated 220,000 people in the U.S. are diagnosed with the disease, and 150,000 die of it annually, according to the American Cancer Society.


News Article | October 28, 2016
Site: www.prweb.com

New York Gov. Andrew Cuomo today announced that a partnership formed during his historic New York State Trade Mission to Cuba last year has resulted in a milestone of international collaboration: the launch of a U.S. clinical trial of a Cuban immunotherapy developed by the Center of Molecular Immunology (CIM) for lung cancer. Buffalo, N.Y.-based Roswell Park Cancer Institute has received authorization from the U.S. Food and Drug Administration (FDA) to begin offering the lung cancer treatment vaccine CIMAvax-EGF® to a limited number of patients through a clinical trial, making the National Cancer Institute-designated comprehensive cancer center the first American institution to receive FDA permission to sponsor testing of a Cuban medical therapy in the United States. Roswell Park has also received authorization from the U.S. Department of the Treasury to establish a joint business venture with the CIM, which will be the first U.S.–Cuban joint venture licensed to undertake research, development, manufacture and marketing of biotech products. “This groundbreaking trial at Roswell Park is the result of our historic partnership with Cuba, and is a testament to New York’s storied legacy as a national leader in progress and innovation,” Governor Cuomo says. “With Roswell Park at the forefront of world-renowned medical research, we are this much closer to making a breakthrough that will combat cancer and save lives. This latest milestone marks another chapter in Buffalo’s success story, and we look forward to seeing the impacts of this partnership resonate in New York and across the nation.” CIMAvax-EGF was developed over the course of 25 years by researchers at the CIM, which is located in Havana, Cuba. Gov. Cuomo’s April 2015 trade mission enabled Roswell Park and the CIM to come together through a formal agreement and fast-tracked their collaboration. The new study, expected to open in November 2016, represents a convergence of the strategic visions of both state and federal leaders. “We are grateful to Governor Andrew Cuomo for setting us on the path to this momentous announcement and to the White House and the federal departments of State, Commerce, Treasury and Health & Human Services for working with us on this, supporting and enlightening our path toward this collaborative relationship. This would not have happened without the vision of Governor Cuomo, who brought New York state leaders to Cuba, foreshadowing the enhanced collaborations between our two countries,” says Roswell Park President and CEO Candace S. Johnson, PhD. “The goals of this clinical trial — to speed and enrich the best ideas for defeating cancer — align perfectly with the White House’s bold Cancer Moonshot effort, led with such inspiration and vision by Vice President Biden. The promise of our collaborative research, the affinity that grew between Roswell Park and the Center for Molecular Immunology in Cuba and the pace at which our collaboration has grown are testaments to the fact that these are the right steps at the right time,” adds Dr. Johnson, who, along with Kelvin Lee, MD, Jacobs Family Chair in Immunology at Roswell Park, was invited to take part in Gov. Cuomo’s 2015 trade mission to Cuba. “This is a day we have been working toward for many years,” says CIM Director Agustín Lage, MD, PhD. “Our partnership with Roswell Park will allow us to learn things about our vaccine faster than what we could achieve working on our own, and we believe it is the best and quickest path for helping a great number of people both in Cuba and the U.S.” The Roswell Park–CIM joint venture initiative, negotiation and establishment of which is now authorized by a new license from the Office of Foreign Assets Control, will enable expanded collaborative research and development activities in the U.S. and Cuba on the part of CIMAB S.A., the commercial arm of the CIM, and Roswell Park subsidiary Global Biotechnology & Cancer Therapeutics (GBCT). “This is a historic time with historic opportunities to break down barriers and combine efforts,” says Thomas Schwaab, MD, PhD, an immunologist and urologic oncologist who serves as Chief of Strategy, Business Development and Outreach at Roswell Park and a founding member of GBCT. “Roswell Park and the CIM have so much to learn from one another. The whole goal of our groundbreaking clinical and commercial collaborations is to unite ideas and resources to maximize the possible benefits for patients worldwide, as quickly as possible.” Roswell Park will be the only site for the new clinical trial, a phase I/II study of CIMAvax-EGF in combination with another immunotherapy, the checkpoint inhibitor nivolumab (Opdivo®). The study, which will be funded largely by donations through the Roswell Park Alliance Foundation, will take roughly three years to complete, and will enroll approximately 60–90 patients. Studies have shown that nivolumab, the approved second-line standard therapy, is comparatively effective in treating lung cancer recurrence. The Roswell Park study, to be conducted under the leadership of Principal Investigator Grace Dy, MD, will assess whether these two immunotherapies are more effective when given together as a combination. “Lung cancer is the leading cause of cancer-related death in the United States, with a five-year survival rate of only 17 percent, and rates that are even lower for the many whose disease is already at an advanced stage when they’re diagnosed. We need to be able to offer patients something that improves these odds,” says Dr. Dy, Chief of Thoracic Oncology in the Department of Medicine at Roswell Park. “We’re at an early stage in the development of this vaccine, which has never before been given to U.S. patients, so we have a lot to learn through this study, but the evidence so far is encouraging.” More than 4,000 lung cancer patients have been treated with CIMAvax-EGF in worldwide clinical trials. The most recent, a randomized phase III study conducted by CIM scientists, showed that patients treated with the vaccine had significantly improved overall survival and quality of life compared to lung cancer patients who did not receive the vaccine, and with minimal side effects. CIMAvax is an approved therapy not only in Cuba but also in Bosnia and Herzegovina, Colombia, Paraguay and Peru. Roswell Park researchers believe that CIMAvax-EGF may one day prove effective in preventing primary lung cancers — and possibly as a treatment for other cancers, such as head and neck, colon, breast, prostate and pancreas cancers. “Because this is the first U.S. clinical trial of CIMAvax, we have to focus our efforts at this early stage on seeing whether the vaccine works as well in our patients as it seemed to in the Cuban studies, and how it works in combination with nivolumab,” says Roswell Park’s Dr. Lee, one of the key figures in forging the collaboration with the CIM. “But what we find so intriguing is the possibility that CIMAvax might actually help to prevent some cancers from developing — particularly in people who are at high risk of developing lung cancer — and that it might also be effective against some other cancers. Those are things we may look into down the road, but we need to start at step one with this first study.” Congressman Brian Higgins says, "Roswell Park Cancer Institute is a special place, home to the best medical professionals and researchers fighting alongside those diagnosed with cancer each and every day. The new partnership between Roswell Park Cancer Institute and CIM, supported by Governor Cuomo, has the potential to revolutionize lung cancer treatment – giving more people the care and hope they deeply deserve and need. This partnership shows what is possible when the talent and ambition of doctors and researchers is combined with a will to improve the world around us – and it’s happening right here in Buffalo.” Lieutenant Governor Kathy Hochul says, “Today’s announcement is further evidence that the eyes of the world are on Buffalo like never before, bolstered by strategic investments and international relationships. By reaching across borders and bringing together the brightest minds in the medical research field, this first-in-the-nation project brings the real potential to save lives.” Assemblywoman Crystal Peoples-Stokes says, “New York has a long history of leadership in pioneering innovative medical research, and this latest momentous project puts New York on the forefront of the latest advancements in medical care and cancer treatment. Thanks to Governor Cuomo’s commitment to the global exchange of ideas, patients in need will be able to access this potentially life-saving treatment. Today’s announcement will bring new hope to patients and families in New York, and I look forward to seeing other states follow Governor Cuomo’s inspiring leadership on this issue.” Mayor Byron Brown says, “The future of New York State depends on us building a strong and healthy generation today. The Buffalo region, with unprecedented attention from New York State, has established itself as a capital of innovation and expertise in every sector from biology to technology – and now, we are a home for hope. I applaud Governor Cuomo for bridging the partnership between Roswell Park and CIM as they work to further development of this promising treatment for cancer, and pledge my continued support in advancing our collective fight against cancer for a brighter tomorrow.” Empire State Development President, CEO & Commissioner Howard Zemsky says, “When I travelled to Cuba last year with Governor Cuomo and Dr. Johnson, we were eager to facilitate relationships between New York State and Cuba and today we can proudly say that our historic New York Trade Mission to Cuba may save lives. As the first American center to receive FDA authorization to sponsor a clinical trial of a Cuban immunotherapy, Roswell Park will be helping to lead the fight against cancer.” To learn more about the new clinical trial of CIMAvax-EGF and nivolumab for patients with advanced non-small cell lung cancer, please visit RoswellPark.org/cancer-vaccine or call 1-877-ASK-RPCI (1-877-275-7724). For an online version of this release, please visit: https://www.roswellpark.org/media/news/gov-cuomo-announces-landmark-roswell-park-study-bringing-cuban-lung-cancer-vaccine-us The mission of Roswell Park Cancer Institute (RPCI) is to understand, prevent and cure cancer. Founded in 1898, RPCI is one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in Upstate New York. The Institute is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs. For more information, visit http://www.roswellpark.org, call 1-877-ASK-RPCI (1-877-275-7724) or email askrpci@roswellpark.org. Follow Roswell Park on Facebook and Twitter.


Renaudineau Y.,European University of Brittany | Renaudineau Y.,Brest University Hospital Center | Renaudineau Y.,Brest University Medical School Hospital | Garaud S.,European University of Brittany | And 7 more authors.
Clinical Reviews in Allergy and Immunology | Year: 2010

Autoreactive B cells are central in the pathogenesis of autoimmune diseases (AID) not only by producing autoantibodies but also by secreting cytokines and by presenting autoantigens. Changes in DNA methylation, histone modifications, and miRNA expression, the hallmarks of epigenetic failure, characterize B cells isolated from patients with AID, highlighting the contribution of epigenetic processes to autoreactivity. Additional evidence of epigenetic involvement in the development of B cell autoreactivity comes from in vivo and in vitro studies using DNA demethylating agents as accelerating factors or histone deacetylase inhibitors as repressing factors. As a result, a better understanding of the altered epigenetic processes in AID and in particular in B cells opens perspectives for the development of new therapeutics. © 2009 Humana Press Inc.


Van Rij C.M.,Radboud University Nijmegen | Lutje S.,Radboud University Nijmegen | Frielink C.,Radboud University Nijmegen | Sharkey R.M.,Immunomedics, Inc. | And 8 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2013

Purpose: TF12 is a trivalent bispecific antibody that consists of two anti-TROP-2 Fab fragments and one anti-histamine-succinyl-glycine (HSG) Fab fragment. The TROP-2 antigen is found in many epithelial cancers, including prostate cancer (PC), and therefore this bispecific antibody could be suitable for pretargeting in this cancer. In this study, the characteristics and the potential for pretargeted radioimmunoimaging and radioimmunotherapy with TF12 and the radiolabeled di-HSG peptide IMP288 in mice with human PC were investigated. Methods: The optimal TF12 protein dose, IMP288 peptide dose, and dose interval for PC targeting were assessed in nude mice with s.c. PC3 xenografts. Immuno-positron emission tomography (PET)/CT was performed using TF12/68Ga-IMP288 at optimized conditions. The potential of pretargeted radioimmunotherapy (PRIT) using the TF12 pretargeted 177Lu-IMP288 was determined. Results: TF12 and 111In- IMP288 showed high and fast accumulation in the tumor [20.4 ± 0.6 %ID/g at 1 h post-injection (p.i.)] at optimized conditions, despite the internalizing properties of TF12. The potential for PRIT was shown by retention of 50 % of the 111In-IMP288 in the tumor at 48 h p.i. One cycle of treatment with TF12 and 177Lu-IMP288 showed significant improvement of survival compared to treatment with 177Lu-IMP288 alone (90 vs. 67 days, p < 0.0001) with no renal or hematological toxicity. Conclusion: TROP-2-expressing PC can be pretargeted efficiently with TF12, with very rapid uptake of the radiolabeled hapten-peptide, IMP288, sensitive immuno-PET, and effective therapy. © 2013 Springer-Verlag Berlin Heidelberg.


Coronel J.,Federal University of Rio de Janeiro | Klausing S.,Xell AG | Heinrich C.,Xell AG | Noll T.,Bielefeld University | And 2 more authors.
Biochemical Engineering Journal | Year: 2016

Aiming at increasing productivity in mammalian cell processes, mild hypothermia and supplementation with short-chain fatty acids have been investigated in literature, but usually separately. The combined effects of butyric acid and hypothermia were investigated in a few studies, but despite the lower cytotoxicity of valeric acid no reports were found on its use under low temperatures. In this work, DOE was used to compare supplementation with both butyrate and valerate at 31, 34 and 37 °C to enhance recombinant protein productivity in a CHO cell process. Due to the promising results obtained with valerate, this fatty acid was further investigated. According to the results obtained, 1 mM valeric acid at 31 °C enables high cell viabilities, higher product titres and increases cell specific productivity (qp) by approximately 4-fold. Cell cycle analysis showed that at 31 °C, especially with valerate, a higher percentage of cells was in G0 + G1 phase. Overall, an inverse relation between qp and cell proliferation state [S/(G0 + G1) ratio] was observed. To our knowledge, this is the first work describing the effects of valeric acid under mild hypothermia on CHO cell cultivations. The results provide a promising tool to increase qp under lower proliferation rates, which can be very useful to develop robust high-cell-density, high-productivity perfusion processes. © 2016 Elsevier B.V.


Casaco A.,Center for Molecular Immunology | Fuente D.,Biomodels Unit | Ledon N.,Center for Molecular Immunology | Fernandez A.,Center for Molecular Immunology | Crombet T.,Center for Molecular Immunology
Journal of Cancer Science and Therapy | Year: 2012

Cutaneous wound healing is a complex process involving blood clotting, inflammation, tissue formation, and tissue remodeling. Many experimental and clinical studies have demonstrated varied, but in most cases beneficial, effects of exogenous growth factors on the healing process. The use of targeted anti-cancer agents is increasing. It is common to utilize a multi-modal treatment approach towards solid tumors, often including surgical resection, and it has become apparent that some targeted agents can impair wound healing or cause increasing risk of perioperative complications. There are limited data regarding the wound healing process of anti-cancer target drugs blocking the EGF/EGFR system. The aim of this paper is to review and to comment the effects of anti- EGF/EGFR drugs on the skin wound healing process after programmed or emergency surgical procedures. A review of the current literature, including our own results, was undertaken. We included the monoclonal antibodies cetuximab, panitumumab, nimotuzumab; the small tyrosine kinase molecules erlotinib and gefitinib; and the EGF-based cancer vaccine; CIMAvax and the EGFR-based cancer vaccine; HER-1 vaccine. Apparently, there are no deleterious effects of the anti-EGF/EGFR drugs in the wound healing post-operative process. Taking into account that treatment with anti-EGF/EGFR drugs inhibits tumor cell proliferation, and the lack of deleterious effects of these EGF/EGFR specific inhibitors in the wound healing post-operative process; we suggest that these kinds of drugs could be maintained and their effects tested, with very special surveillance during the post-surgical period. © 2012 Casaco ́ A, et al.


Alpizar Y.A.,Center for Molecular Immunology | Chain B.,University College London | Collins M.K.,University College London | Greenwood J.,University College London | And 3 more authors.
Cancer Immunology, Immunotherapy | Year: 2011

Although cancer immunology has made vigorous progress over the last decade, its future remains uncertain. Tumors have clearly proved subject to immune surveillance, leading to antigenic editing, and means of activating both T and B arms of the immune system have been devised. Therapeutic vaccination and monoclonal antibody therapy have so far proved disappointing, because tumors prove adept at evasion from immune control. Dual targeting could well counteract evasion, provided that the two targets are independent and are attacked simultaneously. This stage has nearly but not quite been reached in several forms of immunotherapy, particularly of B-cell cancers, although such treatment also carries hazards. © 2011 Springer-Verlag.


Prieto Y.,Center for Molecular Immunology | Garcia K.,Center for Molecular Immunology | Ochoa D.,Center for Molecular Immunology
Chromatographia | Year: 2016

Techniques based on high-resolution liquid chromatography are currently widely used to quantify recombinant proteins from culture supernatants. Such assays can be easily and rapidly developed. In this paper, we describe the development and validation of an analytical technique for quantifying HER1 extracellular domain (HER1 ECD) in bioreactor supernatant of HEK 293 transfectomes using reversed-phase chromatography with a C8 column in an HPLC system. The HER1 ECD protein was quantified by monitoring the absorbance of the sample at 214 nm. The resulting analytical methodology was found to provide precise and accurate results for a wide range of concentrations (10–120 µg/mL) of HER1 ECD. The accuracy of the method varied from 86 to 109 % depending on the protein concentration, while the repeatability and the day-to-day intermediate precision were less than 7.25 and 7.85 %, respectively. This methodology constitutes a useful tool that can be applied during the production of the HER1 ECD vaccine. © 2016, Springer-Verlag Berlin Heidelberg.


Figueroa-Morales N.,University of Habana | Leon K.,Center for Molecular Immunology | Mulet R.,University of Habana
Journal of Theoretical Biology | Year: 2012

We develop a stochastic model to study the specific response of the immune system. The model is based on the dynamical interaction between Regulatory and Effector CD4+ T cells in the presence of Antigen Presenting Cells inside a lymphatic node. At a mean field level the model predicts the existence of different regimes where active, tolerant, or cyclic immune responses are possible. To study the model beyond mean field and to understand the specific responses of the immune system we use the Linear Noise Approximation and show that fluctuations due to finite size effects may strongly alter the mean field scenario. Moreover, it was found that the existence of a certain characteristic frequency for the fluctuations. All the analytical predictions were compared with simulations using Gillespie's algorithm. © 2011 Elsevier Ltd.

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