Imiter la réponse immunitaire humorale polyclonale : de l'association de deux anticorps monoclonaux aux productions oligoclonales

International audienceMonoclonal antibodies have revolutionized the treatment of many diseases, but their clinical effectiveness remains limited in some cases. Associations of antibodies binding to the same target (homo-combination) or to several different targets (hetero-combination), thereby mimicking a polyclonal humoral immune response, have demonstrated a therapeutic improvement in pre-clinical and clinical trials, mainly in the field of oncology and infectious diseases. The combinations increase the efficacy of the biological responses and override resistance mechanisms observed with antibody monotherapy. The most common method of formulating and administering antibody combinations is a separate formulation, with sequential injection of each antibody as individual drug substance. Alternatively, combined formulations are developed where the separately-produced antibodies are mixed before administration or produced simultaneously by a single cell line, or a mixture of cell lines as a polyclonal master cell bank. The regulation, the toxicity and the injection sequence of these oligoclonal antibody-based mixtures remain points to be clarified and optimized for a better therapeutic effect.Les anticorps monoclonaux ont révolutionné le traitement de nombreuses maladies mais leur efficacité clinique reste limitée dans certains cas. Des associations d'anticorps se liant à une même cible (homo-combinaisons) ou à plusieurs cibles différentes (hétéro-combinaisons), mimant ainsi une réponse immunitaire humorale polyclonale, ont conduit à une amélioration thérapeutique dans des essais précliniques et cliniques, essentiellement en cancérologie et en infectiologie. Ces combinaisons augmentent l'efficacité des réponses biologiques et court-circuitent les mécanismes de résistances observés lors d'une monothérapie par anticorps. Le procédé de formulation et d'administration des combinaisons d'anticorps le plus fréquent est une formulation séparée, avec injection séquentielle de chaque anticorps « principe actif ». Alternativement, se développent des formulations combinées, où les anticorps produits séparément sont mélangés avant administration, ou produits simultanément par une lignée cellulaire unique ou un mélange de lignées cellulaires correspondant à une master-bank 2 cellulaire polyclonale. La réglementation, la toxicité et la séquence d'injection des mélanges oligoclonaux restent des points à éclaircir et à optimiser pour un meilleur effet thérapeutique

Letrozole sensitizes breast cancer cells to ionizing radiation

INTRODUCTION: Radiotherapy (RT) is considered a standard treatment option after surgery for breast cancer. Letrozole, an aromatase inhibitor, is being evaluated in the adjuvant setting. We determined the effects of the combination of RT and letrozole in the aromatase-expressing breast tumour cell line MCF-7CA, stably transfected with the CYP19 gene. METHODS: Irradiations were performed using a cobalt-60 source with doses ranging from 0 to 4 Gy. Cells were incubated with androstenedione in the presence or absence of letrozole. Effects of treatment were evaluated using clonogenic assays, tetrazolium salt colorimetric (MTT) assays, and cell number determinations. Cell-cycle analyses were conducted using flow cytometry. RESULTS: The survival fraction at 2 Gy was 0.66 for RT alone and was 0.44 for RT plus letrozole (P = 0.02). Growth of MCF-7CA cells as measured by the cell number 6 days after radiotherapy (2 and 4 Gy) was decreased by 76% in those cells treated additionally with letrozole (0.7 μM) compared with those receiving radiotherapy alone (P = 0.009). Growth inhibition, assessed either by cell number (P = 0.009) or by the MTT assay (P = 0.02), was increased after 12 days of the combination treatment. Compared with radiation alone, the combination of radiation and letrozole produced a significant decrease in radiation-induced G(2 )phase arrest and a decrease of cells in the S phase, with cell redistribution in the G(1 )phase. CONCLUSIONS: These radiobiological results may form the basis for concurrent use of letrozole and radiation as postsurgical adjuvant therapy for breast cancer

Agricultural Recovery: Food Security and Beyond

Burundi is still experiencing a major food crisis. One important element that will help to avoid new episodes of violence is revised agricultural policies that support sustainable food security. Food crops and livestock supply 91 percent of agricultural GDP and the major livelihood for most households, thus it is essential to promote production and commercialization of subsistence crops and livestock. These subsectors currently perform poorly and foster a chronic food deficit, a condition that underlines the extreme vulnerability of the population to production-related risks. With food demand increasing at an annual rate of 3 to 6 percent, it is urgent to improve the contribution of the subsistence crops and livestock subsectors. The potential for improvement is great, and beyond the need for reforms that will benefit all sectors, improvements will require public investments to enhance productivity and better market access. Necessary changes in the short-run include fostering the use of high quality seed and fertilizer, and improving the management of small livestock. In the long run, research-extension links should be strengthened, producer organizations should be encouraged and supported, and sustainable land and water management practices should be promoted. Investments in infrastructure and market intelligence will need to meet demands generated by the development of urban centers and foster competitiveness of Burundian agricultural commodities relative to those from the region. This chapter explains the food security issue in Burundi and identifies priority actions that will help overcome the major obstacles that prevent growth and improvement of the subsistence crops and livestock subsectors.Burundi; agriculture; food security

Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts

Background: Pancreatic carcinoma remains a treatment-refractory cancer with a poor prognosis. Here, we compared anti-epidermal growth factor receptor (EGFR) and anti-HER2 monoclonal antibodies (2mAbs) injections with standard gemcitabine treatment on human pancreatic carcinoma xenografts. Materials and methods: Nude mice, bearing human pancreatic carcinoma xenografts, were treated with either combined anti-EGFR (cetuximab) and anti-HER2 (trastuzumab) or gemcitabine, and tumor growth was observed. Results and conclusion: In first-line therapy, mice survival was significantly longer in the 2mAbs group compared with gemcitabine (P < 0.0001 for BxPC-3, P = 0.0679 for MiaPaCa-2 and P = 0.0019 for Capan-1) and with controls (P < 0.0001). In second-line therapy, tumor regressions were observed after replacing gemcitabine by 2mAbs treatment, resulting in significantly longer animal survival compared with mice receiving continuous gemcitabine injections (P = 0.008 for BxPC-3, P = 0.05 for MiaPaCa-2 and P < 0.001 for Capan-1). Therapeutic benefit of 2mAbs was observed despite K-Ras mutation. Interestingly, concerning the mechanism of action, coinjection of F(ab′)2 fragments from 2mAbs induced significant tumor growth inhibition, compared with controls (P = 0.001), indicating that the 2mAbs had an Fc fragment-independent direct action on tumor cells. This preclinical study demonstrated a significant improvement of survival and tumor regression in mice treated with anti-EGFR/anti-HER2 2mAbs in first- and second-line treatments, compared with gemcitabine, independently of the K-Ras statu

HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models.

International audienceThe anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling. As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer. We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression. HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy. Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it. Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers. The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells. Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry. HER3 is essential for pertuzumab efficacy in HER2low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers. Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies

Relance agricole: Sécurité alimentaire et plus

Burundi is still experiencing a major food crisis. One important element that will help to avoid new episodes of violence is revised agricultural policies that support sustainable food security. Food crops and livestock supply 91 percent of agricultural GDP and the major livelihood for most households, thus it is essential to promote production and commercialization of subsistence crops and livestock. These subsectors currently perform poorly and foster a chronic food deficit, a condition that underlines the extreme vulnerability of the population to production-related risks. With food demand increasing at an annual rate of 3 to 6 percent, it is urgent to improve the contribution of the subsistence crops and livestock subsectors. The potential for improvement is great, and beyond the need for reforms that will benefit all sectors, improvements will require public investments to enhance productivity and better market access. Necessary changes in the short-run include fostering the use of high quality seed and fertilizer, and improving the management of small livestock. In the long run, research-extension links should be strengthened, producer organizations should be encouraged and supported, and sustainable land and water management practices should be promoted. Investments in infrastructure and market intelligence will need to meet demands generated by the development of urban centers and foster competitiveness of Burundian agricultural commodities relative to those from the region. This chapter explains the food security issue in Burundi and identifies priority actions that will help overcome the major obstacles that prevent growth and improvement of the subsistence crops and livestock subsectors

Agricultural Recovery: Food Security and Beyond

Burundi is still experiencing a major food crisis. One important element that will help to avoid new episodes of violence is revised agricultural policies that support sustainable food security. Food crops and livestock supply 91 percent of agricultural GDP and the major livelihood for most households, thus it is essential to promote production and commercialization of subsistence crops and livestock. These subsectors currently perform poorly and foster a chronic food deficit, a condition that underlines the extreme vulnerability of the population to production-related risks. With food demand increasing at an annual rate of 3 to 6 percent, it is urgent to improve the contribution of the subsistence crops and livestock subsectors. The potential for improvement is great, and beyond the need for reforms that will benefit all sectors, improvements will require public investments to enhance productivity and better market access. Necessary changes in the short-run include fostering the use of high quality seed and fertilizer, and improving the management of small livestock. In the long run, research-extension links should be strengthened, producer organizations should be encouraged and supported, and sustainable land and water management practices should be promoted. Investments in infrastructure and market intelligence will need to meet demands generated by the development of urban centers and foster competitiveness of Burundian agricultural commodities relative to those from the region. This chapter explains the food security issue in Burundi and identifies priority actions that will help overcome the major obstacles that prevent growth and improvement of the subsistence crops and livestock subsectors

Agricultural Recovery: Food Security and Beyond

Burundi is still experiencing a major food crisis. One important element that will help to avoid new episodes of violence is revised agricultural policies that support sustainable food security. Food crops and livestock supply 91 percent of agricultural GDP and the major livelihood for most households, thus it is essential to promote production and commercialization of subsistence crops and livestock. These subsectors currently perform poorly and foster a chronic food deficit, a condition that underlines the extreme vulnerability of the population to production-related risks. With food demand increasing at an annual rate of 3 to 6 percent, it is urgent to improve the contribution of the subsistence crops and livestock subsectors. The potential for improvement is great, and beyond the need for reforms that will benefit all sectors, improvements will require public investments to enhance productivity and better market access. Necessary changes in the short-run include fostering the use of high quality seed and fertilizer, and improving the management of small livestock. In the long run, research-extension links should be strengthened, producer organizations should be encouraged and supported, and sustainable land and water management practices should be promoted. Investments in infrastructure and market intelligence will need to meet demands generated by the development of urban centers and foster competitiveness of Burundian agricultural commodities relative to those from the region. This chapter explains the food security issue in Burundi and identifies priority actions that will help overcome the major obstacles that prevent growth and improvement of the subsistence crops and livestock subsectors

Relance agricole: Sécurité alimentaire et plus

Burundi is still experiencing a major food crisis. One important element that will help to avoid new episodes of violence is revised agricultural policies that support sustainable food security. Food crops and livestock supply 91 percent of agricultural GDP and the major livelihood for most households, thus it is essential to promote production and commercialization of subsistence crops and livestock. These subsectors currently perform poorly and foster a chronic food deficit, a condition that underlines the extreme vulnerability of the population to production-related risks. With food demand increasing at an annual rate of 3 to 6 percent, it is urgent to improve the contribution of the subsistence crops and livestock subsectors. The potential for improvement is great, and beyond the need for reforms that will benefit all sectors, improvements will require public investments to enhance productivity and better market access. Necessary changes in the short-run include fostering the use of high quality seed and fertilizer, and improving the management of small livestock. In the long run, research-extension links should be strengthened, producer organizations should be encouraged and supported, and sustainable land and water management practices should be promoted. Investments in infrastructure and market intelligence will need to meet demands generated by the development of urban centers and foster competitiveness of Burundian agricultural commodities relative to those from the region. This chapter explains the food security issue in Burundi and identifies priority actions that will help overcome the major obstacles that prevent growth and improvement of the subsistence crops and livestock subsectors