The Experts below are selected from a list of 87 Experts worldwide ranked by ideXlab platform
Roisin E Ocearbhaill - One of the best experts on this subject based on the ideXlab platform.
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a phase i study of unimolecular pentavalent globo h gm2 stn tf tn immunization of patients with epithelial ovarian fallopian tube or peritoneal cancer in first remission
Cancers, 2016Co-Authors: Roisin E Ocearbhaill, Maria Spassova, Govind Ragupathi, Jianglong Zhu, Qian Wan, Svetlana Mironov, Guangbin Yang, Alexia Iasonos, Sara Kravetz, Ouathek OuerfelliAbstract:We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent Carbohydrate Vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient’s pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The Vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent Vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.
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890punimolecular pentavalent globo h gm2 stn tf tn immunization of patients pts with epithelial ovarian eoc fallopian tube or peritoneal cancer in first remission
Annals of Oncology, 2014Co-Authors: Roisin E Ocearbhaill, Govind Ragupathi, Alexia Iasonos, Samuel J Danishefsky, Paul SabbatiniAbstract:ABSTRACT Aim: We conducted an IRB-approved phase I study to evaluate the safety and immunogenicity of a unimolecular pentavalent Carbohydrate Vaccine, bearing five antigens (AGs), Globo-H, GM2, STn, TF and Tn conjugated to keyhole limpet hemocyanin(KLH) and mixed with QS-21 adjuvant, in EOC pts in 1st remission. We previously demonstrated the safe induction of antibody (ab) responses to these individual AGs in a series of monovalent-KLH trials. Methods: Pts with stage III or IV OC in 1st remission were enrolled from 1/2011-09/2013. Three dose levels were planned (25, 50,100mcg) with 3 cohorts of 6 pts to be treated at each dose level (with an additional expansion cohort of 6 pts at the MTD). The schedule was 5 Vaccines administered subcutaneously during weeks 1, 2, 3, 7 and 19. Serologic IgM and IgG responses were measured by ELISA against each AG. Serologic response per AG was defined as 1) Ab titer ≥1:80 for pts with no detectable baseline titer or 2) Ab titer ≥8-fold increase over baseline if detectable baseline titer. If ≥4 of 12 pts treated at the MTD were immune responders for ≥3AGs then the study would be considered positive. Results: n = 24 Median age 56yrs (36-79); 22 (92%) high grade serous; 21 (88%) stage III; 3 (12%) stage IV. No DLTs. Immune Results: IgG +/or IgM: ≥3 AGs 20/24 pts (83%). At MTD 100mcg n = 12: IgG +/or IgM: ≥3 AGs 9/12 pts (75%), ≥4 AGs 7/12 pts (58%), 5 AGs 3/12 pts (25%). IgM: ≥1 AG in pts, ≥3 AGs in pts. IgG: ≥1 AG in pts, ≥3 AGs in pts. With a median follow-up of 19mos (2-39), 8pts (33%) had recurred and 4 pts (17%) had died. Immune Response AG GM2 GM2 GloboH GloboH Tn Tn TF TF sTn sTn Ab IgM IgG IgM IgG IgM IgG IgM IgG IgM IgG n = 12 MTD responders 3 2 1 7 7 10 8 3 11 8 Conclusions: The unimolecular Vaccine was shown to be safe and immunogenic. 9/12 (75%) pts at MTD (83% of all treated pts) responded to ≥3 AGs. This immune response was comparable to our previously reported immune response in a phase I trial of a heptavalent Vaccine with individual antigens conjugated to KLH. The unimolecular construct warrants further investigation and permits multiple AG-targeting. The construct greatly simplifies manufacturing and allows easy scalability of the Vaccine. Disclosure: S. Danishefsky: Dr Danifshesky has financial interest in the Vaccine being studied. MSKCC holds the patent on this invention. All other authors have declared no conflicts of interest.
Dennis R. Burton - One of the best experts on this subject based on the ideXlab platform.
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2G12-Expressing B Cell Lines May Aid in HIV Carbohydrate Vaccine Design Strategies
Journal of Virology, 2012Co-Authors: Katherine Doores, Khoa M. Le, Colleen Doyle-cooper, Anthony B. Cooper, Ralph Pantophlet, Sheng-kai Wang, David Nemazee, Chi-huey Wong, Michael Huber, Dennis R. BurtonAbstract:The highly conserved cluster of high-mannose glycans on the HIV-1 envelope glycoprotein, gp120, has been highlighted as a target for neutralizing antibodies. 2G12, the first HIV-1 antiglycan neutralizing antibody described, binds with an unusual domain-exchanged structure that creates a high-affinity multivalent binding surface. It is an interesting challenge for rational Vaccine design to generate immunogens capable of eliciting domain-exchanged 2G12-like responses. We recently showed that di-mannose recognition by the variable domains of 2G12 is independent of domain exchange but that exchange is critical for virus neutralization. Carbohydrate-based immunogens aimed at inducing 2G12-like antibodies may need to drive both di-mannose recognition and domain exchange through interactions with B cell receptors. Here we assessed the ability of such immunogens to activate mouse B cell lines displaying domain-exchanged wild-type 2G12 (2G12 WT), a non-domain-exchanged Y-shaped variant (2G12 I19R), and germ line 2G12 (2G12 gl). We show that several immunogens, including heat-killed yeast and bacteria, can activate both 2G12 WT and 2G12 I19R B cells. However, only discrete clusters of high-mannose glycans, as on recombinant forms of the HIV-1 envelope trimer and oligodendrons, activate 2G12 WT B cells. Furthermore, no immunogen tested activated 2G12 gl cells. Our results support the hypothesis that in order to drive domain exchange of an antimannose antibody response, a boost with an immunogen displaying discrete clusters of high-mannose glycans not recognized by conventional Y-shaped antibodies will be required. Additionally, a molecule capable of activating 2G12 gl cells might also be required. The results highlight broadly neutralizing antibody-expressing mouse B cells as potentially useful tools for Carbohydrate immunogen screening.
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Carbohydrate Vaccines developing sweet solutions to sticky situations
Nature Reviews Drug Discovery, 2010Co-Authors: Rena D Astronomo, Dennis R. BurtonAbstract:Recent technological advances in glycobiology and glycochemistry are paving the way for a new era in Carbohydrate Vaccine design. This is enabling greater efficiency in the identification, synthesis and evaluation of unique glycan epitopes found on a plethora of pathogens and malignant cells. Here, we review the progress being made in addressing challenges posed by targeting the surface Carbohydrates of bacteria, protozoa, helminths, viruses, fungi and cancer cells for Vaccine purposes.
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Carbohydrate Vaccines: developing sweet solutions to sticky situations?
Nature Reviews Drug Discovery, 2010Co-Authors: Rena D Astronomo, Dennis R. BurtonAbstract:Antibiotic drug resistance has increased interest in developing Vaccines against Carbohydrate structures on the surface of bacterial pathogens. Astronomo and Burton examine recent progress in the identification, synthesis and evaluation of glycan epitopes found not only on bacteria, but also on protozoa, helminths, viruses, fungi and cancer cells for Vaccine design. Carbohydrate structures decorate the surface of pathogens and malignant cells and could be exploited as potential targets for Vaccine design. Indeed, most Vaccines against bacterial infections are Carbohydrate Vaccines. The steady increase in drug resistance has catalysed a renewed interest in Carbohydrate Vaccine development against a wide range of pathogens (that is, bacteria, fungi, protozoa, helminths and viruses) as well as cancer. Recent advances in glycomics, particularly Carbohydrate synthesis, protein conjugation methods, analysis, structural determination and array fabrication, are accelerating progress in the Carbohydrate Vaccine field. For example, improvements in synthetic methods facilitate the identification and evaluation of potential glycan antigens by providing usable amounts of pure material. A number of challenges are associated with targeting glycan structures in a Vaccine context. Generally speaking, the main challenges include the poor immunogenicity of Carbohydrates, low affinity of protein–Carbohydrate interactions, structural diversity of glycans between species and/or strains and microheterogeneity. A major breakthrough in improving immunogenicity came with the discovery that chemical conjugation of glycans to a suitable protein scaffold can convert Carbohydrates from T-cell-independent antigens to T-cell-dependent antigens. Co-administration of adjuvants has also been shown to improve the strength of the immune response against Carbohydrate immunogens. Certain pathogen-associated Carbohydrate antigens as well as tumour-associated Carbohydrate antigens may be poorly immunogenic owing to the expression of similar or identical structures in humans, albeit at a lower density or during early developmental stages. To address this issue, strategies are being developed to better mimic the presentation (for example, clustering) of glycans on target cells or organisms and to introduce conservative chemical modifications to the target antigens to render them more immunogenic. The ability to elicit specific, potent and long-lasting anti-Carbohydrate antibody responses that are therapeutic and/or protect against diseases caused by pathogens or tumours is a complex goal dependent on the antigen(s) and the disease. In many cases, the mechanisms of disease and potential of antibody-mediated protection need further clarification to facilitate the development of more effective Vaccines or passive immunization approaches. Recent technological advances in glycobiology and glycochemistry are paving the way for a new era in Carbohydrate Vaccine design. This is enabling greater efficiency in the identification, synthesis and evaluation of unique glycan epitopes found on a plethora of pathogens and malignant cells. Here, we review the progress being made in addressing challenges posed by targeting the surface Carbohydrates of bacteria, protozoa, helminths, viruses, fungi and cancer cells for Vaccine purposes.
Ouathek Ouerfelli - One of the best experts on this subject based on the ideXlab platform.
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a phase i study of unimolecular pentavalent globo h gm2 stn tf tn immunization of patients with epithelial ovarian fallopian tube or peritoneal cancer in first remission
Cancers, 2016Co-Authors: Roisin E Ocearbhaill, Maria Spassova, Govind Ragupathi, Jianglong Zhu, Qian Wan, Svetlana Mironov, Guangbin Yang, Alexia Iasonos, Sara Kravetz, Ouathek OuerfelliAbstract:We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent Carbohydrate Vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient’s pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The Vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent Vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.
Alexia Iasonos - One of the best experts on this subject based on the ideXlab platform.
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a phase i study of unimolecular pentavalent globo h gm2 stn tf tn immunization of patients with epithelial ovarian fallopian tube or peritoneal cancer in first remission
Cancers, 2016Co-Authors: Roisin E Ocearbhaill, Maria Spassova, Govind Ragupathi, Jianglong Zhu, Qian Wan, Svetlana Mironov, Guangbin Yang, Alexia Iasonos, Sara Kravetz, Ouathek OuerfelliAbstract:We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent Carbohydrate Vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient’s pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The Vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent Vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.
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890punimolecular pentavalent globo h gm2 stn tf tn immunization of patients pts with epithelial ovarian eoc fallopian tube or peritoneal cancer in first remission
Annals of Oncology, 2014Co-Authors: Roisin E Ocearbhaill, Govind Ragupathi, Alexia Iasonos, Samuel J Danishefsky, Paul SabbatiniAbstract:ABSTRACT Aim: We conducted an IRB-approved phase I study to evaluate the safety and immunogenicity of a unimolecular pentavalent Carbohydrate Vaccine, bearing five antigens (AGs), Globo-H, GM2, STn, TF and Tn conjugated to keyhole limpet hemocyanin(KLH) and mixed with QS-21 adjuvant, in EOC pts in 1st remission. We previously demonstrated the safe induction of antibody (ab) responses to these individual AGs in a series of monovalent-KLH trials. Methods: Pts with stage III or IV OC in 1st remission were enrolled from 1/2011-09/2013. Three dose levels were planned (25, 50,100mcg) with 3 cohorts of 6 pts to be treated at each dose level (with an additional expansion cohort of 6 pts at the MTD). The schedule was 5 Vaccines administered subcutaneously during weeks 1, 2, 3, 7 and 19. Serologic IgM and IgG responses were measured by ELISA against each AG. Serologic response per AG was defined as 1) Ab titer ≥1:80 for pts with no detectable baseline titer or 2) Ab titer ≥8-fold increase over baseline if detectable baseline titer. If ≥4 of 12 pts treated at the MTD were immune responders for ≥3AGs then the study would be considered positive. Results: n = 24 Median age 56yrs (36-79); 22 (92%) high grade serous; 21 (88%) stage III; 3 (12%) stage IV. No DLTs. Immune Results: IgG +/or IgM: ≥3 AGs 20/24 pts (83%). At MTD 100mcg n = 12: IgG +/or IgM: ≥3 AGs 9/12 pts (75%), ≥4 AGs 7/12 pts (58%), 5 AGs 3/12 pts (25%). IgM: ≥1 AG in pts, ≥3 AGs in pts. IgG: ≥1 AG in pts, ≥3 AGs in pts. With a median follow-up of 19mos (2-39), 8pts (33%) had recurred and 4 pts (17%) had died. Immune Response AG GM2 GM2 GloboH GloboH Tn Tn TF TF sTn sTn Ab IgM IgG IgM IgG IgM IgG IgM IgG IgM IgG n = 12 MTD responders 3 2 1 7 7 10 8 3 11 8 Conclusions: The unimolecular Vaccine was shown to be safe and immunogenic. 9/12 (75%) pts at MTD (83% of all treated pts) responded to ≥3 AGs. This immune response was comparable to our previously reported immune response in a phase I trial of a heptavalent Vaccine with individual antigens conjugated to KLH. The unimolecular construct warrants further investigation and permits multiple AG-targeting. The construct greatly simplifies manufacturing and allows easy scalability of the Vaccine. Disclosure: S. Danishefsky: Dr Danifshesky has financial interest in the Vaccine being studied. MSKCC holds the patent on this invention. All other authors have declared no conflicts of interest.
Govind Ragupathi - One of the best experts on this subject based on the ideXlab platform.
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a phase i study of unimolecular pentavalent globo h gm2 stn tf tn immunization of patients with epithelial ovarian fallopian tube or peritoneal cancer in first remission
Cancers, 2016Co-Authors: Roisin E Ocearbhaill, Maria Spassova, Govind Ragupathi, Jianglong Zhu, Qian Wan, Svetlana Mironov, Guangbin Yang, Alexia Iasonos, Sara Kravetz, Ouathek OuerfelliAbstract:We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent Carbohydrate Vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient’s pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The Vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent Vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.
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890punimolecular pentavalent globo h gm2 stn tf tn immunization of patients pts with epithelial ovarian eoc fallopian tube or peritoneal cancer in first remission
Annals of Oncology, 2014Co-Authors: Roisin E Ocearbhaill, Govind Ragupathi, Alexia Iasonos, Samuel J Danishefsky, Paul SabbatiniAbstract:ABSTRACT Aim: We conducted an IRB-approved phase I study to evaluate the safety and immunogenicity of a unimolecular pentavalent Carbohydrate Vaccine, bearing five antigens (AGs), Globo-H, GM2, STn, TF and Tn conjugated to keyhole limpet hemocyanin(KLH) and mixed with QS-21 adjuvant, in EOC pts in 1st remission. We previously demonstrated the safe induction of antibody (ab) responses to these individual AGs in a series of monovalent-KLH trials. Methods: Pts with stage III or IV OC in 1st remission were enrolled from 1/2011-09/2013. Three dose levels were planned (25, 50,100mcg) with 3 cohorts of 6 pts to be treated at each dose level (with an additional expansion cohort of 6 pts at the MTD). The schedule was 5 Vaccines administered subcutaneously during weeks 1, 2, 3, 7 and 19. Serologic IgM and IgG responses were measured by ELISA against each AG. Serologic response per AG was defined as 1) Ab titer ≥1:80 for pts with no detectable baseline titer or 2) Ab titer ≥8-fold increase over baseline if detectable baseline titer. If ≥4 of 12 pts treated at the MTD were immune responders for ≥3AGs then the study would be considered positive. Results: n = 24 Median age 56yrs (36-79); 22 (92%) high grade serous; 21 (88%) stage III; 3 (12%) stage IV. No DLTs. Immune Results: IgG +/or IgM: ≥3 AGs 20/24 pts (83%). At MTD 100mcg n = 12: IgG +/or IgM: ≥3 AGs 9/12 pts (75%), ≥4 AGs 7/12 pts (58%), 5 AGs 3/12 pts (25%). IgM: ≥1 AG in pts, ≥3 AGs in pts. IgG: ≥1 AG in pts, ≥3 AGs in pts. With a median follow-up of 19mos (2-39), 8pts (33%) had recurred and 4 pts (17%) had died. Immune Response AG GM2 GM2 GloboH GloboH Tn Tn TF TF sTn sTn Ab IgM IgG IgM IgG IgM IgG IgM IgG IgM IgG n = 12 MTD responders 3 2 1 7 7 10 8 3 11 8 Conclusions: The unimolecular Vaccine was shown to be safe and immunogenic. 9/12 (75%) pts at MTD (83% of all treated pts) responded to ≥3 AGs. This immune response was comparable to our previously reported immune response in a phase I trial of a heptavalent Vaccine with individual antigens conjugated to KLH. The unimolecular construct warrants further investigation and permits multiple AG-targeting. The construct greatly simplifies manufacturing and allows easy scalability of the Vaccine. Disclosure: S. Danishefsky: Dr Danifshesky has financial interest in the Vaccine being studied. MSKCC holds the patent on this invention. All other authors have declared no conflicts of interest.