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Vaccines and Antibodies for Therapeutic Use in Cancers  [PDF]
G. P. Talwar, Jagdish C. Gupta, M. Diwan, J. Frick, S. K. Sharma, S. N. Wadhwa, R. M. Gupta, S. K. Gupta, Shilpi Purswani, Hemant K. Vyas
Journal of Cancer Therapy (JCT) , 2016, DOI: 10.4236/jct.2016.76040
Abstract: This review describes briefly the beneficial use of two vaccines developed by us for treatment of cancers. The vaccine against Luteinizing Hormone Releasing Hormone (LHRH) is effective in carcinoma of prostate as well as in breast cancers dependent on androgens and estrogens respectively. LHRH being identical in both males and females, the same vaccine is usable in both Prostate and Breast steroid hormones-dependent-cancers. Monoclonal antibodies are finding therapeutic utility in several cancers, and many have received Drugs Regulatory approval. The monoclonals developed by us against hCG and against epitopes present on androgen-independent castration resistant prostate cancers are briefly recapitulated. Anti-hCG antibodies kill several cancers expressing hCG. An example is given of A549 lung carcinoma. MoAb730 and MoAb7B2G10 kill DU-145 and PC-3 androgen-independent castration resistant prostate cancer cells. Some cancers such as MOLT-4, a T-lymphoblastic leukemia, though expressing hCG are not killed by PiPP, the high affinity anti-hCG antibody. Linking the antibody to curcumin however works like a “Magic Bullet”. All MOLT-4 cells are killed by this conjugate, the antibody homes selectively to cancer cells expressing hCG to deliver curcumin which exercises the killing effect. A recombinant vaccine, hCGβ-LTB (human chorionic gonadotropin subunit β linked to B subunit of heat-labile enterotoxin of E. coli) has been made, which induces high titre bioeffective antibodies not only in BalbC, but also in other genetic strains of mice. The vaccine employs autoclaved Mycobacterium indicus pranii (MiP) as adjuvant. MiP invigorates both humoral and cell mediated immune responses against Human chorionic gonadotropin (hCG). Besides being a potent adjuvant, MiP used alone heals anogenital warts in humans and has the property of preventing and curing SP2/O Myelomas in mice.
Determining the Binding Affinity of Therapeutic Monoclonal Antibodies towards Their Native Unpurified Antigens in Human Serum  [PDF]
Christine Bee, Yasmina N. Abdiche, Jaume Pons, Arvind Rajpal
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080501
Abstract: Monoclonal antibodies (mAbs) are a growing segment of therapeutics, yet their in vitro characterization remains challenging. While it is essential that a therapeutic mAb recognizes the native, physiologically occurring epitope, the generation and selection of mAbs often rely on the use of purified recombinant versions of the antigen that may display non-native epitopes. Here, we present a method to measure both, the binding affinity of a therapeutic mAb towards its native unpurified antigen in human serum, and the antigen’s endogenous concentration, by combining the kinetic exclusion assay and Biacore’s calibration free concentration analysis. To illustrate the broad utility of our method, we studied a panel of mAbs raised against three disparate soluble antigens that are abundant in the serum of healthy donors: proprotein convertase subtilisin/kexin type 9 (PCSK9), progranulin (PGRN), and fatty acid binding protein (FABP4). We also determined the affinity of each mAb towards its purified recombinant antigen and assessed whether the interactions were pH-dependent. Of the six mAbs studied, three did not appear to discriminate between the serum and recombinant forms of the antigen; one mAb bound serum antigen with a higher affinity than recombinant antigen; and two mAbs displayed a different affinity for serum antigen that could be explained by a pH-dependent interaction. Our results highlight the importance of taking pH into account when measuring the affinities of mAbs towards their serum antigens, since the pH of serum samples becomes increasingly alkaline upon aerobic handling.
Distinct expression profiles of Notch-1 protein in human solid tumors: Implications for development of targeted therapeutic monoclonal antibodies
Yuan Li, Janine A Burns, Carol A Cheney, et al
Biologics: Targets and Therapy , 2010, DOI: http://dx.doi.org/10.2147/BTT.S11021
Abstract: tinct expression profiles of Notch-1 protein in human solid tumors: Implications for development of targeted therapeutic monoclonal antibodies Original Research (4507) Total Article Views Authors: Yuan Li, Janine A Burns, Carol A Cheney, et al Published Date June 2010 Volume 2010:4 Pages 163 - 171 DOI: http://dx.doi.org/10.2147/BTT.S11021 Yuan Li1, Janine A Burns1, Carol A Cheney1, Ningyan Zhang1, Salvatore Vitelli1, Fubao Wang1, Andrew Bett2, Michael Chastain2, Laurent P Audoly1, Zhi-Qiang Zhang1,3 1Department of Biologics Research, 2Department of Vaccine Research, Merck Research Laboratories, West Point, PA, USA; 3Clinical Development Laboratory, Merck Research Laboratories, Rahway, NJ, USA Abstract: Biological therapies, such as monoclonal antibodies (mAbs) that target tumor-associated antigens have been considered an effective therapeutic approach in oncology. In considering Notch-1 receptor as a potential target, we performed immunohistochemistry on tissue microarrays to determine 1) whether the receptor is overexpressed in tumor cells as compared to their corresponding normal tissues and 2) the clinical significance of its expression levels in human breast, colorectal, lung and prostate cancers. We found that the expression of Notch-1 protein was overexpressed in primary colorectal adenocarcinoma and nonsmall cell lung carcinoma (NSCLC), but not in primary ductal breast carcinoma or prostate adenocarcinoma. Further analysis revealed that higher levels of Notch-1 protein expression were significantly associated with poorer differentiation of breast and prostate tumors. Strikingly, for NSCLC, the expression levels of Notch-1 protein were found to be inversely correlated with tumor differentiation and progression. For colorectal tumors, however, no correlation of Notch-1 protein expression was found with any tumor clinicopathological parameters, in spite of its overexpression in tumor cells. Our data demonstrated the complexity of Notch-1 protein expression in human solid tumors and further supported the notion that the roles of Notch-1 expression in tumorigenesis are highly context-dependent. The findings could provide the basis for development of distinct therapeutic strategies of Notch-1 mAbs for its applications in the treatment of suitable types of human cancers.
Distinct expression profiles of Notch-1 protein in human solid tumors: Implications for development of targeted therapeutic monoclonal antibodies  [cached]
Yuan Li,Janine A Burns,Carol A Cheney,et al
Biologics: Targets and Therapy , 2010,
Abstract: Yuan Li1, Janine A Burns1, Carol A Cheney1, Ningyan Zhang1, Salvatore Vitelli1, Fubao Wang1, Andrew Bett2, Michael Chastain2, Laurent P Audoly1, Zhi-Qiang Zhang1,31Department of Biologics Research, 2Department of Vaccine Research, Merck Research Laboratories, West Point, PA, USA; 3Clinical Development Laboratory, Merck Research Laboratories, Rahway, NJ, USAAbstract: Biological therapies, such as monoclonal antibodies (mAbs) that target tumor-associated antigens have been considered an effective therapeutic approach in oncology. In considering Notch-1 receptor as a potential target, we performed immunohistochemistry on tissue microarrays to determine 1) whether the receptor is overexpressed in tumor cells as compared to their corresponding normal tissues and 2) the clinical significance of its expression levels in human breast, colorectal, lung and prostate cancers. We found that the expression of Notch-1 protein was overexpressed in primary colorectal adenocarcinoma and nonsmall cell lung carcinoma (NSCLC), but not in primary ductal breast carcinoma or prostate adenocarcinoma. Further analysis revealed that higher levels of Notch-1 protein expression were significantly associated with poorer differentiation of breast and prostate tumors. Strikingly, for NSCLC, the expression levels of Notch-1 protein were found to be inversely correlated with tumor differentiation and progression. For colorectal tumors, however, no correlation of Notch-1 protein expression was found with any tumor clinicopathological parameters, in spite of its overexpression in tumor cells. Our data demonstrated the complexity of Notch-1 protein expression in human solid tumors and further supported the notion that the roles of Notch-1 expression in tumorigenesis are highly context-dependent. The findings could provide the basis for development of distinct therapeutic strategies of Notch-1 mAbs for its applications in the treatment of suitable types of human cancers.Keywords: Notch-1, target therapy, tissue microarray, immunohistochemistry
Generation of Monoclonal Antibodies against Highly Conserved Antigens  [PDF]
Hongzhe Zhou, Yunbo Wang, Wei Wang, Junying Jia, Yuan Li, Qiyu Wang, Yanfang Wu, Jie Tang
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006087
Abstract: Background Therapeutic antibody development is one of the fastest growing areas of the pharmaceutical industry. Generating high-quality monoclonal antibodies against a given therapeutic target is very crucial for the success of the drug development. However, due to immune tolerance, some proteins that are highly conserved between mice and humans are not very immunogenic in mice, making it difficult to generate antibodies using a conventional approach. Methodology/Principal Findings In this report, the impaired immune tolerance of NZB/W mice was exploited to generate monoclonal antibodies against highly conserved or self-antigens. Using two highly conserved human antigens (MIF and HMGB1) and one mouse self-antigen (TNF-alpha) as examples, we demonstrate here that multiple clones of high affinity, highly specific antibodies with desired biological activities can be generated, using the NZB/W mouse as the immunization host and a T cell-specific tag fused to a recombinant antigen to stimulate the immune system. Conclusions/Significance We developed an efficient and universal method for generating surrogate or therapeutic antibodies against “difficult antigens” to facilitate the development of therapeutic antibodies.
Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer  [PDF]
L. Guilleminault, E. Lemarié, N. Heuzé-Vourc’h
Journal of Cancer Therapy (JCT) , 2012, DOI: 10.4236/jct.2012.36153
Abstract: Lung cancer is the leading cause of cancer-related deaths in industrialized countries and non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Cisplatin doublet based chemotherapy, which is the recommended regimen in first line therapy in advanced or metastatic NSCLC, improves survival but in low proportion. Monoclonal antibodies (mAbs) are a novel promising therapeutic class used with great results in inflammatory diseases such as rheumatoid arthritis. Antibodies are natural proteins with modular structure, specific pharmacodynamics and pharmacokinetics and possibly produced against any antigens, thus giving them several advantages over small drug therapeutics. In solid tumors, therapeutic mAbs improved progression free survival (PFS) and overall survival (OS) of patients with breast and colon cancers and had considerably changed the treatment in clinical practice. In NSCLC, bevacizumab, an anti-VEGF mAb, and cetuximab, an anti-EGFR mAb, are the most studied antibodies. Bevacizumab acts on angiognenesis and improved PFS of non squamous NSCLC but in low proportion as shown in two large phase III trials. It was approved by European Medicines Agency (EMEA) and Food and Drug administration (FDA) as a first line therapy in combination with cisplatin doublet chemotherapy. Cetuximab slightly enhanced OS but did not improve PFS in two large phase III trials. These results added to high adverse effect lead to cetuximab refusal by EMEA and FDA in NSCLC. At first glance, the results of mAbs in NSCLC are somewhat disappointing, in contrast to the benefits obtained with mAb treatments in other solid tumors. However, many other mAbs directed against novel targets, such as IGF1-R or CTLA-4, and new mAbs targeting VEGFR and EGFR pathways with different pharmacodymamical and pharmacokinetic properties are under evaluation and may change our vision of taking care of patients with NSCLC. In conclusion, it seems that mAbs therapy in NSCLC clearly marks the start of a new era in NSCLC treatment, with promises in improving patient survival and quality of life.
Optimization And Pharmacokinetics Of Therapeutic Antibodies  [cached]
Tarun Virmani,Prof. Kamla Pathak
Pharmaceutical Reviews , 2007,
Abstract: Since the mid-1990s, antibodies have emerged as an important new class of drug for therapeutic use across diverse clinical settings, including oncology, chronic inflammatory diseases, transplantation, infectious diseases and cardiovascular medicine. The FDA approved antibody therapeutics include 14 unmodified IgG molecules, 2 radioimmunoconjugates, 1 antibody–drug conjugate and 1 Fab.At least 150 additional antibodies are in various stages of clinical development. One of the strengths of antibody therapeutics is that they belong to a well established drug class that has a high success rate from the first use in humans to regulatory approval, the success rate amounting to 29% for chimeric antibodies, and 25% for humanized antibodies 1 . This compares favorably with the 11% success rate for small-molecule drugs 2 . Moreover, much of the development and clinical experience that is gained from the generation and optimization of one antibody is applicable to other antibodies, thereby streamlining certain activities and decreasing some of the many risks that are intrinsic to drug development. In general, antibodies are well tolerated by humans, although infusion reactions (particularly for the first dose) are common but usually manageable 3 . For example, most patients treated with rituximab (Rituxan; Genentech, Inc. and Biogen Idec Inc.; and MabThera; F.Hoffman- LaRoche Ltd) a CD20-specific monoclonal antibody, experience mild to moderate first infusion reactions that include fever and chills, and these reactions occur less frequently with subsequent doses. Infusion reactions with rituximab are commonly attenuated by premedication and by incremental increase in the rate of infusion of rituximab.
Production of monoclonal antibodies against Streptococcus mutans antigens
Canettieri, Antonio Carlos Victor;Kretchetoff, Fujiko Yamasiro;Koga-Ito, Cristiane Yumi;Moreira, Daniella;Fujarra, Fabio José Condino;Unterkircher, Carmelinda Schmidt;
Brazilian Oral Research , 2006, DOI: 10.1590/S1806-83242006000400003
Abstract: several studies have been conducted in the last decades aiming to obtain an anti-caries vaccine, however some studies have demonstrated cross reactivity between streptococcus mutans surface antigens and the human cardiac tissue. in this work, the reactivity of five anti-streptococcus mutans monoclonal antibodies (moab) (24a, 56g, c8, e8 and f6) was tested against oral streptococci, cardiac antigens and skeletal and cardiac myosins, aiming to evaluate the specificity of these moab. the hybrid producers of immunoglobulins of the igg2b class were cloned by limit dilution and expanded in vivo. moab were tested by elisa. the hybrid 24a reacted with s. mutans cct 1910, s. salivarius cct 0365 and s. pyogenes t23. no reactivity difference was observed among the tested species. cross reactivity with heart and cardiac myosin was not confirmed and only reaction with myosin of skeletal muscle was observed (p = 0.0381). the hybrid 56g reacted with all the tested microorganisms and there was statistically significant difference between s. mutans and s. pyogenes t23 (p < 0.001). this hybrid also reacted with myosin of skeletal muscle (p = 0.0095). c8, e8 and f6 presented low reactivity against oral streptococci strains and no reactivity against cardiac antigens. the data of this study showed that the 24a and 56g anti-s. mutans moab presented reactivity with s. pyogenes and s. salivarius, reinforcing the occurrence of common antigens between these species. the tested moab presented low cross-reactivity with myosin of skeletal muscle, but anti-heart activity could not be confirmed.
Evaluation of an Innovative Diagnostic Method for Detection of Antibodies and Antigens  [PDF]
Mandana Asalkhou, Navid Alem, Neda A. Ahmadi, Nina Hamedi, Mehdi Alem
International Journal of Clinical Medicine (IJCM) , 2017, DOI: 10.4236/ijcm.2017.85029
Abstract: Reports manifest a continuing need for the development of rapid and on-site (point of care) assays. Current diagnostic methods commonly used for detection of antibodies and antigens have significant limitations. Scientists at Micro Detect, Inc. have developed an innovative diagnostic device (method) that can be utilized broadly for antibody/antigen interactions including diagnostic assays in the medical, veterinary and food industries. The developed device can be utilized for the detection of antibodies against a single antigen or vice versa. It can also be tailored for specific panels that detect antigens or antibodies for diverse infectious agents, proteins, hormones, tumor markers, autoimmune markers, and allergens. Additionally, it can also be used for detection of toxins, antitoxins, nucleic acids, enzymes, drugs, etc. in both humans and animals. Specimens used in different formats of the device can be tears, saliva, whole blood, serum, plasma, urine, stool, and other bodily discharges. The good intra and inter precisions and acceptable linearity of the device support reliable use of the device. The CV of the device is 1.9% - 2.2%. Likewise, the performance of the device using 92 confirmed negative and positive specimens via a typical assay showed 100% sensitivity, 80% specificity, 96.8% efficacy, 80% positive predictive value, and 100% negative predictive value. The results of our feasibility study suggest reliable utility of a device for rapid, easy-to-use, inexpensive, and on-site (point of care) diagnostic assays. This presents a potential breakthrough in diagnostic methodologies that can be integrated into modern medicine and food industries.
Development of antibodies to human embryonic stem cell antigens
Jingli Cai, Judith M Olson, Mahendra S Rao, Marisa Stanley, Eva Taylor, Hsiao-Tzu Ni
BMC Developmental Biology , 2005, DOI: 10.1186/1471-213x-5-26
Abstract: In this report, we have developed and validated antibodies (either monoclonal or polyclonal) specific to human embryonic stem cell antigens and early differentiation transcriptional factors/markers that are critical for cell differentiation into definite lineage.These antibodies enable stem cell biologists to conveniently identify stem cell characteristics and to quantitatively assess differentiation.Although the stem cell concept was introduced decades ago, to date, stem cells can only be defined functionally, not morphologically or phenotypically. Two functions define stem cells. Firstly, they are self-renewing, thus able to propagate to generate additional stem cells. Secondly they can differentiate into various progenitor cells, which commit to further maturation along a specific lineage. While stem cells can be best defined functionally, a good number of molecular markers have been used to prospectively identify various stem cell populations. Although the functional importance of many of these antigens remains unknown, their unique expression pattern and timing of expression provide a useful tool for scientists to identify as well as isolate stem cells.Embryonic stem cells (ESC), derived from the inner cell mass of pre-implantation embryos, have been recognized as the earliest stem cell population [1,2]. This pluripotent population can differentiate into all somatic tissue including germ cells. In the case of human ESC, they can differentiate into some extra-embryonic derivatives as well. Like mouse ESC, human ES cells can be maintained and propagated on mouse fibroblast feeders for extended periods in media containing basic fibroblast growth factor (bFGF) [3]. Gene expression of undifferentiated human ES cells has been investigated among several ES cell lines by a variety of techniques. They include comparison with databases, reverse transcriptase-polymerase chain reaction, focused cDNA microarrays, and immunocytochemistry. A list of molecules comprised of kno
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