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Therapeutic Vaccines and Antibodies for Treatment of Orthopoxvirus Infections  [PDF]
Yuhong Xiao,Stuart N. Isaacs
Viruses , 2010, DOI: 10.3390/v2102381
Abstract: Despite the eradication of smallpox several decades ago, variola and monkeypox viruses still have the potential to become significant threats to public health. The current licensed live vaccinia virus-based smallpox vaccine is extremely effective as a prophylactic vaccine to prevent orthopoxvirus infections, but because of safety issues, it is no longer given as a routine vaccine to the general population. In the event of serious human orthopoxvirus infections, it is important to have treatments available for individual patients as well as their close contacts. The smallpox vaccine and vaccinia immune globulin (VIG) were used in the past as therapeutics for patients exposed to smallpox. VIG was also used in patients who were at high risk of developing complications from smallpox vaccination. Thus post-exposure vaccination and VIG treatments may again become important therapeutic modalities. This paper summarizes some of the historic use of the smallpox vaccine and immunoglobulins in the post-exposure setting in humans and reviews in detail the newer animal studies that address the use of therapeutic vaccines and immunoglobulins in orthopoxvirus infections as well as the development of new therapeutic monoclonal antibodies.
Conditions of tumor-associated antigens as a proper target for therapeutic antibodies against solid cancers  [cached]
Yoshikazu Kurosawa
Journal of Stem Cells and Regenerative Medicine , 2011,
Abstract: Since the success of rituximab and trastuzumab for treatment of non-Hodgkin’s lymphoma and breast cancer, respectively, a huge therapeutic potential of monoclonal antibodies (mAbs) was realized and development of therapeutic mAbs has been widely tried against various cancers. However, the successful examples are still limited and therapeutic mAbs are not yet available for the majority of human cancers. We established a procedure for comprehensive identification of tumor-associated antigens (TAAs) through the extensive isolation of human mAbs that may become therapeutic. Thirty-twoTAAs have been identified and 555 mAbs that bound to one of the TAAs have been isolated to date. Now we are trying to select TAAs as proper targets for therapy and candidate mAbs as drugs from among them. The immunohistochemical analysis using many fresh lung cancer specimens suggested probabilities of proper targets, and moreover, presence of cancer-specific epitopes that could be distinguished from normal epitopes on the same molecules by mAbs. For Abs to efficiently kill the cancer cells they should have the ability to induce immunological cytotoxicity such as ADCC and/or CDC. They should also be able to inhibit the function mediated by the target Ags. For clinical point of view, the continuous presence of the target molecule on the cell surface until cell death might be essential for successful treatment. Therefore, it will be required for targets TAAs to play essential roles in tumorigenesis. Otherwise the cancer cells that do not express them could selectively survive during treatment and finally become dominant. It was also suggested that even the same molecules could play different roles in tumorigenesis quite often in different patients. Therefore when we develop therapeutic Abs, we should obtain information about the conditions of patients including genetic background to whom the treatment will be effective. I will discuss how we can accomplish this purpose.
Therapeutic Cancer Vaccines: Past Situation and Current Developments
Irina Luceska
Macedonian Journal of Medical Sciences , 2009,
Abstract: Therapeutic vaccines represent an option for active immunotherapy of cancers. The immunotherapy of cancer has been practiced already in the 19th century. With the advances in the fields of immunology, genomics and production technologies, it started to be accepted as an attractive investment option among the innovators. The early trends in the development of cancer vaccines, or immunotherapeutics, as referred to by some professional circles, were towards the autologous or personalized products, while recently they shift more towards the generalized types of vaccines. Number of various different antigens and adjuvants are used in the design of cancer vaccines. There is a small portfolio of already registered and commercialized cancer therapeutic vaccines, but the pipeline of Phase II and III products looks promising. The accumulation of clinical expertise offers a hope for understanding of the mechanisms, therapeutic regimes, combinations with other therapies, and safety of the immunotherapeutics.
The Consequence of Immune Suppressive Cells in the Use of Therapeutic Cancer Vaccines and Their Importance in Immune Monitoring
Matteo Vergati,Jeffrey Schlom,Kwong Y. Tsang
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/182413
Abstract: Evaluating the number, phenotypic characteristics, and function of immunosuppressive cells in the tumor microenvironment and peripheral blood could elucidate the antitumor immune response and provide information to evaluate the efficacy of cancer vaccines. Further studies are needed to evaluate the correlation between changes in immunosuppressive cells and clinical outcomes of patients in cancer vaccine clinical trials. This paper focuses on the role of T-regulatory cells, myeloid-derived suppressor cells, and tumor-associated macrophages in cancer and cancer immunotherapy and their role in immune monitoring.
The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines  [PDF]
Peter Chin Wan Fung, Regina Kit Chee Kong
Journal of Cancer Therapy (JCT) , 2017, DOI: 10.4236/jct.2017.811086
Abstract: Heat shock proteins (HSPs) serve to correct proteins’ conformation, send the damaged proteins for degradation (quality control function). Heat shock factors (HSFs) are their transcription factors. The protein complexes mTOR1 and 2 (with the same core mTOR), the phosphoinositide-dependent protein kinase-1 (PDK1), the seine/threonine-specific protein kinase (Akt), HSF1, plus their associated proteins form a network participating in protein synthesis, bio-energy generation, signaling for apoptosis with the help of HSPs. A cancer cell synthesizes proteins at fast rate and needs more HSPs to work on quality control. Shutting down this network would lead to cell death. Thus inhibitors of mTOR (mTORI) and inhibitors of HSPs (HSPI) could drive cancer cell to apoptosis—a “passive approach”. On the other hand, HSPs form complexes with polypeptides characteristic of the cancer cells; on excretion from the cell, they becomes antigens for the immunity cells, eventually leading to maturation of the cytotoxic T cells, forming the basic principle of preparing cancer-specific, person-specific vaccine. Recent finding shows that HSP70 can penetrate cancer cell and expel its analog to extracellular region, giving the hope to prepare a non-person-specific vaccine covering a variety of cancers. Activation of anti-cancer immunity is the “active approach”. On the other hand, mild hyperthermia, with increase of intracellular HSPs, has been found to activate the immunity response, and demonstrate anti-cancer effects. There are certain “mysteries” behind the mechanisms of the active and passive approaches. We analyze the mechanisms involved and provide explanations to some mysteries. We also suggest future research to improve our understanding of these two approaches, in which HSPs play many roles.
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.
The Therapeutic Value of Monoclonal Antibodies Directed Against Immunogenic Tumor Glycoproteins  [cached]
Myron Arlen, Philip Arlen, Al Tsang, XuePing Wang, Rishab Gupta
Journal of Cancer , 2010,
Abstract: Monoclonal antibodies developed against immunogenic proteins (Tumor Specific Antigens/TSA's) that are expressed in human cancers, display a unique behavioral pattern. They appear to serve in a dual role. This includes the early recognition of these immunogenic membrane proteins that can serve as diagnostic markers, and the targeting of such markers for the destruction of the tumor, primarily thru ADCC. The monoclonals (mAbs) that we have developed against specific immunogenic tumor membrane proteins have been studied in detail. These tumor proteins, when first defined, were referred to as tumor associated antigens. With the ability of the mAbs to demonstrate therapeutic antitumor activity in those patients with relatively advanced malignancies, the term tumor specific was introduced. Monoclonals that we were able to develop from tumor specific proteins derived from colon and pancreas cancer were found capable of targeting those tumors to induce apoptosis. We were also able to define immunogenic membrane proteins from lung (squamous and adenoCa) as well as prostate neoplasms. Monoclonals developed from these tumor antigens are in the initial phases of investigation with regard to their specificity and antitumor activity. Mabs capable of targeting the malignancies noted above were produced following immunization of BALBc mice with the Tumor Specific Antigens. The hybridomas that were screened and found to express the antibodies of interest appeared for the most part as IgG2a's. It became apparent after a short period of time that stability of the Fab CDR loops as well as the therapeutic efficacy of the hybridoma mAbs could be lost. Stability was achieved by chimerization and or humanization. The resulting mAbs were found to switch their isotypes to an IgG1 subsequent to chimerization and or humanization, when expressed in CHO cells. The monoclonals, so produced, were not only more efficient in controlling tumor growth but minimized the development of a HAMA response. Because of 1) the specificity of this group of monoclonal antibodies in targeting well defined immunogenic proteins that were expressed on the tumor cell membrane,2) their lack of cross reactivity to normal tissue, 3) relatively low toxicity when delivered intravenously, 4) rapid targeting of tumor cell populations (4-6 hrs in vitro) and their 5) ability to destroy xenograft transplants (in vivo) within days of delivery, these mAbs were felt to be ideal for possible use in the treatment of patients with recurrent and or metastatic tumors. Initial clinical studies have been planned for followin
Therapeutic Cancer Vaccines in Combination with Conventional Therapy
Mads Hald Andersen,Niels Junker,Eva Ellebaek,Inge Marie Svane,Per thor Straten
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/237623
Abstract: The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination with chemotherapy may lead to improved clinical efficacy by clearing suppressor cells, reboot of the immune system, by rendering tumor cells more susceptible to immune mediated killing, or by activation of cells of the immune system. In addition, a range of tumor antigens have been characterized to allow targeting of proteins coupled to intrinsic properties of cancer cells. For example, proteins associated with drug resistance can be targeted, and form ideal target structures for use in combination with chemotherapy for killing of surviving drug resistant cancer cells. Proteins associated with the malignant phenotype can be targeted to specifically target cancer cells, but proteins targeted by immunotherapy may also simultaneously target cancer cells as well as suppressive cells in the tumor stroma.
Characterization of Botulinum Neurotoxin Type A Neutralizing Monoclonal Antibodies and Influence of Their Half-Lives on Therapeutic Activity  [PDF]
Christelle Mazuet,Julie Dano,Michel R. Popoff,Christophe Créminon,Hervé Volland
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012416
Abstract: Botulinum toxins, i.e. BoNT/A to/G, include the most toxic substances known. Since botulism is a potentially fatal neuroparalytic disease with possible use as a biowarfare weapon (Centers for Disease Control and Prevention category A bioterrorism agent), intensive efforts are being made to develop vaccines or neutralizing antibodies. The use of active fragments from non-human immunoglobulins (F(ab')2, Fab', scFv), chemically modified or not, may avoid side effects, but also largely modify the in vivo half-life and effectiveness of these reagents. We evaluated the neutralizing activity of several monoclonal anti-BoNT/A antibodies (mAbs). F(ab')2 fragments, native or treated with polyethyleneglycol (PEG), were prepared from selected mAbs to determine their half-life and neutralizing activity as compared with the initial mAbs. We compared the protective efficiency of the different biochemical forms of anti-toxin mAbs providing the same neutralizing activity. Among fourteen tested mAbs, twelve exhibited neutralizing activity. Fragments from two of the best mAbs (TA12 and TA17), recognizing different epitopes, were produced. These two mAbs neutralized the A1 subtype of the toxin more efficiently than the A2 or A3 subtypes. Since mAb TA12 and its fragments both exhibited the greatest neutralizing activity, they were further evaluated in the therapeutic experiments. These showed that, in a mouse model, a 2- to 4-h interval between toxin and antitoxin injection allows the treatment to remain effective, but also suggested an absence of correlation between the half-life of the antitoxins and the length of time before treatment after botulinum toxin A contamination. These experiments demonstrate that PEG treatment has a strong impact on the half-life of the fragments, without affecting the effectiveness of neutralization, which was maintained after preparation of the fragments. These reagents may be useful for rapid treatment after botulinum toxin A contamination.
Therapeutic vaccines for malignant brain tumors  [cached]
Michael P Gustafson,Keith L Knutson,Allan B Dietz
Biologics: Targets and Therapy , 2008,
Abstract: Michael P Gustafson1, Keith L Knutson2, Allan B Dietz11Division of Transfusion Medicine; 2Department of Immunology, Mayo Clinic, Rochester, MN, USAAbstract: Malignant gliomas are the most common and aggressive form of brain tumors. Current therapy consists of surgical resection, followed by radiation therapy and concomitant chemotherapy. Despite these treatments, the prognosis for patients is poor. As such, investigative therapies including tumor vaccines have targeted this devastating condition. Recent clinical trials involving immunotherapy, specifically dendritic cell (DC) based vaccines, have shown promising results. Overall, these vaccines are well tolerated with few documented side effects. In many patients receiving vaccines, tumor progression was delayed and the median overall survival of these patients was prolonged. Despite these encouraging results, several factors have limited the efficacy of DC vaccines. Here we discuss the potential of DC vaccines as adjuvant therapy and current obstacles of generating highly pure and potent DC vaccines in the context of malignant glioma. Taken together, the results from earlier clinical studies justify additional clinical trials aimed at improving the efficacy of DC vaccines.Keywords: malignant glioma, glioblastoma multiforme, vaccine, immunotherapy, dendritic cells
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