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Journal Cover Antibodies
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   ISSN (Print) 2073-4468
   Published by MDPI Homepage  [156 journals]
  • Antibodies, Vol. 6, Pages 14: Epitope Sequences in Dengue Virus NS1
           Protein Identified by Monoclonal Antibodies

    • Authors: Leticia Rocha, Rubens Alves, Bruna Caetano, Lennon Pereira, Thais Mitsunari, Jaime Amorim, Juliana Polatto, Viviane Botosso, Neuza Gallina, Ricardo Palacios, Alexander Precioso, Celso Granato, Danielle Oliveira, Vanessa Silveira, Daniela Luz, Luís Ferreira, Roxane Piazza
      First page: 14
      Abstract: Dengue nonstructural protein 1 (NS1) is a multi-functional glycoprotein with essential functions both in viral replication and modulation of host innate immune responses. NS1 has been established as a good surrogate marker for infection. In the present study, we generated four anti-NS1 monoclonal antibodies against recombinant NS1 protein from dengue virus serotype 2 (DENV2), which were used to map three NS1 epitopes. The sequence 193AVHADMGYWIESALNDT209 was recognized by monoclonal antibodies 2H5 and 4H1BC, which also cross-reacted with Zika virus (ZIKV) protein. On the other hand, the sequence 25VHTWTEQYKFQPES38 was recognized by mAb 4F6 that did not cross react with ZIKV. Lastly, a previously unidentified DENV2 NS1-specific epitope, represented by the sequence 127ELHNQTFLIDGPETAEC143, is described in the present study after reaction with mAb 4H2, which also did not cross react with ZIKV. The selection and characterization of the epitope, specificity of anti-NS1 mAbs, may contribute to the development of diagnostic tools able to differentiate DENV and ZIKV infections.
      Citation: Antibodies
      PubDate: 2017-10-15
      DOI: 10.3390/antib6040014
      Issue No: Vol. 6, No. 4 (2017)
       
  • Antibodies, Vol. 6, Pages 9: Potential Roles of Antiphospholipid
           Antibodies in Generating Platelet-C4d in Systemic Lupus Erythematosus

    • Authors: Chau-Ching Liu, Travis Schofield, Amy Tang, Susan Manzi, Joseph M. Ahearn
      First page: 9
      Abstract: Premature, accelerated onset of atherothrombotic disease is prevalent in patients with systemic lupus erythematosus (SLE). Most, if not all, atherothrombotic diseases are likely to involve platelets and complement. Previously, we discovered that platelets bearing complement activation product C4d (P-C4d) are present in SLE patients, and are significantly associated with antiphospholipid (aPL) antibody positivity and stroke in SLE patients. The goal of the present study was to further elucidate the role of aPL and other platelet-reactive autoantibodies in the generation of P-C4d. To determine the association between P-C4d and aPL antibodies, the serum levels of aPL antibodies and P-C4d of 180 SLE patients were measured by enzyme-linked immunoassays and flow cytometry, respectively. To investigate the role of aPL antibodies, and possibly other autoantibodies as well, in mediating the generation of P-C4d, in vitro 2-step P-C4d induction experiments were performed. The results showed that the presence and levels of aPL antibodies in the serum were specifically elevated in SLE patients with positive P-C4d. The plasma and immunoglobulins purified from SLE patients who were positive for P-C4d and aPL were capable of inducing C4d deposition on normal platelets in vitro. The capacity of SLE plasma in inducing P-C4d appeared to correlate proportionately to the serum aPL levels. Collectively, the results demonstrate that both aPL and other platelet-reactive autoantibodies may participate in mediating the generation of P-C4d in SLE patients.
      PubDate: 2017-07-02
      DOI: 10.3390/antib6030009
      Issue No: Vol. 6, No. 3 (2017)
       
  • Antibodies, Vol. 6, Pages 10: Strategies for Selecting Membrane
           Protein-Specific Antibodies using Phage Display with Cell-Based Panning

    • Authors: Mohamed Alfaleh, Martina Jones, Christopher Howard, Stephen Mahler
      First page: 10
      Abstract: Membrane proteins are attractive targets for monoclonal antibody (mAb) discovery and development. Although several approved mAbs against membrane proteins have been isolated from phage antibody libraries, the process is challenging, as it requires the presentation of a correctly folded protein to screen the antibody library. Cell-based panning could represent the optimal method for antibody discovery against membrane proteins, since it allows for presentation in their natural conformation along with the appropriate post-translational modifications. Nevertheless, screening antibodies against a desired antigen, within a selected cell line, may be difficult due to the abundance of irrelevant organic molecules, which can potentially obscure the antigen of interest. This review will provide a comprehensive overview of the different cell-based phage panning strategies, with an emphasis placed on the optimisation of four critical panning conditions: cell surface antigen presentation, non-specific binding events, incubation time, and temperature and recovery of phage binders.
      Citation: Antibodies
      PubDate: 2017-08-05
      DOI: 10.3390/antib6030010
      Issue No: Vol. 6, No. 3 (2017)
       
  • Antibodies, Vol. 6, Pages 11: Monoclonal Antibodies against Plasmodium
           falciparum Circumsporozoite Protein

    • Authors: Min Zhang, Rajakumar Mandraju, Urvashi Rai, Takayuki Shiratsuchi, Moriya Tsuji
      First page: 11
      Abstract: Malaria is a mosquito-borne infectious disease caused by the parasite Plasmodium spp. Malaria continues to have a devastating impact on human health. Sporozoites are the infective forms of the parasite inside mosquito salivary glands. Circumsporozoite protein (CSP) is a major and immunodominant protective antigen on the surface of Plasmodium sporozoites. Here, we report a generation of specific monoclonal antibodies that recognize the central repeat and C-terminal regions of P. falciparum CSP. The monoclonal antibodies 3C1, 3C2, and 3D3—specific for the central repeat region—have higher titers and protective efficacies against challenge with sporozoites compared with 2A10, a gold standard monoclonal antibody that was generated in early 1980s.
      Citation: Antibodies
      PubDate: 2017-08-23
      DOI: 10.3390/antib6030011
      Issue No: Vol. 6, No. 3 (2017)
       
  • Antibodies, Vol. 6, Pages 12: Functional, Biophysical, and Structural
           Characterization of Human IgG1 and IgG4 Fc Variants with Ablated Immune
           Functionality

    • Authors: Susan Tam, Stephen McCarthy, Anthony Armstrong, Sandeep Somani, Sheng-Jiun Wu, Xuesong Liu, Alexis Gervais, Robin Ernst, Dorina Saro, Rose Decker, Jinquan Luo, Gary Gilliland, Mark Chiu, Bernard Scallon
      First page: 12
      Abstract: Engineering of fragment crystallizable (Fc) domains of therapeutic immunoglobulin (IgG) antibodies to eliminate their immune effector functions while retaining other Fc characteristics has numerous applications, including blocking antigens on Fc gamma (Fcγ) receptor-expressing immune cells. We previously reported on a human IgG2 variant termed IgG2σ with barely detectable activity in antibody-dependent cellular cytotoxicity, phagocytosis, complement activity, and Fcγ receptor binding assays. Here, we extend that work to IgG1 and IgG4 antibodies, alternative subtypes which may offer advantages over IgG2 antibodies. In several in vitro and in vivo assays, the IgG1σ and IgG4σ variants showed equal or even lower Fc-related activities than the corresponding IgG2σ variant. In particular, IgG1σ and IgG4σ variants demonstrate complete lack of effector function as measured by antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and in vivo T-cell activation. The IgG1σ and IgG4σ variants showed acceptable solubility and stability, and typical human IgG1 pharmacokinetic profiles in human FcRn-transgenic mice and cynomolgus monkeys. In silico T-cell epitope analyses predict a lack of immunogenicity in humans. Finally, crystal structures and simulations of the IgG1σ and IgG4σ Fc domains can explain the lack of Fc-mediated immune functions. These variants show promise for use in those therapeutic antibodies and Fc fusions for which the Fc domain should be immunologically “silent”.
      Citation: Antibodies
      PubDate: 2017-09-01
      DOI: 10.3390/antib6030012
      Issue No: Vol. 6, No. 3 (2017)
       
  • Antibodies, Vol. 6, Pages 13: Host Cell Proteins in Biologics
           Manufacturing: The Good, the Bad, and the Ugly

    • Authors: Martin Kornecki, Fabian Mestmäcker, Steffen Zobel-Roos, Laura Heikaus de Figueiredo, Hartmut Schlüter, Jochen Strube
      First page: 13
      Abstract: Significant progress in the manufacturing of biopharmaceuticals has been made by increasing the overall titers in the USP (upstream processing) titers without raising the cost of the USP. In addition, the development of platform processes led to a higher process robustness. Despite or even due to those achievements, novel challenges are in sight. The higher upstream titers created more complex impurity profiles, both in mass and composition, demanding higher separation capacities and selectivity in downstream processing (DSP). This creates a major shift of costs from USP to DSP. In order to solve this issue, USP and DSP integration approaches can be developed and used for overall process optimization. This study focuses on the characterization and classification of host cell proteins (HCPs) in each unit operation of the DSP (i.e., aqueous two-phase extraction, integrated countercurrent chromatography). The results create a data-driven feedback to the USP, which will serve for media and process optimizations in order to reduce, or even eliminate nascent critical HCPs. This will improve separation efficiency and may lead to a quantitative process understanding. Different HCP species were classified by stringent criteria with regard to DSP separation parameters into “The Good, the Bad, and the Ugly” in terms of pI and MW using 2D-PAGE analysis depending on their positions on the gels. Those spots were identified using LC-MS/MS analysis. HCPs, which are especially difficult to remove and persistent throughout the DSP (i.e., “Bad” or “Ugly”), have to be evaluated by their ability to be separated. In this approach, HCPs, considered “Ugly,” represent proteins with a MW larger than 15 kDa and a pI between 7.30 and 9.30. “Bad” HCPs can likewise be classified using MW (>15 kDa) and pI (4.75–7.30 and 9.30–10.00). HCPs with a MW smaller than 15 kDa and a pI lower than 4.75 and higher than 10.00 are classified as “Good” since their physicochemical properties differ significantly from the product. In order to evaluate this classification scheme, it is of utmost importance to use orthogonal analytical methods such as IEX, HIC, and SEC.
      Citation: Antibodies
      PubDate: 2017-09-16
      DOI: 10.3390/antib6030013
      Issue No: Vol. 6, No. 3 (2017)
       
  • Antibodies, Vol. 6, Pages 6: Collagen Autoantibodies and Their
           Relationship to CCP Antibodies and Rheumatoid Factor in the Progression of
           Early Rheumatoid Arthritis

    • Authors: Senga Whittingham, Alex Stockman, Merrill Rowley
      First page: 6
      Abstract: Serum autoantibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF) are important markers for diagnosis and prognosis of rheumatoid arthritis (RA), but their autoantigens are not cartilage-specific. Autoantibodies to joint-specific type II collagen (CII) also occur in RA, and monoclonal antibodies of similar specificity induce collagen antibody-induced arthritis in animals, but their role in RA is uncertain. We utilized an enzyme-linked immunosorbent assay (ELISA) with the CB10 peptide of CII to compare the frequency of autoantibodies with those of anti-CCP and RF in stored sera from a prospective study of 82 patients with early RA to examine the outcome, defined as remission (n = 23), persisting non-erosive arthritis (n = 27), or erosions (n = 32). Initial frequencies of anti-CB10, anti-CCP and RF were 76%, 54%, and 57% in RA, and 4%, 0%, and 9% in 136 controls. The frequency of anti-CB10 was unrelated to outcome, but anti-CCP and RF increased with increasing severity, and the number of autoantibodies mirrored the severity. We suggest RA is an immune complex-mediated arthritis in which the three antibodies interact, with anti-CII inducing localized cartilage damage and inflammation resulting in citrullination of joint proteins, neoepitope formation, and a strong anti-CCP response in genetically-susceptible subjects, all amplified and modified by RF.
      PubDate: 2017-04-05
      DOI: 10.3390/antib6020006
      Issue No: Vol. 6, No. 2 (2017)
       
  • Antibodies, Vol. 6, Pages 7: Asymmetric Fc Engineering for Bispecific
           Antibodies with Reduced Effector Function

    • Authors: Eric Escobar-Cabrera, Paula Lario, Jason Baardsnes, Joseph Schrag, Yves Durocher, Surjit Dixit
      First page: 7
      Abstract: Asymmetric bispecific antibodies are a rapidly expanding therapeutic antibody class, designed to recognize two different target epitopes concurrently to achieve novel functions not available with normal antibodies. Many therapeutic designs require antibodies with reduced or silenced effector function. Although many solutions have been described in the literature to knockout effector function, to date all of them have involved the use of a specific antibody subtype (e.g., IgG2 or IgG4), or symmetric mutations in the lower hinge or CH2 domain of traditional homodimeric monospecific antibodies. In the context of a heterodimeric Fc, we describe novel asymmetric Fc mutations with reduced or silenced effector function in this article. These heteromultimeric designs contain asymmetric charged mutations in the lower hinge and the CH2 domain of the Fc. Surface plasmon resonance showed that the designed mutations display much reduced binding to all of the Fc gamma receptors and C1q. Ex vivo ADCC and CDC assays showed a consistent reduction in activity. Differential scanning calorimetry showed increased thermal stability for some of the designs. Finally, the asymmetric nature of the introduced charged mutations allowed for separation of homodimeric impurities by ion exchange chromatography, providing, as an added benefit, a purification strategy for the production of bispecific antibodies with reduced or silenced effector function.
      PubDate: 2017-05-16
      DOI: 10.3390/antib6020007
      Issue No: Vol. 6, No. 2 (2017)
       
  • Antibodies, Vol. 6, Pages 8: Dimerized Domain V of Beta2-Glycoprotein I Is
           Sufficient to Upregulate Procoagulant Activity in PMA-Treated U937
           Monocytes and Require Intact Residues in Two Phospholipid-Binding Loops

    • Authors: Alexey Kolyada, David Barrios, Natalia Beglova
      First page: 8
      Abstract: Upregulation of the procoagulant activity of monocytes by antibodies to beta2-glycoprotein I (β2GPI) is one of the mechanisms contributing to thrombosis in antiphospholipid syndrome. Current knowledge about receptors responsible for the upregulation of procoagulant activity by β2GPI/anti-β2GPI complexes and their binding sites on β2GPI is far from complete. We quantified the procoagulant activity expressed by phorbol 12-myristate 13-acetate (PMA)-differentiated U937 cells by measuring clotting kinetics in human plasma exposed to stimulated cells. Cells stimulated with anti-β2GPI were compared to cells treated with dimerized domain V of β2GPI (β2GPI-DV) or point mutants of β2GPI-DV. We demonstrated that dimerized β2GPI-DV is sufficient to induce procoagulant activity in monocytes. Using site-directed mutagenesis, we determined that the phospholipid-binding interface on β2GPI is larger than previously thought and includes Lys308 in β2GPI-DV. Intact residues in two phospholipid-binding loops of β2GPI-DV were important for the potentiation of procoagulant activity. We did not detect a correlation between the ability of β2GPI-DV variants to bind ApoER2 and potentiation of the procoagulant activity of cells. The region on β2GPI inducing procoagulant activity in monocytes can now be narrowed down to β2GPI-DV. The ability of β2GPI-DV dimers to come close to cell membrane and attach to it is important for the stimulation of procoagulant activity.
      PubDate: 2017-06-02
      DOI: 10.3390/antib6020008
      Issue No: Vol. 6, No. 2 (2017)
       
  • Antibodies, Vol. 6, Pages 1: Pathogenic and Protective Autoantibodies in
           Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)

    • Authors: Sakeen Kashem, Bryce Binstadt
      First page: 1
      Abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare disorder caused by mutations in the autoimmune regulator (AIRE) gene, leading to defects in T cell selection. The disease manifestations include both autoimmune tissue destruction and immunodeficiency, with specific susceptibility to chronic mucocutaneous candidiasis. Studies have demonstrated a wide repertoire of high affinity tissue- and cytokine-specific antibodies in patients with APECED. Here, we review the antigenic targets and function of these disease-causing and disease-ameliorating antibodies.
      PubDate: 2017-01-17
      DOI: 10.3390/antib6010001
      Issue No: Vol. 6, No. 1 (2017)
       
  • Antibodies, Vol. 6, Pages 2: Acknowledgement to Reviewers of Antibodies in
           2016

    • Authors: Antibodies Editorial Office
      First page: 2
      Abstract: The editors of Antibodies would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.[...]
      PubDate: 2017-01-18
      DOI: 10.3390/antib6010002
      Issue No: Vol. 6, No. 1 (2017)
       
  • Antibodies, Vol. 6, Pages 3: Pairing Alpaca and Llama-Derived Single
           Domain Antibodies to Enhance Immunoassays for Ricin

    • Authors: Kendrick Turner, Sabrina Hardy, Jinny Liu, Dan Zabetakis, P. Lee, Ellen Goldman, George Anderson
      First page: 3
      Abstract: Previously, our group isolated and evaluated anti-ricin single domain antibodies (sdAbs) derived from llamas, engineered them to further increase their thermal stability, and utilized them for the development of sensitive immunoassays. In work focused on the development of therapeutics, Vance et al. 2013 described anti-ricin sdAbs derived from alpacas. Herein, we evaluated the utility of selected alpaca-derived anti-ricin sdAbs for detection applications, and engineered an alpaca-derived sdAb to increase its melting temperature, providing a highly thermal stable reagent for use in ricin detection. Four of the alpaca-derived anti-ricin A-chain sdAbs were produced and characterized. All four bound to epitopes that overlapped with our previously described llama sdAbs. One alpaca sdAb, F6, was found to possess both a high melting temperature (73 °C) and to work optimally with a thermally stable llama anti-ricin sdAb in sandwich assays for ricin detection. We employed a combination of consensus sequence mutagenesis and the addition of a non-canonical disulfide bond to further enhance the thermal stability of F6 to 85 °C. It is advantageous to have a choice of recognition reagents when developing assays. This work resulted in defining an additional pair of highly thermal stable sdAbs for the sensitive detection of ricin.
      PubDate: 2017-02-02
      DOI: 10.3390/antib6010003
      Issue No: Vol. 6, No. 1 (2017)
       
  • Antibodies, Vol. 6, Pages 4: Neutrophil Extracellular Traps,
           Antiphospholipid Antibodies and Treatment

    • Authors: Jessica Bravo-Barrera, Maria Kourilovitch, Claudio Galarza-Maldonado
      First page: 4
      Abstract: Neutrophil extracellular traps (NETs) are a network of extracellular fibers, compounds of chromatin, neutrophil DNA and histones, which are covered with antimicrobial enzymes with granular components. Autophagy and the production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are essential in the formation of NETs. There is increasing evidence that suggests that autoantibodies against beta-2-glycoprotein-1 (B2GP1) induce NETs and enhance thrombosis. Past research on new mechanisms of thrombosis formation in antiphospholipid syndrome (APS) has elucidated the pharmacokinetics of the most common medication in the treatment of the disease.
      PubDate: 2017-03-06
      DOI: 10.3390/antib6010004
      Issue No: Vol. 6, No. 1 (2017)
       
  • Antibodies, Vol. 6, Pages 5: Epitope Specificity of Anti-Citrullinated
           Protein Antibodies

    • Authors: Nicole Trier, Gunnar Houen
      First page: 5
      Abstract: Anti-citrullinated protein antibodies are primarily associated with a progressive course in the autoimmune disease rheumatoid arthritis, a disease with a chronic and inflammatory nature. These antibodies do not appear to have any strict dependency for reactivity except from the presence of the non-genetically encoded amino acid citrulline, which is the result of a posttranslational modification, catalyzed by calcium-dependent peptidylarginine deiminase enzymes. Nevertheless, several amino acids surrounding the citrulline residue notably influence antibody reactivity, especially with a central-Cit-Gly-motif being essential for antibody reactivity. Most importantly, these antibodies have been proposed to be divided into two groups, based on their ability to recognize multiple citrullinated peptides. Thus, an “overlapping” antibody group, which appears to recognize several citrullinated peptides, and a “non-overlapping” antibody group, which only recognizes a limited number of citrullinated peptides, have been proposed. Based on these findings, we suggest that antibodies recognizing several citrullinated targets, also referred to as cross-reactive antibodies, primarily are backbone-dependent, whereas less cross-reactive antibodies primarily depend on the side chains of the amino acids comprising the epitopes for stable antibody-antigen interactions, which reduces the degree of cross-reactivity significantly. Clarifying the reactivity pattern of anti-citrullinated protein antibodies may contribute to determining their true nature of origin.
      PubDate: 2017-03-08
      DOI: 10.3390/antib6010005
      Issue No: Vol. 6, No. 1 (2017)
       
  • Antibodies, Vol. 3, Pages 1-15: The Role of CD2 Family Members in NK-Cell
           Regulation of B-Cell Antibody Production

    • Authors: Dorothy Yuan
      Pages: 1 - 15
      Abstract: Natural Killer (NK) cells, an important component of the innate immune system, can mount much more rapid responses upon activation than adaptive antigen specific responses. Among the various functions attributed to NK cells their effect on antibody production merits special attention. The modification of IgG subclasses distribution as well as the amplification of the B cell response can be functionally relevant both for mediation of antibody-dependent cellular cytotoxicity (ADCC) and for control of dysregulated autoantibody production. In this review recent experimental evidence for the mechanistic basis of the effect of NK cells on B cell-responses will be covered. Thus, it will be shown that these effects are mediated not only via activation of cytokine and Toll-like receptors (TLR), but also by direct receptor-ligand interactions. Importantly, the function of these receptor/ligands, CD48 and CD244, do not require recognition of class I-MHC molecules but are more dependent on inflammatory conditions brought about by infection or oncogenesis.
      PubDate: 2013-12-19
      DOI: 10.3390/antib3010001
      Issue No: Vol. 3, No. 1 (2013)
       
  • Antibodies, Vol. 3, Pages 16-36: Invariant Natural Killer T Cells

    • Authors: Antonella Cianferoni
      Pages: 16 - 36
      Abstract: Invariant Natural killer T cell (iNKT cells) are a subset of T cells, which are narrowly defined as a T cell lineage expressing a semi-invariant CD1d-restricted T cell Receptors (TCRs) composed by Vα24-Jα18/Vβ11 in human, and Vα14-Jα18/Vβ8,Vβ7, and Vβ2 in mouse. Unlike conventional T cells which recognize peptides bound to highly polymorphic major histocompatibility complex (MHC) class I and II molecules, iNKT cells recognize lipid antigens, such as glycolipids, presented by CD1d, a non-polymorphic non-classical MHC class I molecule. Lipids derived from microbes, tumors, and allergens, as well as self lipids have been shown to be able to activate iNKT cells. Early on, in an immune response, ligation of the iNKT cell TCR leads to rapid and copious secretion of prototypical Th1 and Th2 cytokines. Moreover, like NK cells, iNKT cells express cytotoxic granules, such as perforin and granzyme that polarize upon activation of TCR and are able to kill target cells. Therefore iNKT cells are a very interesting subset of T cells that may bridge the innate and adaptive immune systems. Indeed, iNKT cells can mount specific responses to antigen with cytokine production and cytotoxic activity, however, their TCR evolved to recognize different glycolipid antigens in a conserved manner and to perform innate-like rather than adaptive functions. iNKT cells are now recognized as important players in atopic, autoimmune, infectious diseases, and cancer.
      PubDate: 2013-12-23
      DOI: 10.3390/antib3010016
      Issue No: Vol. 3, No. 1 (2013)
       
  • Antibodies, Vol. 2, Pages 535-553: Communication between B-Cells and
           Microbiota for the Maintenance of Intestinal Homeostasis

    • Authors: Yuying Liu, Jon Rhoads
      Pages: 535 - 553
      Abstract: The human intestine is populated with an extremely dense and diverse bacterial community. Commensal bacteria act as an important antigenic stimulus producing the maturation of gut-associated lymphoid tissue (GALT). The production of immunoglobulin (Ig) A by B-cells in the GALT is one of the immune responses following intestinal colonization of bacteria. The switch of B-cells from IgM to IgA-producing cells in the Peyer’s patches and neighboring lamina propria proceeds by T-cell-dependent and T-cell-independent mechanisms. Several grams of secretory IgA (SIgA) are released into the intestine each day. SIgA serves as a first-line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms. SIgA has a capacity to directly quench bacterial virulence factors, influence the composition of the intestinal microbiota, and promote the transportation of antigens across the intestinal epithelium to GALT and down-regulate proinflammatory responses associated with the uptake of highly pathogenic bacteria and potentially allergenic antigens. This review summarizes the reciprocal interactions between intestinal B cells and bacteria, specifically, the formation of IgA in the gut, the role of intestinal IgA in the regulation of bacterial communities and the maintenance of intestinal homeostasis, and the effects of probiotics on IgA levels in the gastrointestinal tract.
      PubDate: 2013-10-17
      DOI: 10.3390/antib2040535
      Issue No: Vol. 2, No. 4 (2013)
       
  • Antibodies, Vol. 2, Pages 554-586: Regulation of Germinal Center Reactions
           by B and T Cells

    • Authors: Young Kim, Xindong Liu, Shinya Tanaka, Dat Tran, Yeonseok Chung
      Pages: 554 - 586
      Abstract: Break of B cell tolerance to self-antigens results in the development of autoantibodies and, thus, leads to autoimmunity. How B cell tolerance is maintained during active germinal center (GC) reactions is yet to be fully understood. Recent advances revealed several subsets of T cells and B cells that can positively or negatively regulate GC B cell responses in vivo. IL-21-producing CXCR5+ CD4+ T cells comprise a distinct lineage of helper T cells—termed follicular helper T cells (TFH)—that can provide help for the development of GC reactions where somatic hypermutation and affinity maturation take place. Although the function of TFH cells is beneficial in generating high affinity antibodies against infectious agents, aberrant activation of TFH cell or B cell to self-antigens results in autoimmunity. At least three subsets of immune cells have been proposed as regulatory cells that can limit such antibody-mediated autoimmunity, including follicular regulatory T cells (TFR), Qa-1 restricted CD8+ regulatory T cells (CD8+TREG), and regulatory B cells (BREG). In this review, we will discuss our current understanding of GC B cell regulation with specific emphasis on the newly identified immune cell subsets involved in this process.
      PubDate: 2013-10-23
      DOI: 10.3390/antib2040554
      Issue No: Vol. 2, No. 4 (2013)
       
  • Antibodies, Vol. 2, Pages 587-597: Regulatory B-Cells in Transplantation

    • Authors: David San Segundo, Marcos López-Hoyos, Manuel Arias
      Pages: 587 - 597
      Abstract: B-cells have been long accepted as the main cellular component in humoral responses. Their effector function is based on antibody and cytokine production. The development of donor-specific antibodies by B-cells has deleterious consequences in graft and patients survival. Recently, a new subset of IL-10-secreting B-cells with regulatory capacity in allergic and autoimmune diseases has been shown. Such regulatory function changes the apprehension of B-cells as effector cells and increases the complexity to the immuno-regulatory networks. New therapies targeting B-cells should consider that depleting B-cells potentially impairs regulatory B-cells (Bregs) and that modulating or favoring the maintenance and function of Bregs would be important for the achievement of humoral tolerance. Unfortunately, few direct pieces of evidence of Breg involvement in allograft tolerance models has been described. Here, we summarize the current knowledge of the role of Bregs in transplantation.
      PubDate: 2013-11-20
      DOI: 10.3390/antib2040587
      Issue No: Vol. 2, No. 4 (2013)
       
  • Antibodies, Vol. 2, Pages 598-616: CD20 mAb-Mediated Complement Dependent
           Cytotoxicity of Tumor Cells is Enhanced by Blocking the Action of Factor I
           

    • Authors: Margaret Lindorfer, Paul Beum, Ronald Taylor
      Pages: 598 - 616
      Abstract: The CD20 mAbs, rituximab (RTX) and ofatumumab (OFA), have been used with success in the clinic in the treatment of B cell malignancies. These mAbs can eliminate B cells only by utilizing the body’s immune effector mechanisms, and there is considerable evidence that OFA is particularly effective at eliminating B cells by mediating complement dependent cytotoxicity (CDC). However, effector mechanisms such as complement can be exhausted or down-regulated. Therefore, several approaches are being investigated with the goal of increasing CDC mediated by these mAbs. We reported that when patients with chronic lymphocytic leukemia (CLL) are treated with RTX or with OFA, complement is rapidly activated on circulating, targeted CLL B cells. However, a substantial fraction of these cells escape CDC and clearance due to degradation of covalently deposited active C3b fragments to inactive fragments iC3b and C3d. This process is mediated by a plasma protease, Factor I. Therefore, a rational approach for increasing CDC would be to block this reaction by inhibiting Factor I with a neutralizing mAb. Indeed, we have demonstrated that use of neutralizing mAb A247, specific for factor I, significantly and substantially increases CD20 mAb-mediated CDC of both cell lines and of primary CLL cells in vitro.
      PubDate: 2013-11-28
      DOI: 10.3390/antib2040598
      Issue No: Vol. 2, No. 4 (2013)
       
  • Antibodies, Vol. 2, Pages 617-635: Potential for Natural Killer
           Cell-Mediated Antibody-Dependent Cellular Cytotoxicity for Control of
           Human Cytomegalovirus

    • Authors: Rebecca Aicheler, Eddie Wang, Peter Tomasec, Gavin Wilkinson, Richard Stanton
      Pages: 617 - 635
      Abstract: Human cytomegalovirus (HCMV) is an important pathogen that infects the majority of the population worldwide, yet, currently, there is no licensed vaccine. Despite HCMV encoding at least seven Natural Killer (NK) cell evasion genes, NK cells remain critical for the control of infection in vivo. Classically Antibody-Dependent Cellular Cytotoxicity (ADCC) is mediated by CD16, which is found on the surface of the NK cell in a complex with FcεRI-γ chains and/or CD3ζ chains. Ninety percent of NK cells express the Fc receptor CD16; thus, they have the potential to initiate ADCC. HCMV has a profound effect on the NK cell repertoire, such that up to 10-fold expansions of NKG2C+ cells can be seen in HCMV seropositive individuals. These NKG2C+ cells are reported to be FcεRI-γ deficient and possess variable levels of CD16+, yet have striking ADCC functions. A subset of HCMV cell surface proteins will induce robust antibody responses that could render cells susceptible to ADCC. We will consider how the strong anti-HCMV function of NKG2C+ FcεRI-γ-deficient NK cells could potentially be harnessed in the clinic to treat patients suffering from HCMV disease and in the development of an efficacious HCMV vaccine.
      PubDate: 2013-12-10
      DOI: 10.3390/antib2040617
      Issue No: Vol. 2, No. 4 (2013)
       
  • Antibodies, Vol. 2, Pages 392-414: Antibody Glycosylation and Inflammation

    • Authors: Kai-Ting Shade, Robert Anthony
      Pages: 392 - 414
      Abstract: IgG antibodies are the basis of some of the most effective therapeutics developed over the last 20 years. These antibodies are highly specific, have long serum-half lives, and can be produced relatively routinely, making them ideal drugs for immunotherapy. The degree of regulation on IgG antibody effector functions by the composition of the single, N-linked glycan attached to the Fc is increasingly appreciated. IgG antibodies with identical protein sequences can gain a 50-fold potency, in terms of initiating antibody-dependent cellular cytotoxicity (ADCC) by removal of the single fucose residue from the Fc glycan. Conversely, the addition of sialic acid to the terminus of the Fc glycan converts IgG antibodies into anti-inflammatory mediators, capable of suppressing autoantibody driven inflammation. This review will discuss the contribution of the Fc glycan to IgG antibody effector functions, the regulation of the antibody glycosylation in vivo, implications for the rational design of IgG antibody-based therapeutics, and touch upon the contribution of glycosylation to other immunoglobulin isotypes.
      PubDate: 2013-06-25
      DOI: 10.3390/antib2030392
      Issue No: Vol. 2, No. 3 (2013)
       
  • Antibodies, Vol. 2, Pages 415-425: In Vivo Secretion of Bispecific
           Antibodies Recruiting Lymphocytic Effector Cells

    • Authors: Marta Compte, Natalia Nuñez-Prado, Laura Sanz, Luis Alvarez-Vallina
      Pages: 415 - 425
      Abstract: Engineered Fc-lacking bispecific antibodies have shown an exceptionally high potency for recruiting lymphocyte effector cells and enhancing antitumor activity, which is under evaluation in several clinical trials. However, current treatment regimens raise some issues that should be considered, such as the high cost of clinical-grade bispecific antibodies and the achievement of sustained therapeutic plasma levels. The use of gene transfer methods may circumvent problems related to large-scale production and purification, and result in sustained therapeutic plasma concentrations of the Fc-lacking bispecific antibodies. In fact, terminally differentiated cells and non-terminally differentiated cells can be genetically modified to secrete functionally active bispecific antibodies exerting clear anti-tumor effects. This review highlights the relevance of different promising strategies for in vivo delivery of therapeutic bispecific antibodies.
      PubDate: 2013-06-27
      DOI: 10.3390/antib2030415
      Issue No: Vol. 2, No. 3 (2013)
       
  • Antibodies, Vol. 2, Pages 426-451: Molecular Engineering of Therapeutic
           Cytokines

    • Authors: Rodrigo Vazquez-Lombardi, Brendan Roome, Daniel Christ
      Pages: 426 - 451
      Abstract: Over the past three decades, a large body of work has been directed at the development of therapeutic cytokines. Despite their central role in immune modulation, only a handful of cytokine therapeutics has achieved regulatory approval. One of the major challenges associated with the therapeutic use of cytokines relates to their short serum half-life and low bioavailability. High doses are required to overcome these problems, which often result in dose-limiting toxicities. Consequently, most cytokines require protein engineering approaches to reduce toxicity and increase half-life. For this purpose, PEGylation, fusion proteins, antibody complexes and mutagenesis have been utilized. Here, we summarize past, recent and emerging strategies in this area.
      PubDate: 2013-07-03
      DOI: 10.3390/antib2030426
      Issue No: Vol. 2, No. 3 (2013)
       
  • Antibodies, Vol. 2, Pages 452-500: Developments and Challenges for
           mAb-Based Therapeutics

    • Authors: Sumit Goswami, Wei Wang, Tsutomu Arakawa, Satoshi Ohtake
      Pages: 452 - 500
      Abstract: The continuous increase in the number of approved monoclonal antibody (mAb)-based therapy suggests that mAbs, and their derivatives, will continue to be the focus of the biotherapeutics industry for years to come. Although vast improvements in our capability to manufacture, characterize, and stabilize mAbs have been achieved, there are still challenges to be overcome. These include analytical and stabilization approaches associated with the development of high concentration mAb formulations. In addition, several mAb-based modalities are under development, including antibody drug conjugates (ADCs), fusion proteins, and bispecific antibodies (bsAbs), all designed to overcome the limitations encountered with mAb therapy. The current status of their development, with emphasis on manufacturing challenges as well as preliminary clinical results, will be reviewed.
      PubDate: 2013-08-16
      DOI: 10.3390/antib2030452
      Issue No: Vol. 2, No. 3 (2013)
       
  • Antibodies, Vol. 2, Pages 501-516: Development of an Antibody for
           Detection of Rhamnolipids Characterized as a Major Bacterial Virulence
           Factor

    • Authors: Dimitrios Giagkas, Theodora Choli-Papadopoulou, Anastasia Pantazaki
      Pages: 501 - 516
      Abstract: Rhamnolipids (RLs), the glycolipidic biosurfactants found initially as exoproducts of the opportunistic pathogen Pseudomonas aeruginosa, are characterized as virulence factors contributing to its pathogenesis infections. However, RLs are also produced by various bacterial species. They consist of a gluconic part, usually containing one or two rhamnoses, and a lipid part, containing one or two hydroxy-fatty acids. In this study, we present both the isolation of RLs from bacterial cultures of the non-pathogenic bacterium Thermus thermophilus as well as the development of the rabbit antibody directed against them. The antibody was titrated and evaluated, in respect of its recognition selectivity. Between both RLs constituents, it specifically recognized only the hydroxydecanoic acid between the fatty acids tested, contrary to rhamnose. The potential of the antibody to recognize both purified RLs and RLs present in crude extracellular media produced by T. thermophilus and Escherichia coli cultures, is evidenced by Dot Blot immuno-reaction. The development of this antibody is addressed in detail, as the sensitive analytical technique, and its potential use would facilitate the implementation of rhamnolipids’ detection, or may be a useful and promising tool for determining these microbial secondary metabolites and virulence factors secreted in extracellular culture media or in biological fluids during infections.
      PubDate: 2013-08-28
      DOI: 10.3390/antib2030501
      Issue No: Vol. 2, No. 3 (2013)
       
  • Antibodies, Vol. 2, Pages 517-534: T-Cell Receptor-Like Antibodies:
           Targeting the Intracellular Proteome Therapeutic Potential and Clinical
           Applications

    • Authors: Maya Cohen, Yoram Reiter
      Pages: 517 - 534
      Abstract: Major histocompatibility complex (MHC) class I molecules are key in the immune response against malignant cells by shaping the T-cell repertoire and presenting peptides from endogenous antigens to CD8+ cytotoxic T cells. Because of their unique specificity, MHC-peptide complexes are a desirable target for novel immunotherapeutic approaches. These complexes can be targeted by recombinant T-cell receptors (TCRs). However, most TCRs produced thus far have affinities which are too low for target detection under normal assay conditions, and limited stability (due to their generation in a single-chain version). Developing high-affinity soluble antibody molecules endowed with a TCR-like specificity toward tumor epitopes, termed TCR-like antibodies, addresses the low affinity of TCRs. These TCR-like antibodies are being developed as a new immunotherapeutic class for targeting tumor cells and mediating their specific killing. In addition, these antibodies are valuable research reagents enabling the study of human class I peptide-MHC ligand-presentation and TCR–peptide–MHC interactions.
      PubDate: 2013-09-17
      DOI: 10.3390/antib2030517
      Issue No: Vol. 2, No. 3 (2013)
       
  • Antibodies, Vol. 2, Pages 168-192: Isolation of Panels of Llama
           Single-Domain Antibody Fragments Binding All Nine Neuraminidase Subtypes
           of Influenza A Virus

    • Authors: Michiel Harmsen, Juliette Blokker, Sylvia Pritz-Verschuren, Willem Bartelink, Herman van der Burg, Guus Koch
      Pages: 168 - 192
      Abstract: Avian influenza A virus comprises sixteen hemagglutinin (HA) and nine neuraminidase (NA) subtypes (N1–N9). To isolate llama single-domain antibody fragments (VHHs) against all N subtypes, four llamas were immunized with mixtures of influenza viruses. Selections using influenza virus yielded predominantly VHHs binding to the highly immunogenic HA and nucleoprotein. However, selection using enzymatically active recombinant NA (rNA) protein enabled us to isolate NA binding VHHs. Some isolated VHHs cross-reacted to other N subtypes. These were subsequently used for the capture of N subtypes that could not be produced as recombinant protein (rN6) or were enzymatically inactive (rN1, rN5) in phage display selection, yielding novel VHHs. In total we isolated 188 NA binding VHHs, 64 of which were expressed in yeast. Most VHHs specifically recognize a single N subtype, but some VHHs cross-react with other N-subtypes. At least one VHH bound to all N subtypes, except N4, identifying a conserved antigenic site. Thus, this work (1) describes methods for isolating NA binding VHHs, (2) illustrates the suitability of llama immunization with multiple antigens for retrieving many binders against different antigens and (3) describes 64 novel NA binding VHHs, including a broadly reactive VHH, which can be used in various assays for influenza virus subtyping, detection or serology.
      PubDate: 2013-04-10
      DOI: 10.3390/antib2020168
      Issue No: Vol. 2, No. 2 (2013)
       
  • Antibodies, Vol. 2, Pages 193-208: In Vivo Applications of Single Chain Fv
           (Variable Domain) (scFv) Fragments

    • Authors: Philippe Monnier, Robin Vigouroux, Nardos Tassew
      Pages: 193 - 208
      Abstract: Single chain variable domain (Fv) fragments (scFv) are powerful tools in research and clinical settings, owing to better pharmacokinetic properties compared to the parent monoclonal antibodies and the relative ease of producing them in large quantities, at low cost. Though they offer several advantages, they suffer from lower binding affinity and rapid clearance from circulation, which limits their therapeutic potential. However, these fragments can be genetically modified to enhance desirable properties, such as multivalency, high target retention and slower blood clearance, and as such, a variety of scFv formats have been generated. ScFvs can be administered by systemic injection for diagnostic and therapeutic purposes. They can be expressed in vivo through viral vectors in instances where large infection rates and sustenance of high levels of the antibody is required. ScFvs have found applications as tools for in vivo loss-of-function studies and inactivation of specific protein domains, diagnostic imaging, tumor therapy and treatment for neurodegenerative and infectious diseases. This review will focus on their in vivo applications.
      PubDate: 2013-04-11
      DOI: 10.3390/antib2020193
      Issue No: Vol. 2, No. 2 (2013)
       
  • Antibodies, Vol. 2, Pages 209-235: Diving through Membranes: Molecular
           Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor
           Toxins

    • Authors: Hendrik Fuchs, Christopher Bachran, David Flavell
      Pages: 209 - 235
      Abstract: Membranes are vital barriers by which cells control the flux of molecules and energy between their exterior and interior and also between their various intracellular compartments. While numerous transport systems exist for ions and small molecules, the cytosolic uptake of larger biological molecules and in particular antibody-targeted drugs, is a big challenge. Inducing leakage of the plasma membrane is unfavorable since the target cell specificity mediated by the antibody would likely be lost in this case. After binding and internalization, the antibody drug conjugates reach the endosomes. Thus, enforcing the endosomal escape of anti-tumor toxins without affecting the integrity of other cellular membranes is of paramount importance. Different strategies have been developed in the last decades to overcome endosomal accumulation and subsequent lysosomal degradation of targeted protein-based drugs. In this review we summarize the various efforts made to establish efficient techniques to disrupt the endosomal membrane barrier including the use of molecular ferries such as cell penetrating peptides or viral membrane fusion proteins, endosomal leakage inducing molecules such as saponins or monensin and physicochemical methods as represented by photochemical internalization.
      PubDate: 2013-04-17
      DOI: 10.3390/antib2020209
      Issue No: Vol. 2, No. 2 (2013)
       
  • Antibodies, Vol. 2, Pages 236-269: Ricin and Ricin-Containing
           Immunotoxins: Insights into Intracellular Transport and Mechanism of
           action in Vitro

    • Authors: Monika Słomińska-Wojewódzka, Kirsten Sandvig
      Pages: 236 - 269
      Abstract: Ricin is a type II ribosome inactivating protein (RIP) isolated from castor beans. Its high toxicity classifies it as a possible biological weapon. On the other hand, ricin linked to specific monoclonal antibodies or used in other conjugates has powerful medical applications. Ricin consists of an A-chain (RTA) that damages ribosomes and inhibits protein synthesis, and a B-chain that plays a role in binding and cellular uptake. A number of recent studies have demonstrated that ricin-induced inhibition of protein synthesis is not the only mechanism responsible for cell death. It turns out that ricin is able to induce apoptosis in different cell lines and multiple organs in animals. However, the molecular link between protein synthesis inhibition and ricin-dependent triggering of apoptotic cell death is unclear. This review describes the intracellular transport of ricin and ricin-based immunotoxins and their mechanism of action in different non-malignant and cancer cell lines. Moreover, various ricin-containing immunotoxins, their composition, medical applications and side-effects will be described and discussed. Understanding the mechanism of action of ricin-based immunotoxins will facilitate construction of effectively acting immunotoxins that can be used in the clinic for cancer treatment.
      PubDate: 2013-04-19
      DOI: 10.3390/antib2020236
      Issue No: Vol. 2, No. 2 (2013)
       
  • Antibodies, Vol. 2, Pages 270-305: Antibody-Directed Phototherapy (ADP)

    • Authors: Pye Hayley, Ioanna Stamati, Gokhan Yahioglu, M. Butt, Mahendra Deonarain
      Pages: 270 - 305
      Abstract: Photodynamic therapy (PDT) is a clinically-approved but rather under-exploited treatment modality for cancer and pre-cancerous superficial lesions. It utilises a cold laser or LED to activate a photochemical reaction between a light activated drug (photosensitiser-drug) and oxygen to generate cytotoxic oxygen species. These free radical species damage cellular components leading to cell death. Despite its benefits, the complexity, limited potency and side effects of PDT have led to poor general usage. However, the research area is very active with an increasing understanding of PDT-related cell biology, photophysics and significant progress in molecular targeting of disease. Monoclonal antibody therapy is maturing and the next wave of antibody therapies includes antibody-drug conjugates (ADCs), which promise to be more potent and curable. These developments could lift antibody-directed phototherapy (ADP) to success. ADP promises to increase specificity and potency and improve drug pharmacokinetics, thus delivering better PDT drugs whilst retaining its other benefits. Whole antibody conjugates with first generation ADP-drugs displayed problems with aggregation, poor pharmacokinetics and loss of immuno-reactivity. However, these early ADP-drugs still showed improved selectivity and potency. Improved PS-drug chemistry and a variety of conjugation strategies have led to improved ADP-drugs with retained antibody and PS-drug function. More recently, recombinant antibody fragments have been used to deliver ADP-drugs with superior drug loading, more favourable pharmacokinetics, enhanced potency and target cell selectivity. These improvements offer a promise of better quality PDT drugs.
      PubDate: 2013-04-25
      DOI: 10.3390/antib2020270
      Issue No: Vol. 2, No. 2 (2013)
       
  • Antibodies, Vol. 2, Pages 306-320: Single Domain Antibody Fragments as
           Drug Surrogates Targeting Protein–Protein Interactions inside Cells

    • Authors: Jia Zeng, Jing Zhang, Tomoyuki Tanaka, Terence Rabbitts
      Pages: 306 - 320
      Abstract: Many human diseases are caused by mutant or abnormal protein functions that are largely confined to the inside of cells, rather than being displayed on the abnormal cell surface. Furthermore, many of the functional consequences of aberrant proteins, such as in cancer cells, are due to protein–protein interactions (PPIs). Developing reagents that can specifically interfere with PPI is an important goal for both therapeutic use and as reagents to interrogate the functional importance of PPI. Antibody fragments can be used for inhibiting PPI. Our recent technology development has provided a set of simple protocols that allow development of single antibody variable (V) region domains that can function inside the reducing environment of the cell. The heavy chain variable region (VH) segments mainly used in this technology are based on a designer framework that folds inside cells without the need for the intra-chain disulphide bond and can be used as drug surrogates to determine on-target effects (target validation) and as templates for small molecule drug development. In this review, we discuss our work on single domains as intracellular antibodies and where this work might in the future.
      PubDate: 2013-05-02
      DOI: 10.3390/antib2020306
      Issue No: Vol. 2, No. 2 (2013)
       
  • Antibodies, Vol. 2, Pages 321-337: Characterization of a Phospho-Specific
           Antibody to the Fcε Receptor γ Chain, Reveals Differences in the
           Regulation of Syk and Akt Phosphorylation

    • Authors: Ryo Suzuki, Sarah Leach, Barbara Dema, Juan Rivera
      Pages: 321 - 337
      Abstract: We previously demonstrated that the Fc receptor γ-chain Y58(C-terminal tyrosine) is highly susceptible to dephosphorylation; a mechanism that controls the extent of Syk activation and the downstream signaling in mast cells. Here, we explored the importance of the γ-chain Y47 (N-terminal tyrosine) in mast cell signaling. We generated a highly sensitive and versatile phospho-specific antibody that recognized the phosphorylated Y47 in various species. Using this antibody, we found that mutation of the FcεRIβ Y219 to phenylalanine caused a loss in the phosphorylation of the γ-chain Y47, consistent with the previously described role of Y219 in Lyn association with FcεRIβ and subsequent FcεRIγ phosphorylation. These conditions also diminished the tyrosine phosphorylation of Syk and LAT1 but, surprisingly, not the phosphorylation of Akt at T308. Mutation of Y47 or Y58 of the γ-chain also caused a marked inhibition of Syk and LAT1 phosphorylation, but only the latter mutant showed a reduction in Akt phosphorylation. These findings show that the full phosphorylation of Syk and LAT1 requires the FcεRIβ Y219 and both Y47 and Y58 of the γ-chain. However, T308 phosphorylation of Akt is largely independent of FcεRIγ Y47 phosphorylation and of the Lyn-binding site (Y219) on the FcεRIβ.
      PubDate: 2013-05-13
      DOI: 10.3390/antib2020321
      Issue No: Vol. 2, No. 2 (2013)
       
  • Antibodies, Vol. 2, Pages 338-352: Immunotherapy of B-Cell Lymphoma with
           an Engineered Bispecific Antibody Targeting CD19 and CD5

    • Authors: Sandra Lüttgau, Dorothée Deppe, Saskia Meyer, Regina Fertig, Hossein Panjideh, Martin Lipp, Oliver Schmetzer, Antonio Pezzutto, Frank Breitling, Gerhard Moldenhauer
      Pages: 338 - 352
      Abstract: Using genetic engineering a humanized Fab fragment with specificity for CD19 was fused to a disulfide-stabilized single-chain antibody (dsFv) recognizing CD5. This format should show reduced immunogenicity and improved tissue penetration. The specificity of bsAb FabCD19xdsFvCD5 binding to target cells was verified by flow cytometry on B and T lymphoma cell lines. Binding affinities of both arms were compared with the bivalent parental antibodies against CD19 and CD5 by binding competition assay. Redirected lysis of B lymphoma cells by preactivated PBMC from healthy donors was demonstrated in a chromium-release assay. A clear dose-response relationship could be established in the range from 1 ng/mL to 10 mg/mL bsAb. To evaluate the in vivo efficacy of bsAb FabCD19xdsFvCD5, NOD/SCID mice were intravenously injected with luciferase transfected Raji lymphoma cells together with pre-activated PBMC. Mice received five injections of therapeutic bsAb or control antibodies. While in the control groups all mice died within 40 to 50 days, 40% of bsAb treated animals survived longer than 60 days.
      PubDate: 2013-05-14
      DOI: 10.3390/antib2020338
      Issue No: Vol. 2, No. 2 (2013)
       
  • Antibodies, Vol. 2, Pages 353-370: The Development of Bispecific
           Hexavalent Antibodies as a Novel Class of DOCK-AND-LOCKTM (DNLTM)
           Complexes

    • Authors: Chien-Hsing Chang, Edmund Rossi, Yang Wang, Thomas Cardillo, David Goldenberg
      Pages: 353 - 370
      Abstract: The DOCK-AND-LOCKTM (DNLTM) method provides a modular approach to develop multivalent, multifunctional complexes of defined structures, of which bispecific hexavalent antibodies (bsHexAbs) are prominent examples with potential applications in targeted therapy for malignant, autoimmune, and infectious diseases. Currently, bsHexAbs are constructed by derivatizing a divalent IgG, at the carboxyl termini of either the heavy chain (the CH3-format) or the light chain (the Ck-format), to contain two stabilized dimers of Fab having a different specificity from the IgG. In this review, we briefly outline the features of the DNLTM method and describe key aspects of bsHexAbs examined with diverse preclinical studies, which include binding affinity to target cells, induction of signaling pathways, effector functions, serum stability, pharmacokinetics, and antitumor activity in human tumor xenograft models. Our findings favor the selection of the CK- over the CH3-format for further exploration of bsHexAbs in clinical trials.
      PubDate: 2013-05-23
      DOI: 10.3390/antib2020353
      Issue No: Vol. 2, No. 2 (2013)
       
  • Antibodies, Vol. 2, Pages 371-391: Role and Redirection of IgE against
           Cancer

    • Authors: Elisa Nigro, Antonio Siccardi, Luca Vangelista
      Pages: 371 - 391
      Abstract: IgE is a highly elusive antibody class, yet a tremendously powerful elicitor of immune reactions. Despite huge efforts spent on the characterization and understanding of the IgE system many questions remain either unanswered or only marginally addressed. One above all relates to the role of IgE. A common doubt is based on whether IgE mode of action should only be relegated to anti-parasite immunity and allergic manifestations. In search for a hidden role of IgE, reports from several laboratories are described herein in which a natural IgE link to cancer or the experimental redirection of IgE against cancer have been investigated. Epidemiological and investigational studies are trying to elucidate a possible direct intervention of endogenous IgE against cancer, raising thus far no definitive evidence. Conversely, experimental approaches implementing several strategies and engineered IgE formats built up a series of convincing results indicating that cancer might be tackled by the effector functions of this immunoglobulin class. Because of its peculiar immune features, IgE may present a superior anti-tumor performance as compared to IgG. However, extreme care should be taken on how IgE-based anti-tumor approaches should be devised. Overall, IgE appears as a promising resource, likely destined to enrich the anti-cancer arsenal
      PubDate: 2013-05-28
      DOI: 10.3390/antib2020371
      Issue No: Vol. 2, No. 2 (2013)
       
 
 
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