Male reproductive health statement (XIIIth international symposium on Spermatology,may 9th–12th 2018, Stockholm,Sweden

On the occasion of the XIIIth International Symposium on Spermatology held from 9 to 13 May 2018 in Stockholm (Sweden), participants (guest speakers and audience) collectively felt the need to make a public statement on the general issue of male reproductive health. Our intention is to raise awareness of what we believe is a neglected area of research despite alarming situations around the world. The disclosure strategy desired by the co-authors is to bring it to the attention of the greatest number partly by considering co-publication in the various periodicals dealing with Reproductive Biology and Andrology. BaCA’s editorial office accepted this mission and found it natural that our periodical, the official journal of the French Andrology Society (SALF), should carry this message.     

International Congress of the German Mycological Society,University Hamburg,Sept. 16th–23th 2010

Announcement

International Congress of the German Mycological Society, University Hamburg, Sept. 16th–23th 2010     

Principaux effets neurotropes et psychotropes des méthylxanthines (caféine, théophylline, théobromine, paraxanthine)

Caffeine, the main alkaloid in coffee, corresponds to the 1-3-7 trimethylxanthine. Its concentration is lower in tea and chocolate, where it is associated with theophylline, 1-3 dimethylxanthine, in tea and with theobromine, 3-7 dimethylxanthine, in chocolate. Paraxanthine, 1-7dimethylxanthine, for its part, is produced by the hepatic metabolism of caffeine operated by a cytochrome of 1A2 type. The effects of these methylxanthines on awaking, anxiety, neuroprotection in Alzheimer’s and Parkinson’s diseases, mood, schizophrenia and nociception are briefly considered. This review is concluded by indicating that these effects of methylxanthines may be modified by various associated substances, such as polyphenols displaying antioxydant properties.     

24th International Ornithological Congress, Hamburg, Germany, 13–19 August 2006

Announcement

24th International Ornithological Congress, Hamburg, Germany, 13–19 August 2006     

9th Annual European Antibody Congress,November 11–13, 2013, Geneva,Switzerland

The annual European Antibody Congress (EAC) has traditionally been the key event for updates on critical scientific advances in the antibody field, and 2013 was no exception. Organized by Terrapinn, the well-attended meeting featured presentations on considerations for developing antibodies and antibody-like therapeutics, with separate tracks for antibody-drug conjugates, naked antibodies, and multispecific antibodies or protein scaffolds. The overall focus of the EAC was current approaches to enhance the functionality of therapeutic antibodies or other targeted proteins, with the ultimate goal being improvement of the safety and efficacy of the molecules as treatments for cancer, immune-mediated disorders and other diseases. Roundtable discussion sessions gave participants opportunities to engage in group discussions with industry leaders from companies such as Genmab, Glenmark Pharmaceuticals, MedImmune, Merrimack Pharmaceuticals, and Pierre Fabre. As the 2013 EAC was co-located with the World Biosimilar Congress, participants also received an update on European Medicines Agency guidelines and thoughts on the future direction and development of biosimilar antibodies in the European Union.     

15th Annual spring brain conference,march 10–13, 2004,summary report

The present study was designed (1) to characterize the subliminal responses of dorsal horn neurons to stimulation of the sural nerve, and (2) to correlate the type of response to this stimulus with the responses to natural mechanical stimulation of the skin. To accomplish this, intracellular and extracellular recordings were carried out in L⁶ and L⁷ dorsal horn neurons in the cat. The excitatory responses of each cell to electrical stimulation of the sural nerve and to mechanical stimulation of the skin were noted.

Of 35 dorsal horn cells recorded intracellularly, 11 responded with impulses to sural nerve stimulation, 9 responded with excitatory postsynaptic potentials (EPSPs) but not impulses, and 15 had no excitatory responses to this stimulus. The type of response to sural nerve stimulation was strongly correlated with receptive field modality. Most cells receiving an input from high-threshold cutaneous mechanoreceptors responded with impulses or gave no excitatory response to sural nerve stimulation, whereas most cells that had only low-threshold mechanoreceptor input responded with EPSPs only or gave no response. In cells with only low-threshold (LT) mechanoreceptive input, response to sural nerve stimulation was highly correlated with receptive field locus. Those LT cells with no excitatory responses to sural nerve stimulation had receptive fields confined to the foot and/or toes, whereas those that gave EPSPs had more proximal receptive fields. The possible significance of these data with reference to changes observed after lesions, such as increased response to sural nerve stimulation, increased receptive field size, and somatotopic reorganization, is discussed.     

Human Proteome Organisation’s 7th World Congress, 2008

The annual world congress of Human Proteome Organisation (HUPO) is one of the premier meetings in proteomics. Rotating between Europe, North America and Asia/Oceana, this year’s host city was Amsterdam, The Netherlands. Proteomics still being a rapidly evolving field, HUPO meetings provide a platform for technical advancements in protein purification and separation techniques, innovations in mass spectrometry and applications in bioinformatics and computational biology. A special focus of this year’s meeting was on proteome biology, indicating that the state of technology has progressed to a level permitting interrogation of biological systems in a meaningful way.     

4th European Antibody Congress 2008: December 1–3, 2008, Geneva,Switzerland

The Fourth European Antibody meeting, organized by Terrapin Ltd., was held in Geneva, a center of the European biopharmaceutical industry. Merck-Serono, NovImmune, Pierre Fabre and Therapeomic are located nearby, as are R&D centers of Boehringer-Ingelheim, Novartis, Roche and Sanofi-Aventis. Over 40 speakers and more than 200 delegates attended the event. Companies represented included Abbott, Ablynx, Adnexus/ BMS, Astra-Zeneca/ CAT/ Medimmune, BiogenIdec, BioRad, Centocor (Johnson & Johnson), Crucell/DSM, Domantis, Dyax, Genmab, Genzyme, Glycart/ Roche, Haptogen, Immunogen, Kyowa-Kirin, LFB, Medarex, Merck-Serono, Micromet, Novartis, Pierre Fabre Laboratories, Roche, Sanofi-Aventis, Seattle-Genetics, Transgene, UCB Celltech and Wyeth. Other attendees included those based in academe or government (University of Amsterdam, University of Zurich, Univeristy Hospital-Lyon, Ecole Polytechnique Federale de Lausanne, INSERM, Tufts University, US National Institutes of Health), consultants, and patent attorneys (Edwards, Angell, Palmer & Dodge). The meeting was very interactive and included exchanges during the many scheduled networking times (exhibitions, speed-networking, lunches and evening receptions). The first day of the three day conference was dedicated to advances in understanding antibody structure-function relationships. Challenges and opportunities in antibody development were the focus of the second day and the third day featured discussion of innovative antibodies and antibody alternatives.

• MAbs. 2009 Mar-Apr; 1(2): 93–103.
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• December 1, 2008 Day 1, Therapeutic antibodies: Advances in dissecting structure-function relationships

MAbs. 2009 Mar-Apr; 1(2): 93–103.

December 1, 2008 Day 1, Therapeutic antibodies: Advances in dissecting structure-function relationships

Alain BeckAuthor information Article notes Copyright and License information DisclaimerDepartment of Physico-Chemistry; Center of Immunology Pierre Fabre; Saint-Julien-en-Genevois, FranceCorresponding author.Correspondence to: Alain Beck; Centre d''Immunologie Pierre Fabre; 5 avenue Napoleon III; Saint-Julien-en-Genevois 74160 France; Email: moc.erbaferreip@kceb.nialaReceived 2009 Jan 20; Accepted 2009 Jan 20.Copyright © 2009 Landes BioscienceThe chairman, Alain Beck (Centre d''Immunologie Pierre Fabre), opened the meeting with the following remarks: Monoclonal antibodies (mAbs) and related-products (immunoconjugates, radioimmuno-conjugates, Fab fragments and Fc-fusion proteins) are the fastest growing class of pharmaceuticals, with nearly 30 products currently approved for a wide range of indications.^3,14 In just the last three years, six new antibodies and derivatives have reached the market. These included molecules that are novel formats, as well as first in class drugs in new therapeutic indications. In 2006, panitumumab (Vectibix) was the first fully human IgG2 mAb generated by immunization of humanized transgenic mice and the second anti-EGFR mAb to gain approval. Also in 2006, ranibizumab (Lucentis), the first E. coli-produced Fab fragment and the first affinity matured antibody, was approved as a treatment age-related macular degeneration. Later, tocilizumab (Actemra) a conventional IgG1, but directed against a new target (IL-6R), was registered in Japan; BLAs are pending both in the US and in Europe. In 2007, eculizumab (Soliris) was approved for paroxysmal nocturnal hemoglobinuria. Eculizumab was constituted by an original IgG2/4 hybrid format, and is unable to bind Fc receptors or activate the complement cascade. In 2008, rinolacept (Arcalyst), an IL-1R-Fc fusion protein also called IL-1 trap, was registered for cryopyrin-associated periodic syndromes. Also in 2008, certolizumab pegol (Cimzia) became the first PEGylated Fab fragment to gain approval. The product, indicated for Crohn disease, is produced in E. coli and conjugated to large PEG residues (40 kDa). Interestingly, from a structure-function standpoint, certolizumab was crystallized and the 3D model of this original PEG-Fab was recently reported.⁴ In addition to these six new antibody or antibody-related product approvals, the first two biosimilar antibodies, Reditux (a copy of rituximab developed by Dr Reddy) and Clotinab (a biogeneric of abciximab developed by ISU ABXIS), were recently launched in India and in South Korea, respectively. Active discussions are ongoing regarding whether such generic biopharmaceuticals may also be approved in Europe, following approval of other glycoproteins such as erythropoietin.¹⁶     

5th Annual Monoclonal Antibodies Conference: March 24–25, 2009, London,UK

The conference, which was organized by Visiongain and held at the BSG Conference Center in London, provided an excellent opportunity for participants to exchange views on the development, production and marketing of therapeutic antibodies, and discuss the current business environment. The conference included numerous interactive panel and group discussions on topics such as isotyping for therapeutic antibodies (panel chair: Nick Pullen, Pfizer), prospects for fully human monoclonal antibodies (chair: Christian Rohlff, Oxford BioTherapeutics), perspectives on antibody manufacturing and development (chair: Bo Kara, Avecia), market impact and post-marketing issues (chair: Keith Rodgers, Bodiam Consulting) and angiogenesis inhibitors (chair: David Blakey, AstraZeneca).

• MAbs. 2009 Jul-Aug; 1(4): 308.
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• March 24, 2009 Day 1

2009 Jul-Aug; 1(4): 308.

March 24, 2009 Day 1

Mari HerigstadAuthor information Copyright and License information DisclaimerVisiongain; London, UKCorresponding author.Correspondence to: Mari Herigstad; Visiongain; BSG House; 226-236 City Road; London EC1V 2QU UK; Email: moc.liamg@datsgireh.iramCopyright © 2009 Landes BioscienceThe first day was dedicated to discussion of antibody development and engineering, as well as debate on use of various types of antibodies. The session was chaired by David Blakey (AstraZeneca). The day opened with an overview on global trends in the antibody development and probabilities of approval success for human and humanized monoclonal antibodies (mAbs). The speakers then provided insights into the engineering and development of new therapeutic antibodies. Prospects for novel antibody formats, and assessment of immunogenicity, stability and aggregation risks in the development of therapeutic antibodies through use of in vivo and in silico methods were reviewed.Global trends in antibody development were discussed by Janice Reichert (Tufts Center for the Study of Drug Development and Editor-in-Chief, mAbs). Dr. Reichert emphasized the increased focus on mAbs as therapeutic agents. Of the therapeutic proteins entering clinical study each year, the majority are mAbs. Major pharmaceutical firms are acquiring biotechnology companies to enter this market and new solutions to problems of immunogenicity, stability, affinity, specificity and production are being developed. The research on clinical pipelines undertaken at Tufts CSDD allows calculation of metrics such as clinical development and approval times and probabilities of approval success. Insights gained from these results are important for strategic planning.The cumulative approval success rate for humanized mAbs was 16% for candidates entering clinical study during 1988 and 2008, and 29% for candidates entering clinical study during 1988 and 1997.¹ A conservative estimate of the success rate for humanized monoclonal antibodies would be somewhere in between, at approximately 20%. The trend, however, is toward fully human monoclonal antibodies. There are currently two marketed human mAbs, with another four in regulatory review. The cumulative US approval success rate for human antibodies is currently low, but will rise to 18% if the four in regulatory review are approved.In terms of therapeutic categories, oncology mAbs comprises approximately 50% of the total. Of 228 oncology mAbs that have entered clinical study since 1988, 56% are currently in clinical development. By comparison, 125 immunological mAb therapeutics have entered clinical study since 1990, of which 54% are currently in clinical development. The cumulative success rate for humanized oncology and immunological mAbs is 15% and 20%, respectively. Other therapeutic categories are being considered, including infectious disease. Sixteen anti-infective mAbs are currently in clinical study and one anti-infective mAb (palivizumab) has been approved to date. Oncology and immunology mAbs exhibit similar patterns for phase lengths and transition probabilities. The phase transition probability for phase 1 to 2 is high, followed by a lower phase 2–3 transition probability due to a proof-of-concept barrier. The transition probability for phase 3 to approval is comparable to that of phase 1 to 2.¹Other interesting trends include an increasing emphasis on antibody fragments.² Fragments may be easier and less costly to produce, but have shorter circulating half-life compared to full size antibodies and no effector functions unless this is added. Also worth noting is the growing prevalence of modified versions of mAbs (glycosylation and Fc region engineering) and improvements on circulation half-life through PEGylation.^3,4 Production methods as well as development and approval pathways for mAbs are well established and marketing approvals are set to increase if success rates are consistent with previous rates. This, together with competitive R&D times and potentially large markets, makes mAbs attractive for development as therapeutics.Julian Burke (Genetix) presented a clinical update on the selection of cell lines for antibody expression and protein production. A hybridoma is a hybrid cell that has been engineered to produce a desired antibody in large amounts. ClonePix FL is an antigen based system for in vitro detection and selection of hybridomas. The system incorporates plating hybridomas into a 3D cell matrix-a method which was first described 25 years ago.⁵ Whilst this method is not new, the novel aspect of the ClonePix system lies in the screening and collection of only those clones secreting a specific antibody. There are two options for screening hybridomas: immunoglobin G (IgG) secretion assays and antigenspecific assays. Unlike IgG secretion assays, antigen-specific assays isolate only antigen-specific clones with the desired IgG isotype. The system can also optimize production through detection of the highest producing cell lines. This approach allows the production of 10,000 clones in three weeks compared to the conventional approach which produces approximately 1,000 clones in two months. After a few days growth post-selection, isolated clones can be rapidly re-screened for cell-line stability. This stability test can be run in parallel with the scaling up of clones, thus making the process highly time efficient. To summarize, ClonePix minimizes the labor requirement, shortens the process timeline and permits parallel interrogation of multiple antigens.Masa Fujiwara (Chiome Bioscience) described the generation of antibodies using a novel antibody-generation technology called the ADLib (Autonomously Diversifying Library) System. This is a selection technology system based on cell-cell interactions and surface-displayed antigens in their native conformations. The system provides high-affinity antibody generation against difficult antigens such as self/human/homologous antigens, GPCRs, sugars/lipids, haptens and pathogens.Dr. Fujiwara explained how the ADLib system can be used to generate specific monoclonal antibodies using a chicken B-cell line (DT40) that undergoes gene conversion at immunoglobulin loci. This gene conversion is enhanced by treatment of the cells with trichostatin A, a histone deacetylase inhibitor. DT40 cells that are specific to the target antigen are obtained through ‘fishing’ the ADLib library with antigens conjugated with magnetic beads. This selection process and the subsequent screening for specificity can be completed in approximately one week.^6,7 As such, one of ADLib''s attractive features is the system''s ability to develop diverse monoclonal antibodies within weeks, not months.Optimization of antibodies, with a focus on structure-function relationships, was discussed by Bryan Edwards (MedImmune). Complementary determining regions (CDRs) are found in the variable domains of antibodies and confer the antigen specificity of the molecule. The CDR regions show high levels of natural sequence variability and are targeted during somatic hypermutation to generate higher affinity antibodies to the antigen. When considering strategies for in vitro optimization of antibodies, the CDR regions are typically targeted for mutagenesis. Three CDRs (CDR1, CDR2 and CDR3) are found on both the heavy and light chain regions of an antibody, and the highest level of natural sequence variability is found in the heavy chain CDR3 domain.Dr. Edwards described the optimization of two lead antibody candidates, where the heavy and light chain CDR3 domains were randomized at all amino acid positions and higher affinity variants isolated by both phage and ribosome display. Further gains in antibody potency were then obtained by combining the beneficial amino changes introduced into the heavy and light chain CDR3 domains. Additional sequence space was also explored outside of the CDR3 regions by the generation of error-prone libraries, and subsequent selection by ribosome display. Lead antibody candidates were improved several thousand-fold in potency through a combination of these approaches.By studying the solved crystal structures of Fab:antigen complexes, Dr. Edwards explained that not all CDR regions make direct contact with the target antigen and that amino acids in the framework regions can also contribute to antibody specificity. Moreover, beneficial changes introduced during optimization are not always due to the introduction of new contacts with the target antigen. Several amino acid changes can indirectly improve the potency of the antibody despite being some distance from the antigen binding site. It has been postulated that these amino acid changes improved affinity by reducing the free energy of the antibody:antigen complex, for example by stabilizing CDR loop conformations or by improving the stability of the VH-VL interface.Pavel Bondarenko (Amgen) presented data on the structure and function of disulfide isoforms of the human IgG2 subclass. There are five different known human antibody isotypes; IgA, IgD, IgE, IgM and IgG, of which IgG is the isotype that provides the majority of immune responses against pathogens. IgG antibodies have predictable properties, controlled function and long circulation half-life. Due to these properties, IgG antibodies are the most common therapeutic modalities. There are four human IgG subclasses, IgG1, IgG2, IgG3 and IgG4, of which IgG1 is the most abundant.One therapeutic function of monoclonal IgG antibodies involves binding Fab regions to target receptors, which blocks ligand-receptor interaction. Additional functions include initiating cell destruction through the attraction of immune complexes by the Fc and hinge region on the antibody. Due to their lower affinity for Fc receptors than IgG1s, IgG2s show reduced propensity for activating immune responses. This may be beneficial in some therapeutic aspects.Scientists at Amgen have recently discovered that structural heterogeneity is a naturally occurring feature of human IgG2 antibodies.^8,9 These distinct IgG2 forms are due to differences in the disulfide connectivity at the hinge region. There are three human IgG2 isoforms; IgG2-A, IgG2-B and IgG2-A/B. IgG2-A is defined by structurally independent Fab domains and hinge region. In IgG2-B, on the other hand, both Fab regions are covalently linked to the hinge. IgG2-A/B is an arrangement in which only one Fab arm is covalently linked to the hinge through disulfide bonds.The disulfide isoforms may show differences in potency. Against a cell-surface receptor, IgG1 and IgG2-A forms of a mAb were shown to have approximately similar potency and both had greater potency that IgG2-B. The difference between the IgG2 isotopes was attributed to the greater flexibility of IgG2-A and its ability to bind with both Fab regions. IgG2 disulfide exchange is facilitated by the close proximity of cysteine residues at the hinge region of IgG2. The mutation of a single cysteine residue in the IgG2 hinge region resulted in a loss of disulfide heterogeneity.¹⁰ Also, redox treatments with a cysteine/cystamine mixture have been shown to cause enrichment of both IgG2-A and IgG2-B.⁹ Human IgG2 isoforms are dynamic and exhibit disulfide rearrangement in both blood and cell culture.¹¹ Initially, IgG2 exists as IgG2-A, and is then rapidly converted to the asymmetric IgG2-A/B, followed by a slower conversion to IgG2-B. The biological relevance of IgG2 isoforms and in vivo conversion is currently being studied.⁹Andrew Popplewell (UCB New Medicines) provided an introduction to the prospects for therapeutic antibody fragments. Out of the 22 currently FDA approved monoclonal antibody therapeutics, three are antibody fragment therapeutics. Antibody fragment formats include Fab regions, single chain variable domains (scFv) and variable loops on the heavy and light chain (dAbs).Antibody fragments are highly flexible formats that may be combined to form new multivalent or multi-specific structures. Compared to full-length IgGs, fragments may have improved biodistribution, tissue penetration,^12,13 target access, or potentially better safety profiles due to the lack of Fc regions. Antibody fragments can also be expressed in microbial systems. They also show shorter serum persistence, which, depending on use, can be either disadvantageous or advantageous. However, antibody fragment circulation time can be modified either through PEGylation,^3,4,14 or through use of serum proteins as carriers.¹⁵ Either strategy may alter the pharmacokinetic properties of fragments, allowing the infrequent therapeutic dosing commonly used for full-length IgG therapy.Stability is a major factor for the successful commercialization of antibody-based drugs. Fabs are generally more stable to thermal or physical stress compared to IgGs, and this stability is not affected by PEGylation or by antibody species origin (e.g. mouse, rat, human). ScFvs and dAbs typically exhibit reduced stability compared to Fabs, however advances in technology may contribute to improve stability in these fragments.Dr. Popplewell emphasized that a more complete understanding of biophysical properties and improved stability engineering are required before antibody fragments can reach their full potential. Full-length IgG1s offer active immune cell recruitment, and may thus be better suited for certain therapeutic uses, such as oncology treatments. The development of products with enhanced Fc functionality, the option of using inactive Fcs, and improvements in yields from mammalian cell expression systems are providing further options for the full length IgG format. Dr. Popplewell summarized by pointing out that the intended mechanism of action should guide the choice of format.The challenge of predicting immunogenicity in a potential drug was discussed by Phillipe Stas (Algonomics). This is a difficult, yet important, process because early and precise immunogenicity assessments can reduce the number of drugs that fail to demonstrate efficacy in clinical trials. In order to generate an accurate risk profile of the potential immunogenicity for a given drug, two questions in particular must be addressed. First, the probability of observing an immunogenic response must be analyzed. Second, the severity of the observed immunogenicity needs to be considered.Neutralizing antibody responses can neutralize not only the therapeutic protein, but also its endogenous counterpart; the latter may induce severe side-effects in the patient.¹⁶ Risk factors for immunogenicity include the degree of ‘non-self’ of the antibody, the dosing of the drug (acute versus repeated), route of administration (intravenous versus subcutaneous) and other drug characteristics such as clearance rate of the drug. The patient''s immune status and the properties of the disease (i.e., severity and availability of concomitant immunosuppressants) should be included in a risk analysis.The different drug development stages offer opportunities to use different strategies for immunogenicity assessment. In the clinical phase, the general approach is to conduct antidrug antibodies (ADA) screening on individuals exposed to the drug. However, efforts are now geared toward assessing immunogenicity at earlier stages. The generation of ADA is dependent on the presence of T-cell epitopes. These can be measured in the preclinical setting using in-vitro T-cell assays. Prior to this stage, in silico methods may be used to identify T-cell epitopes. One such T-cell epitope screening tool is Algonomics'' platform Epibase®, which can rapidly analyze and predict the potential immunogenicity of therapeutic protein leads. An in silico approach to T-cell identification can offer relatively inexpensive mapping of epitopes from a wide genetic background.¹⁷ Also, perhaps more importantly, the combined use of in vitro and in silico tools allows for a much more accurate and less time-consuming assessment of expected immunogenicity in a drug.In silico methods in the development of therapeutic antibodies were reviewed by Jesús Zurdo (Lonza Biologics). Dr. Zurdo focused on assessment of stability and aggregation risks. In addition to increased production costs, aggregation reduces product stability, increases immunogenicity and may also elevate the toxicity. AggreSolve is an in silico protein analysis platform that can be applied to predict and overcome protein stability and aggregation issues. The Aggresolve platform assesses protein aggregation propensity and identifies aggregation ‘hot-spots.’ The platform can also predict sequence changes that are likely to reduce aggregation propensity. This library of potential substitutions can then be used to re-engineer antibodies with elevated stability and fewer aggregation problems. Compared to wild-type, selected re-engineered molecules achieve significantly reduced aggregation levels whilst retaining biological activity. Furthermore, protein stabilisation using re-engineering methods can also translate into elevated antibody productivity.