International intellectual property strategies for therapeutic antibodies

Therapeutic antibodies need international patent protection as their markets expand to include industrialized and emerging countries. Because international intellectual property strategies are frequently complex and costly, applicants require sound information as a basis for decisions regarding the countries in which to pursue patents. While the most important factor is the size of a given market, other factors should also be considered.Key words: antibody, patent, international, PCT, filing strategy     

Implicit Attitudes towards People with Intellectual Disabilities: Their Relationship with Explicit Attitudes,Social Distance,Emotions and Contact

Implicit attitude research has expanded rapidly over the last decade and is seen as very promising as it counters biases present in much attitude research such as social desirability. However, most research in the area of intellectual disabilities has focused on explicit attitudes alone. This study examined implicit attitudes to this population and also examined their association with emotional reactions and contact, which have previously been found to have a significant influence on attitudes and stigma. A web based survey consisting of a single target Implicit Association Test, measures of explicit attitudes, social distance, and emotional reactions towards and contact with individuals with intellectual disabilities was completed by 326 adult UK residents. Implicit attitudes were not significantly associated with explicit attitudes, social distance or emotional reactions. Instead there were small to moderate associations between emotional reactions and explicit attitudes and social distance. Implicit attitudes did not vary according to participants’ level of contact with individuals with intellectual disabilities, type of the contact relationship (voluntary versus involuntary), gender or educational attainment. In contrast, these participant characteristics did affect explicit attitudes and social distance. Implicit attitudes towards individuals with intellectual disabilities were somewhat negative and, unlike explicit attitudes and stigma, did not vary according to participant demographics or contact. As they may have a negative impact on the lives of people with intellectual disabilities, implicit attitudes merit increased attention in research and interventions in the intellectual disabilities field.     

Molecular biology and Pauling's immunochemistry: a neglected dimension

This paper argues that there is a substantial overlap between the history of immunology and the history of molecular biology, an overlap manifested in the researches on antibodies during the 1930s and 1940s. This common ground is a product of intellectual developments, as well as institutional trends. Viewed from an intellectual vantage point of the 1930s and 1940s, molecular biology was essentially the study of the biological specificities of the so-called 'giant protein molecules'. Within the conceptual framework of early molecular biology, which was rooted in the protein view of life, the concepts of protein template, autocatalysis, and heterocatalysis were central in explaining the protein syntheses of genes, viruses, enzymes, hormones, and antibodies. Immunochemistry and serological genetics were at the heart of that research agenda. This paper also shows that the immunochemistry program of Linus Pauling, which focused on molecular mechanisms of antibody structure and function, and the projects in serological genetics at Caltech's biology division were supported by the Rockefeller Foundation under the aegis of its molecular biology program. Based on the close examination of intellectual and institutional factors, the histories of molecular biology and immunology in the pre-DNA era are seen as closely linked.     

Empowering the inventor--the case of monoclonal antibodies

Academic ownership of intellectual property facilitated wide dissemination and commercialization of antibody technology. Moves at the University of Cambridge to reclaim institutional IP rights should thus be treated with caution.     

Tales of the phylogenetic woods: The evolution and significance of evolutionary trees

The styles of continuing intellectual traditions can have a major effect on the way in which scientific findings are expressed. Darwin and Huxley, for all their intellectual daring followed the skeptical tactics of the Scottish Enlightenment and avoided the construction of human phylogenetic trees, even though they were aware of the evidence on which such could have been constructed. The romantic evolutionism of Haeckel, Keith, and many subsequent writers in English produced suggested phylogenies on the basis of largely hypothetical forms including Homo “alalus,” “stupidus,” and “Eoanthropus.” The structural aspects of phylogenetic schemes that derive from the French intellectual ethos, from catastrophism to cladistics and punctuated equilibria, have stressed discrete categorical entities in the tradition of Platonic essentialism and have tended to avoid a consideration of evolutionary dynamics.     

Suppression of <Emphasis Type="Italic">CCR</Emphasis> impacts metabolite profile and cell wall composition in <Emphasis Type="Italic">Pinus radiata</Emphasis> tracheary elements

Many plant-based systems have been developed as bioreactors to produce recombinant proteins. The choice of system for large-scale production depends on its intrinsic expression efficiency and its propensity for scale-up, post-harvest storage and downstream processing. Factors that must be considered include the anticipated production scale, the value and intended use of the product, the geographical production area, the proximity of processing facilities, intellectual property, safety and economics. It is also necessary to consider whether different species and organs affect the subcellular trafficking, structure and qualitative properties of recombinant proteins. In this article we discuss the subcellular localization and N-glycosylation of two commercially-relevant recombinant glycoproteins (Aspergillus niger phytase and anti-HIV antibody 2G12) produced in different plant species and organs. We augment existing data with novel results based on the expression of the same recombinant proteins in Arabidopsis and tobacco seeds, focusing on similarities and subtle differences in N-glycosylation that often reflect the subcellular trafficking route and final destination, as well as differences generated by unique enzyme activities in different species and tissues. We discuss the potential consequences of such modifications on the stability and activity of the recombinant glycoproteins.     

Non-human primate immune libraries combined with germline humanization

Panning of libraries constructed from immunised non-human primates (NHP) has not been widely used, even though this has proven to be a successful approach for the isolation of human-like antibody fragments with affinities in the nanomolar to the picomolar range. As recently demonstrated, after initial isolation of antibodies with such high affinities, germline humanization may be applied to these Fabs or scFvs to increase the similarity of their framework regions with those encoded by human germline genes. ‘Germlinized’ antibody fragments may be converted to full size IgGs; indications are given that these IgGs could be better tolerated in clinical use than human antibodies. The use of the combination of NHP immune libraries and germline humanization thus may compete with use of libraries of human origin, whether naïve or immune, and with synthetic libraries. In this report, the various approaches will be compared, and advantages of the two-step NHP-based method, as well as corresponding intellectual property aspects, will be discussed.     

Non-human primate immune libraries combined with germline humanization: An (almost) new,and powerful approach for the isolation of therapeutic antibodies

Panning of libraries constructed from immunised non-human primates (NHP) has not been widely used, even though this has proven to be a successful approach for the isolation of human-like antibody fragments with affinities in the nanomolar to the picomolar range. As recently demonstrated, after initial isolation of antibodies with such high affinities, germline humanization may be applied to these Fabs or scFvs to increase the similarity of their framework regions with those encoded by human germline genes. ‘Germlinized’ antibody fragments may be converted to full size IgGs; indications are given that these IgGs could be better tolerated in clinical use than human antibodies. The use of the combination of NHP immune libraries and germline humanization thus may compete with use of libraries of human origin, whether naïve or immune, and with synthetic libraries. In this report, the various approaches will be compared, and advantages of the two-step NHP-based method, as well as corresponding intellectual property aspects, will be discussed.Key words: non-human primate, antibody, naïve library, synthetic library, immune library, affinity, epitope, tolerance, patent     

Emotional intimacy with nature and life & intellectual interest in life of pre-service biology teachers for environmental education

We investigated emotional intimacy with nature and life, and intellectual interest in life among South Korean pre-service teachers (N = 114) training in biology education, analysing the differences between these two constructs as well as their relationship to environmental behaviour and sensitivity. In addition, differences in the respondents’ experiences of nature, concerns about environmental problems and willingness to perform environmental education were explored. Four groups of pre-service biology teachers, categorised by the two investigated personal variables, showed different responses for the environment-related characteristics and other variables. Our results suggest that biology teachers should have higher emotional and intellectual interest in nature and life, and a balance between emotional intimacy with nature and life, and intellectual interest in life is needed to prepare them.     

The Phenomenology of True Dreams in Maimonides

Maimonides' conception of true dreams posits an important role for the faculty of imagination within the growth of the intellectual self. However, unlike many modern theories of the dream, Maimonides requires one to subject the imagination to intellectual processes, in order to be able to harness the imagination for the practical knowledge. The imagination found in the dream images consists of objective graded levels based on the purity of the imagination from desire and the use of the intellect. The content of the dream is new piece of knowledge, a solution, a political agenda, or a vision for the future that needs to be contextualized within one's own life. Maimonides emphasizes the image as an intellectual object, specifically a single object and not the event. For Maimonides dreams do not give supernatural content nor are true dreams a universal part of daily life. They are extraordinary and do not have presentational immediacy.     

Phenotype and Micro-array characterization of duplication 11q22.1-q25 and review of the literature

Partial duplication of 11q is related to several malformations like growth retardation, intellectual disability, hypoplasia of corpus callosum, short nose, palate defects, cardiac, urinary tract abnormalities and neural tube defects. We have studied the clinical and molecular characteristics of a patient with severe intellectual disabilities, dysmorphic features, congenital inguinal hernia and congenital cerebral malformation which is referred to as cytogenetic exploration. We have used FISH and array CGH analysis for a better understanding of the double chromosomic aberration involving a 7p microdeletion along with a partial duplication of 11q due to adjacent segregation of a paternal reciprocal translocation t(7;11)(p22;q21) revealed after banding analysis. The patient's karyotype formula was: 46,XY,der(7)t(7;11)(p22;q21)pat. FISH study confirmed these rearrangement and array CGH technique showed precisely the loss of at least 140 Kb on chromosome7p22.3pter and 33.4 Mb on chromosome11q22.1q25. Dysmorphic features, severe intellectual disability and brain malformations could result from the 11q22.1q25 trisomy. Our study provides an additional case for better understanding and delineating the partial duplication 11q.     

Differences in Perception and in the Operational Level of Thinking of Children Four to Eight Years Old

Today the importance for intellectual development of a child's acquisition of the conservation of quantity is generally recognized. However, the question of the mechanism of the ontogeny of invariant perception has not yet been definitively resolved. Piaget and his disciples thought that the genesis of invariant perception depended basically on internal structural equilibria, as a result of which new structures (inventions) constituting the basis of intellectual development are formed. In recent years, adherents to this theory have begun to admit a limited possibility of intervening in the development of intelligence [7,8,12].     

Epitope mapping by solution NMR spectroscopy

Antibodies play an ever more prominent role in basic research as well as in the biotechnology and pharmaceutical sectors. Characterizing their epitopes, that is, the region that they recognize on their target molecule, is useful for purposes ranging from molecular biology research to vaccine design and intellectual property protection. Solution NMR spectroscopy is ideally suited to the atomic level characterization of intermolecular interfaces and, as a consequence, to epitope discovery. Here, we illustrate how NMR epitope mapping can be used to rapidly and accurately determine protein antigen epitopes. The basic concept is that differences in the NMR signal of an antigen free or bound by an antibody will identify epitope residues. NMR epitope mapping provides more detailed information than mutagenesis or peptide mapping and can be much more rapid than X‐ray crystallography. Advantages and drawbacks of this technique are discussed together with practical considerations. Copyright © 2015 John Wiley & Sons, Ltd.     

Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis–ptosis–intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello–Carey syndrome as well as the patient reported to have a “new” syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello–Carey syndrome, and suggest the single designation “Kaufman oculocerebrofacial syndrome”.     

The nature and evolution of intelligence in orangutans (Pongo pygmaeus)

Orangutans share many intellectual qualities with African great apes and humans, likely because of their recent common ancestry. They may also show unique intellectual adaptations because of their long evolutionary divergence from the African lineage. This paper assesses orangutan intelligence in light of this evolutionary history. Evidence derives from observations of juvenile ex-captive orangutans reintroduced to free forest life by the Wanariset Orangutan Reintroduction Project, East Kalimantan, Indonesia. The intellectual qualities shared by great apes and humans point to a distinct “great ape” intelligence with hierarchization as a pivotal cognitive mechanism. Evolutionary reconstructions jibe with this view and suggest that technically difficult foods may have been key selection pressures. Orangutans should then show hierarchical intelligence when obtaining difficult foods. Evidence on ex-captive orangutans' techniques for processing difficult foods concurs. Intellectual qualities distinct to orangutans may owe to arboreal travel pressures; in particular arboreality may aggravate foraging problems. Evidence confirms that ex-captive orangutans' techniques for accessing difficult foods located arboreally are intellectually complex—i.e. they show hierarchization. These findings suggest other factors probably important to understanding great ape and orangutan forms of intelligence and their evolutionary origins.     

Early Mortality and Primary Causes of Death in Mothers of Children with Intellectual Disability or Autism Spectrum Disorder: A Retrospective Cohort Study

Introduction

Mothers of children with intellectual disability or autism spectrum disorder (ASD) have poorer health than other mothers. Yet no research has explored whether this poorer health is reflected in mortality rates or whether certain causes of death are more likely. We aimed to calculate the hazard ratios for death and for the primary causes of death in mothers of children with intellectual disability or ASD compared to other mothers.

Methods

The study population comprised all mothers of live-born children in Western Australia from 1983–2005. We accessed state-wide databases which enabled us to link socio-demographic details, birth dates, diagnoses of intellectual disability or ASD in the children and dates and causes of death for all mothers who had died prior to 2011. Using Cox Regression with death by any cause and death by each of the three primary causes as the event of interest, we calculated hazard ratios for death for mothers of children intellectual disability or ASD compared to other mothers.

Results and Discussion

During the study period, mothers of children with intellectual disability or ASD had more than twice the risk of death. Mothers of children with intellectual disability were 40% more likely to die of cancer; 150% more likely to die of cardiovascular disease and nearly 200% more likely to die from misadventure than other mothers. Due to small numbers, only hazard ratios for cancer were calculated for mothers of children with ASD. These mothers were about 50% more likely to die from cancer than other mothers. Possible causes and implications of our results are discussed.

Conclusion

Similar studies, pooling data from registries elsewhere, would improve our understanding of factors increasing the mortality of mothers of children with intellectual disability or ASD. This would allow the implementation of informed services and interventions to improve these mothers'' longevity.     

Effect of Ascaris infection on the nutritional status and I.Q. of children

It was estimated that about 1.3 billion persons all over the world were infected with Ascaris Lumbricoides (A.L.), Especially children in tropical and subtropical countries. AIM To investigate the effects of A.L. infection on the nutritional status and the intellectual level in a sample of Egyptian primary school children from rural Giza province. SUBJECTS AND METHODS A sample of 637 children (329 boys and 308 girls) aged 6–12 years, have been subjected to some anthropometric measurements including body weight, body height, arm circumference, head circumference and triceps skinfold thickness. In addition, the I.Q. was determined using “Draw-a-man” test. Blood hemoglobin concentration was also determined using a spectrophotometric method. All the children were then subjected to stools and urine examinations, and peri-anal swab. Only 242 children were included for further study, of whom 45 boys and 38 girls were found infected with A.L. solely, and 81 boys and 78 girls of about the same age free of parasitic infections were taken as control. RESULTS Children infected with A.L. has significantly lower body weight, height, and arm circumference but insignificantly lower skinfold thickness and head circumference as comparedto the control group. Infected children had significantly lower hemoglobin concentration and I.Q. than the controls. CONCLUSIONS Selected anthropometric measurements, biochemical and intellectual tests from a useful complementary battery for reliable and informative investigation of the effects of parasitic infection on child nutrition and health. A.L. was found to have a significant effect on the physical and intellectual status of the rural Egyptian children of age 6–12 years.     

IBC's 21st Annual Antibody Engineering and 8th Annual Antibody Therapeutics International Conferences and 2010 Annual Meeting of The Antibody Society

The 21^st Annual Antibody Engineering and 8^th Annual Antibody Therapeutics international conferences, and the 2010 Annual Meeting of The Antibody Society, organized by IBC Life Sciences with contributions from The Antibody Society and two Scientific Advisory Boards, was held December 5–9, 2010 in San Diego, CA. The conferences featured over 100 presentations and 100 posters, and included a pre-conference workshop on deep-sequencing of antibody genes. The total number of delegates exceeded 800, which set a new attendance record for the conference.

The conferences were organized with a focus on antibody engineering only on the first day and a joint engineering/therapeutics session on the last day. Delegates could select from presentations that occurred in two simultaneous sessions on days 2 and 3. Day 1 included presentations on neutralizing antibodies and the identification of vaccine targets, as well as a historical overview of 20 years of phage display utilization. Topics presented in the Antibody Engineering sessions on day 2 and 3 included antibody biosynthesis, structure and stability; antibodies in a complex environment; antibody half-life; and targeted nanoparticle therapeutics. In the Antibody Therapeutics sessions on days 2 and 3, preclinical and early stage development and clinical updates of antibody therapeutics, including TRX518, SYM004, MM111, PRO140, CVX-241, ASG-5ME, U3-1287 (AMG888), R1507 and trastuzumab emtansine, were discussed and perspectives were provided on the development of biosimilar and biobetter antibodies, including coverage of regulatory and intellectual property issues. The joint engineering/therapeutics session on the last day focused on bispecific and next-generation antibodies. Summaries of most of the presentations are included here, but, due to the large number of speakers, it was not possible to include summaries for every presentation.

Delegates enjoyed the splendid views of the San Diego Bay and proximity to the Gaslamp Quarter provided by the venue. The 22^nd Annual Antibody Engineering and 9th Annual Antibody Therapeutics conferences, and the 2011 Annual Meeting of The Antibody Society, are planned for December 5–8, 2011 at the same location in San Diego, and will include two two-day short courses on Introduction to Antibody Engineering and Protein Characterization for Biotechnology Product Development.     

Protective efficacy of IgM monoclonal antibodies in experimental group B streptococcal infection is a function of antibody avidity

We have produced and characterized six mAb directed against group B streptococci (GBS). All antibodies are IgM. We have previously shown that some of these antibodies are highly protective in the treatment of experimental infections in neonatal rats, whereas others do not appear to have any protective efficacy. Using an ELISA, we demonstrate the specificity of both protective and nonprotective antibodies. Two antibodies, binding different epitopes, are directed against antigenic structures present on all GBS; two are specific for type III carbohydrate determinants; one binds to a protein Ag present on all type I and II GBS; and one appears to bind to type Ia GBS only. Quantitative absorption assays provide evidence that the difference between protective antibodies and nonprotective antibodies is the avidity that the antibody demonstrates for the epitope recognized on the surface of the bacteria; 10 to 15 times as much protective antibody binds to GBS as does nonprotective antibody. Direct binding experiments with radiolabeled antibody confirm this conclusion.     

Transformative Knowledge Transfer Through Empowering and Paying Community Researchers

Environmental research is often conducted independently of the community in which the environment is situated, with transfer of results into policy and on-ground action occurring independently of the community's interests or aspirations. Increasingly the need for greater community involvement in the research process has been recognized. For community members, however, such engagement usually involves trade-offs. While it is often assumed that community members should participate voluntarily because they will gain from the research, any benefits from knowledge, understanding and a capacity to influence the research have to be offset against time and potential loss of unremunerated intellectual property. We argue, using case studies from tropical Australia and Africa, that a more effective means of engagement and knowledge transfer is training and remuneration of community members as coresearchers. This engagement is much more than payment for labor—it is investment in local intellectual property and requires researcher humility, power-sharing and recognition that access to research funding provides no moral or intellectual authority. Further, we argue that, for effective adoption of research results, community members need to be part of negotiated agreements on the initial nature of the research to ensure it answers questions of genuine local relevance and that local researchers have the capacity to place locally conducted research into a wider context. We argue that immediate rewards for involvement not only secure engagement but, where appropriate, are likely to lead to effective implementation of research results, enhanced local capacity and greater equity in intellectual power-sharing.