Protein therapeutics and its enabling sister discipline, protein engineering, have emerged since the early 1980s. The first protein therapeutics were recombinant versions of natural proteins. ...Proteins purposefully modified to increase their clinical potential soon followed with enhancements derived from protein or glycoengineering, Fc fusion or conjugation to polyethylene glycol. Antibody-based drugs subsequently arose as the largest and fastest growing class of protein therapeutics. The rationale for developing better protein therapeutics with enhanced efficacy, greater safety, reduced immunogenicity or improved delivery comes from the convergence of clinical, scientific, technological and commercial drivers that have identified unmet needs and provided strategies to address them. Future protein drugs seem likely to be more extensively engineered to improve their performance, e.g., antibodies and Fc fusion proteins with enhanced effector functions or extended half-life. Two old concepts for improving antibodies, namely antibody-drug conjugates and bispecific antibodies, have advanced to the cusp of clinical success. As for newer protein therapeutic platform technologies, several engineered protein scaffolds are in early clinical development and offer differences and some potential advantages over antibodies.
•Bispecific antibodies (BsAb) bind 2 distinct antigens or epitopes on the same antigen.•Antibody domain structure has been exploited to make >60 alternative BsAb formats.•2 BsAb are approved for ...therapy and >30 BsAb are in clinical development.•A common clinical application of BsAb is retargeting T cells to kill tumor cells.•Other clinical uses of BsAb include dual blockade of different disease mediators.
Bispecific antibodies are on the cusp of coming of age as therapeutics more than half a century after they were first described. Two bispecific antibodies, catumaxomab (Removab®, anti-EpCAM×anti-CD3) and blinatumomab (Blincyto®, anti-CD19×anti-CD3) are approved for therapy, and >30 additional bispecific antibodies are currently in clinical development. Many of these investigational bispecific antibody drugs are designed to retarget T cells to kill tumor cells, whereas most others are intended to interact with two different disease mediators such as cell surface receptors, soluble ligands and other proteins. The modular architecture of antibodies has been exploited to create more than 60 different bispecific antibody formats. These formats vary in many ways including their molecular weight, number of antigen-binding sites, spatial relationship between different binding sites, valency for each antigen, ability to support secondary immune functions and pharmacokinetic half-life. These diverse formats provide great opportunity to tailor the design of bispecific antibodies to match the proposed mechanisms of action and the intended clinical application.
The development of AlphaFold2 marked a paradigm-shift in the structural biology community. Herein, we assess the ability of AlphaFold2 to predict disordered regions against traditional sequence-based ...disorder predictors. We find that AlphaFold2 performs well at discriminating disordered regions, but also note that the disorder predictor one constructs from an AlphaFold2 structure determines accuracy. In particular, a naïve, but non-trivial assumption that residues assigned to helices, strands, and H-bond stabilized turns are likely ordered and all other residues are disordered results in a dramatic overestimation in disorder; conversely, the predicted local distance difference test (pLDDT) provides an excellent measure of residue-wise disorder. Furthermore, by employing molecular dynamics (MD) simulations, we note an interesting relationship between the pLDDT and secondary structure, that may explain our observations and suggests a broader application of the pLDDT for characterizing the local dynamics of intrinsically disordered proteins and regions (IDPs/IDRs).
Building upon the work of Agnes Callard on the moral philosophy and psychology of anger, I attempt to critically reframe the ways in which the anger of internal critics and dissidents within ...psychoanalysis is understood. Through a consideration of the literature, and of my own intergenerational family history (with psychoanalysis and otherwise), I offer a challenge to a common (and, I argue, often bigoted) framing of such anger as wantonly rageful and indicative of a desire to destroy psychoanalysis. Rather, I propose we should understand and engage with this anger as provoked by a failure of white-, straight-, and male-dominated institutions and communities to join with and share psychoanalysis with people not from those groups. In this light, the anger of internal critics of psychoanalysis should properly be understood as both a protest and an invitation into a process of contrition and repair that can return all parties to a state of co-valuation of, and cohabitation in, the psychoanalytic community.
Whiteness, understood in psychoanalytic terms as a complex emerging in relation to an invidious object, catalyzes character disorder and mass violence. Drawing on historical analyses of the early ...American colonial period and a 2014 mass shooting in Isla Vista, California, I articulate a theory of the workings of Whiteness, with an eye toward the interrelationship of psychodynamics and sociocultural, structural, and ideological forces. I conclude with a consideration of how and why psychoanalysis has failed to fully contend with Whiteness because of the discipline's own investment in Whiteness and White aggression.
The African American Policy Forum and the Center for Intersectionality and Social Policy Studies states, "The risks that Black and other girls of color confront rarely receive the full attention of ...researchers, advocates, policymaker and funders." The limited awareness of the challenges that Black girls face perpetuates the mischaracterization of their attitudes, abilities, and achievement. Thus, school becomes an inhospitable place where Black girls receive mixed messages about femininity and goodness and are held to unreasonable standards. This study explores how Black girls describe and understand their school experiences as racialized and gendered and the ways a conversation space allows Black girls' meaning making about and critical examination of individual and collective schooling experiences.
Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome, which if not promptly treated, can lead rapidly to critical illness and death. HLH is termed macrophage activation ...syndrome (MAS) when associated with rheumatic disease (where it is best characterized in systemic JIA) and secondary HLH (sHLH) when associated with other triggers including malignancy and infection. MAS/sHLH is rare and coupled with its mimicry of other conditions, is underrecognized. These inherent challenges can lead to diagnostic and management challenges in multiple medical specialties including haematology, infectious diseases, critical care and rheumatology. In this review we highlight the pathogenesis of MAS/sHLH including its underlying triggers, key clinical features and diagnostic challenges, prognostic factors and current treatments in adults.
Reformers are increasingly calling for and adopting practice-based approaches to teacher preparation, with particular emphasis on identifying and centering core practices. In this article, we argue ...that organizing teacher education around core practices brings its own risks, including the risk of peripheralizing equity and justice. Situating our argument within the broad economic trends affecting labor and higher education in the 21st century, we begin by examining the linkages between the core practices movement and organizations that advocate market-based solutions to education. We then explore how constructs of practice and improvisation and commitments to equity and justice are taken up, and with what implications and consequences, in core practices scholarship and its applications. In conclusion, we consider how work being done around core practices might contribute to a collective struggle for greater equity and justice in schools and in society.
The development of therapeutic antibodies has evolved over the past decade into a mainstay of therapeutic options for patients with autoimmune and inflammatory diseases. Substantial advances in ...understanding the biology of human diseases have been made and tremendous benefit to patients has been gained with the first generation of therapeutic antibodies. The lessons learnt from these antibodies have provided the foundation for the discovery and development of future therapeutic antibodies. Here we review how key insights obtained from the development of therapeutic antibodies complemented by newer antibody engineering technologies are delivering a second generation of therapeutic antibodies with promise for greater clinical efficacy and safety.
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