Targeting of immune checkpoint regulator V-domain Ig suppressor of T-cell activation (VISTA) with 89Zr-labelled CI-8993.

BACKGROUND: CI-8993 is a fully human IgG1κ monoclonal antibody (mAb) that binds specifically to immune checkpoint molecule VISTA (V-domain Ig suppressor of T-cell activation). Phase I safety has been established in patients with advanced cancer (NCT02671955). To determine the pharmacokinetics and biodistribution of CI-8993 in patients, we aimed to develop 89Zr-labelled CI-8993 and validate PET imaging and quantitation in preclinical models prior to a planned human bioimaging trial. METHODS: CI-8993 and human isotype IgG1 control were conjugated to the metal ion chelator p-isothiocyanatobenzyl-desferrioxamine (Df). Quality of conjugates were assessed by SE-HPLC, SDS-PAGE, and FACS. After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. [89Zr]Zr-Df-CI-8993 alone (1 mg/kg, 4.6 MBq) or in combination with 30 mg/kg unlabelled CI-8993, as well as isotype control [89Zr]Zr-Df-IgG1 (1 mg/kg, 4.6 MBq) were assessed in human VISTA knock-in female (C57BL/6 N-Vsirtm1.1(VSIR)Geno, huVISTA KI) or control C57BL/6 mice bearing syngeneic MB49 bladder cancer tumours; and in BALB/c nu/nu mice bearing pancreatic Capan-2 tumours. RESULTS: Stable constructs with an average chelator-to-antibody ratio of 1.81 were achieved. SDS-PAGE and SE-HPLC showed integrity of CI-8993 was maintained after conjugation; and ELISA indicated no impact of conjugation and radiolabelling on binding to human VISTA. PET imaging and biodistribution in MB49 tumour-bearing huVISTA KI female mice showed specific localisation of [89Zr]Zr-Df-CI-8993 to VISTA in spleen and tumour tissues expressing human VISTA. Specific tumour uptake was also demonstrated in Capan-2 xenografted BALB/c nu/nu mice. CONCLUSIONS: We radiolabelled and validated [89Zr]Zr-Df-CI-8993 for specific binding to huVISTA in vivo. Our results demonstrate that 89Zr-labelled CI-8993 is now suitable for targeting and imaging VISTA expression in human trials.

Men, bodywork, health and the potentiality of performance and image-enhancing drugs.

In a qualitative study on masculinity, embodiment and sexuality, we interviewed men who were recreational gym-goers about their bodywork practices in Melbourne, Australia. We also asked whether the men had used performance and image-enhancing drugs (PIEDs) as an adjunct to their bodywork practices. While none had used PIEDs, all were considering, or had considered, using them. We found that participants held varying opinions on PIED use and those who used them. The literature on PIEDs noted men's concerns with body appearance and health and focused largely on individual problematic use, but non-users were not mentioned. A second issue in the literature focused on social influences on PIED use, but again with no mention of non-users. Discussion on risk reduction as a public health response did not mention non-users either. This paper, therefore, reports on non-users' thoughts on, regular exposure to, and considerations of PIEDs and other men who use them. We propose that PIEDs might more usefully be understood as an everyday, if contradictory, consideration within most men's bodywork and health practices. We argue that PIEDs constitute a discursive practice exposing a potentiality that engages non-users also and this requires new health promotion approaches.

Historicizing (bi)sexuality: a rejoinder for gay/lesbian studies, feminism, and queer theory.

One of the principal aims of queer theory has been to challenge heteronormative constructions of sexuality and to work the hetero/homosexual structure to the point of critical collapse. Despite an epistemic location within this very structure, however, the category of bisexuality has been largely marginalized and even erased from the deconstructive field of queer theory. This article explores some of the factors behind this treatment of bisexuality and suggests that bisexuality's marginalization and erasure brings into relief the strained relationship between the fields of gay/lesbian history, feminism, and queer theory. In exploring some early influential queer deconstructionist texts, it argues that in overlooking the role the category of bisexuality has played in the formation of the hetero/homosexual structure, the project of queer deconstruction has in important ways fallen short of its goals. The author concludes with a call to rethink conventional deconstructive reading practices.

Historicizing affect, psychoanalyzing history: pedophilia and the discourse of child sexuality.

Within the last two decades in Australia, Britain, and the United States, we have seen a veritable explosion of cultural panic regarding the problem of pedophilia. Scarcely a day passes without some mention in the media of predatory pedophiles or organized pedophile networks. Many social constructionist historians and sociologists have described this incitement to discourse as indicative of a moral panic. The question that concerns me in this article is: If this incitement to discourse is indicative of a moral panic, to what does the panic refer? I begin by detailing, first, how social constructionism requires psychoanalytic categories in order to understand the notion of panic, and second, how a psychoanalytic reading of history might reveal important unconscious forces at work in the current pedophilia "crisis" that our culture refuses to confront. Here, I will suggest a repressed discourse of child sexuality is writ large. I will argue that the hegemonic discourse of pedophilia is contained largely within a neurotic structure and that many of our prevailing responses to pedophilia function as a way to avoid tackling crucial issues about the reality and trauma of childhood sexuality.