RUBY® - a tetravalent (2+2) bispecific antibody format with excellent functionality and IgG-like stability, pharmacology and developability properties.

Despite the large number of existing bispecific antibody (bsAb) formats, the generation of novel bsAbs is still associated with development and bioprocessing challenges. Here, we present RUBY, a novel bispecific antibody format that allows rapid generation of bsAbs that fulfill key development criteria. The RUBY format has a 2 + 2 geometry, where two Fab fragments are linked via their light chains to the C-termini of an IgG, and carries mutations for optimal chain pairing.

ATOR-1017 (evunzekibart), an Fc-gamma receptor conditional 4-1BB agonist designed for optimal safety and efficacy, activates exhausted T cells in combination with anti-PD-1.

Background: 4-1BB (CD137) is a co-stimulatory receptor highly expressed on tumor reactive effector T cells and NK cells, which upon stimulation prolongs persistence of tumor reactive effector T and NK cells within the tumor and induces long-lived memory T cells. 4-1BB agonistic antibodies have been shown to induce strong anti-tumor effects that synergize with immune checkpoint inhibitors. The first generation of 4-1BB agonists was, however, hampered by dose-limiting toxicities resulting in suboptimal dose levels or poor agonistic activity.

The Bispecific Tumor Antigen-Conditional 4-1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies.

4-1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4-1BB on tumor-specific cytotoxic T cells makes 4-1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4-1BB function when co-engaged with the tumor-associated antigen 5T4.

CD137 (4-1BB) costimulation of CD8 T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation.

CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human.

Education, immigration and rising mental health inequality in Sweden.

Educational and income gradients in health are well established in the literature but there is need for a better understanding of how mental health inequalities change over time, and what drives the development. We aim to study how psychiatric diagnosis and its income-related inequality have changed over time in Sweden and to make a first attempt at disentangling the development by decomposing any changes in terms of changes in two important demographic characteristics: education and migration background. We use administrative patient data to study psychiatric inpatient diagnosis in the years 1994 and 2011.

Child living arrangements following separation and mental health of parents in Sweden.

Father involvement and joint physical custody in post-separation families are increasingly common. In Sweden, 35 percent of the children of separated parents live equally much with both parents. Since parenthood is gendered, the associations between child living arrangement and parental health may vary between women and men.

Inequalities in the economic consequences of depression and anxiety in Europe: a systematic scoping review.

Background: Depression and anxiety are associated with adverse outcomes in educational achievements and economic performances. Moreover, the prevalence of these disorders is unequally distributed among different population subgroups. Our objective is to investigate whether the economic consequences of depression and anxiety differ between population subgroups of different gender, socioeconomic status (SES), ethnicity and age, in Europe.

The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation.

Background: The CTLA-4 blocking antibody ipilimumab has demonstrated substantial and durable effects in patients with melanoma. While CTLA-4 therapy, both as monotherapy and in combination with PD-1 targeting therapies, has great potential in many indications, the toxicities of the current treatment regimens may limit their use. Thus, there is a medical need for new CTLA-4 targeting therapies with improved benefit-risk profile.

The effect of locally delivered cisplatin is dependent on an intact immune function in an experimental glioma model.

Several chemotherapeutic drugs are now considered to exert anti-tumour effects, by inducing an immune-promoting inflammatory response. Cisplatin is a potent chemotherapeutic agent used in standard medulloblastoma but not glioblastoma protocols. There is no clear explanation for the differences in clinical efficacy of cisplatin between medulloblastomas and glioblastomas, despite the fact that cisplatin is effective in vitro against the latter.

Teleconsultation Using Mobile Phones for Diagnosis and Acute Care of Burn Injuries Among Emergency Physicians: Mixed-Methods Study.

Background: The referral process in acute care remains challenging in many areas including burn care. Mobile phone apps designed explicitly for medical referrals and consultations could streamline the referral process by using structured templates and integrating features specific to different specialties. However, as these apps are competing with commercial chat services, usability becomes a crucial factor for successful uptake.

Family Structure, Child Living Arrangement and Mothers' Self-rated Health in Sweden-A Cross-Sectional Study.

Alternate living, i.e. children living 50-50 with their parents following separation is emerging as a new family form.

The discourses on induced abortion in Ugandan daily newspapers: a discourse analysis.

Background: Ugandan law prohibits abortion under all circumstances except where there is a risk for the woman's life. However, it has been estimated that over 250 000 illegal abortions are being performed in the country yearly. Many of these abortions are carried out under unsafe conditions, being one of the most common reasons behind the nearly 5000 maternal deaths per year in Uganda.

Intratumorally implanted mesenchymal stromal cells potentiate peripheral immunotherapy against malignant rat gliomas.

Bone marrow-derived mesenchymal stromal cells (MSCs) target glioma extensions and micro-satellites efficiently when implanted intratumorally. Here, we report that intratumoral implantation of MSCs and peripheral immunotherapy with interferon-gamma (IFNγ) producing tumor cells improve the survival of glioma-bearing rats (54% cure rate) compared to MSC alone (0% cure rate) or immunotherapy alone (21% cure rate) by enforcing an intratumoral CD8(+) T cell response. Further analysis revealed that the MSCs up-regulate MHC classes I and II in response to IFNγ treatment in vitro and secrete low amounts of immunosuppressive molecules prostaglandin E2 and interleukin-10.

Immunizations with unmodified tumor cells and simultaneous COX-2 inhibition eradicate malignant rat brain tumors and induce a long-lasting CD8(+) T cell memory.

Malignant brain tumors induce pronounced immunosuppression, which diminishes immune responses generated by immunotherapy. Here we report that peripheral immunotherapy, using irradiated unmodified whole tumor cells, and systemic cyclooxygenase-2 inhibition induce cure in glioma-bearing rats (60% cure rate), whereas neither monotherapy was sufficient to cure any animal. Moreover, the combined therapy protected against secondary tumor challenges (89% cure rate) and the secondary immune response was correlated with increased plasma interferon-gamma levels and CD8(+) T cells systemically and intratumorally.

Family policy and inequalities in health in different welfare states.

This article focuses on differences in health and welfare outcomes for families with children in three European countries, discussed in relation to national policies for child and family welfare. Data consist of policy documents and cross-national surveys. The document analysis was based on policy documents that described government policies.

Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors.

Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E2 (PGE2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE2 and COX-2 have been shown in several tumor types, including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.

Intratumoral temozolomide synergizes with immunotherapy in a T cell-dependent fashion.

Despite temozolomide (TMZ) treatment, the prognosis for patients with glioblastoma multiforme is still dismal. As dose escalation of TMZ is limited by systemic toxicity, intratumoral delivery emerges as an attractive treatment modality, which may sustain cytotoxic drug concentrations intratumorally and induce immunogenic cell death. Both clinical and experimental gliomas have responded to immunotherapy, but the benefit of simultaneous chemo- and immunotherapy is inadequately studied.

IFNγ in combination with IL-7 enhances immunotherapy in two rat glioma models.

Peripheral immunization, using a combination of interferon-gamma (IFNγ)- and interleukin-7 (IL-7)-producing tumor cells, eradicated 75% of pre-established intracerebral N32 rat glioma tumors, and prolonged survival in the more aggressive RG2 model. Rats immunized with IFNγ- and IL7-transduced N32 cells displayed increases in IFNγ plasma levels and proliferating circulating T cells when compared with rats immunized with N32-wild type cells. Following irradiation, the expression of MHC I and II was high on N32-IFNγ cells, but low on RG2-IFNγ cells.

Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors.

Glioblastoma multiforme is the most common and aggressive malignant brain tumor in humans, and the prognosis is very poor despite conventional therapy. Immunotherapy represents a novel treatment approach, but the effect is often weakened by release of immune-suppressive molecules such as prostaglandins. In the current study, we investigated the effect of immunotherapy with irradiated interferon-γ (IFN-γ)-secreting tumor cells and administration of the selective cyclooxygenase-2 (COX-2) inhibitor parecoxib as treatment of established rat brain tumors.

Does non-employment contribute to the health disadvantage among lone mothers in Britain, Italy and Sweden? Synergy effects and the meaning of family policy.

This study analyses self-rated health and non-employment and potential synergy effects among lone and couple mothers aged 25-59 in Britain, Sweden and Italy, representing different family policy categories using data from national surveys (2000-2005). Synergy effects on health were calculated by synergy index. Non-employment only marginally contributed to the excess risk of poor health among lone mothers but there were synergy effects between lone motherhood and non-employment in all three countries, producing a higher risk of poor health than would be expected from a simple addition of these exposures.

Health inequalities between lone and couple mothers and policy under different welfare regimes - the example of Italy, Sweden and Britain.

This study examines the welfare state arrangements and social policy, living conditions and health among lone and couple mothers in three contrasting policy environments: Italy, Sweden and Britain. These countries fall into distinctive family policy categories. Data were drawn from representative national household interview surveys.

Immunizations with IFNgamma secreting tumor cells can eliminate fully established and invasive rat gliomas.

Immunotherapy of malignant primary brain tumors holds the potential to improve the dismal prognosis after current clinical therapy. Although immunotherapy of experimental gliomas has been demonstrated to have the capacity to cure intracerebral tumors no convincing effects of immunotherapy have been shown in clinical trials. One reason for this could be that some of the models used do not display full features of human glioblastomas.

Cure of established GL261 mouse gliomas after combined immunotherapy with GM-CSF and IFNgamma is mediated by both CD8+ and CD4+ T-cells.

We were the first to demonstrate that combined immunotherapy with GM-CSF producing GL261 cells and recombinant IFNgamma of preestablished GL261 gliomas could cure 90% of immunized mice. To extend these findings and to uncover the underlying mechanisms, the ensuing experiments were undertaken. We hypothesized that immunizations combining both GM-CSF and IFNgamma systemically would increase the number of immature myeloid cells, which then would mature and differentiate into dendritic cells (DCs) and macrophages, thereby augmenting tumor antigen presentation and T-cell activation.

From macro to micro: the health of Swedish lone mothers during changing economic and social circumstances.

The deep recession in Sweden in the early 1990s led to high unemployment levels. In addition, policy changes and reductions in welfare benefits increased costs of living. These changes may have affected lone mothers to a greater extent than other groups.