Inhibition of LILRB2 by a Novel Blocking Antibody Designed to Reprogram Immunosuppressive Macrophages to Drive T-Cell Activation in Tumors.

Tumor-associated macrophages (TAM) play an important role in maintaining the immunosuppressive state of the tumor microenvironment (TME). High levels of CD163+ TAMs specifically are associated with poor prognosis in many solid tumor types. Targeting TAMs may represent a key approach in development of the next generation of cancer immune therapeutics. Members of the leukocyte immunoglobulin-like receptor B (LILRB) family, including LILRB2 (ILT4), are known to transmit inhibitory signals in macrophages and other myeloid cells. Leveraging bulk and single cell RNA-sequencing datasets, as well as extensive immunophenotyping of human tumors, we found that LILRB2 is highly expressed on CD163+ CD11b+ cells in the TME and that LILRB2 expression correlates with CD163 expression across many tumor types. To target LILRB2, we have developed JTX-8064, a highly potent and selective antagonistic mAb. JTX-8064 blocks LILRB2 binding to its cognate ligands, including classical and nonclassical MHC molecules. In vitro, JTX-8064 drives the polarization of human macrophages and dendritic cells toward an immunostimulatory phenotype. As a result, human macrophages treated with a LILRB2 blocker are reprogrammed to increase the activation of autologous T cells in co-culture systems. Furthermore, JTX-8064 significantly potentiates the activity of anti-PD-1 in allogeneic mixed lymphocyte reaction. In a human tumor explant culture, pharmacodynamic activity of JTX-8064 was observed in monotherapy and in combination with anti-PD-1. Collectively, our work provides strong translational and preclinical rationale to target LILRB2 in cancer.

Promoting healthy trajectories for urban middle school youth through county-funded, parks-based after-school programming.

Ongoing pressure for public schools to prioritize academics has increased attention on after-school settings as a critical space for social-emotional learning (SEL). After-school programs are uniquely positioned to build protective and promotive factors that contribute to positive future orientation, especially within communities where systemic inequities create barriers to high school graduation, higher education, employment, and earnings. This study examines Fit2Lead Youth Enrichment and Sports (YES), a county-funded, parks-based after-school collaboration for middle schoolers that merges mental health and recreation to promote healthy trajectories. Eight Miami neighborhood parks were selected based on county data indicating high rates of violence. An open trial design (N = 9 parks, 198 youth; ages 9-15; 40.5% female; 66.5% Black/African American, 24.9% Hispanic/Latinx, and 76.3% low-income) tested hypotheses that participation for adolescents exposed to community violence would disrupt a commonly reported decline in self-regulation and self-efficacy, and mitigate risk for anxiety and depression. Youth completed questionnaires at the beginning and end of one school year. Paired t-tests revealed no changes from pre to post, and no differences by baseline levels of youth and parent mental health. Findings highlight the promise of prevention programs to disrupt downward trajectories for youth during the risky time of early adolescence.

A Systematic Review of Organizational and Workforce Interventions to Improve the Culture and Climate of Youth-Service Settings.

Both organizational culture and climate are associated with service quality and outcomes across youth-service settings. Increasing evidence indicates capacity of organizational interventions to promote a positive and effective culture and climate. Less is known about common intervention components across studies and service settings. The current systematic review reviewed 9223 citations and identified 31 studies, across six youth-service settings, measuring changes over time in organizational culture and climate following implementation of an organizational or workforce support intervention. Results highlight the promise of organizational interventions, a need for more comparison and randomized designs, and future directions for maximizing capacity of organizations to promote health for frontline providers and the children they serve.

BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice.

Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-D'D3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.

Intrinsic differences between FVIIIa mimetic bispecific antibodies and FVIII prevent assignment of FVIII-equivalence.

Essentials Non-factor VIII (FVIII) therapies for hemophilia A, such as bispecific antibodies (bsAbs), are in development. Bispecific antibodies are intrinsically different from FVIII and lack many of the same regulatory mechanisms. These differences complicate assignment and interpretation of FVIII-equivalent activity. Inability to assign FVIII equivalence compromises our capacity to assess hemostatic potential of bsAb therapies. BACKGROUND: Activated factor VIII (FVIIIa) mimetic bsAbs aim to enable prophylactic treatment of hemophilia A patients with and without inhibitors. With different mechanisms of action, benchmarking their activity against FVIII to determine efficacious yet safe dosage is difficult. OBJECTIVE: To compare the activities of sequence identical emicizumab (SI-Emi) and another bsAb, BS-027125, to recombinant FVIII (rFVIII) using clinical and nonclinical assays and to evaluate our ability to assign a FVIII-equivalent value to bsAbs and implications thereof. METHODS: Activities of SI-Emi, BS-027125, and rFVIII were measured by one-stage clotting assay, chromogenic factor Xa generation assay, and thrombin generation assay. We also assessed the activity of anti-FIXa and anti-FX bivalent homodimers of each bsAb and probed the effect of different reagents in thrombin generation assay (TGA). RESULTS: The FVIII-like activity of SI-Emi and BS-027125 ranged greatly across each assay, varying both by parameter measured within an assay and by reagents used. Notably, SI-Emi anti-FIXa bivalent homodimer had meaningful activity in several assays, whereas BS-027125 anti-FIXa bivalent homodimer only had activity in the chromogenic assay. Surprisingly, SI-Emi displayed activity in the absence of phospholipids, while BS-027125 had minimal phospholipid-independent activity. CONCLUSIONS: Bispecific antibodies demonstrate little consistency between assays tested here owing to intrinsic differences between FVIII and bsAbs. While some trends are shared, the bsAbs also differ in mechanism. These inconsistencies complicate assignment of FVIII-equivalent values to bsAbs. Ultimately, a deeper mechanistic understanding of bsAbs as well as bsAb-tailored assays are needed to monitor and predict their hemostatic potential and long-term efficacy and safety confidently.