FS222, a CD137/PD-L1 Tetravalent Bispecific Antibody, Exhibits Low Toxicity and Antitumor Activity in Colorectal Cancer Models.

PURPOSE: With the increased prevalence in checkpoint therapy resistance, there remains a significant unmet need for additional therapies for patients with relapsing or refractory cancer. We have developed FS222, a bispecific tetravalent antibody targeting CD137 and PD-L1, to induce T-cell activation to eradicate tumors without the current toxicity and efficacy limitations seen in the clinic. EXPERIMENTAL DESIGN: A bispecific antibody (FS222) was developed by engineering CD137 antigen-binding sites into the Fc region of a PD-L1 IgG1 mAb. T-cell activation by FS222 was investigated using multiple in vitro assays. The antitumor efficacy, survival benefit, pharmacodynamics, and liver pharmacology of a murine surrogate molecule were assessed in syngeneic mouse tumor models. Toxicology and the pharmacokinetic/pharmacodynamic profile of FS222 were investigated in a non-human primate dose-range finding study. RESULTS: We demonstrated simultaneous binding of CD137 and PD-L1 and showed potent T-cell activation across CD8+ T-cell activation assays in a PD-L1-dependent manner with a CD137/PD-L1 bispecific antibody, FS222. FS222 also activated T cells in a human primary mixed lymphocyte reaction assay, with greater potency than the monospecific mAb combination. FS222 showed no signs of liver toxicity up to 30 mg/kg in a non-human primate dose-range finding study. A surrogate molecule caused significant tumor growth inhibition and survival benefit, concomitant with CD8+ T-cell activation, in CT26 and MC38 syngeneic mouse tumor models. CONCLUSIONS: By targeting CD137 agonism to areas of PD-L1 expression, predominantly found in the tumor microenvironment, FS222 has the potential to leverage a focused, potent, and safe immune response augmenting the PD-(L)1 axis blockade.

Atypical frontoamygdala functional connectivity in youth with autism.

Functional connectivity (FC) between the amygdala and the ventromedial prefrontal cortex underlies socioemotional functioning, a core domain of impairment in autism spectrum disorder (ASD). Although frontoamygdala circuitry undergoes dynamic changes throughout development, little is known about age-related changes in frontoamygdala networks in ASD. Here we characterize frontoamygdala resting-state FC in a cross-sectional sample (ages 7-25) of 58 typically developing (TD) individuals and 53 individuals with ASD. Contrary to hypotheses, individuals with ASD did not show different age-related patterns of frontoamygdala FC compared with TD individuals. However, overall group differences in frontoamygdala FC were observed. Specifically, relative to TD individuals, individuals with ASD showed weaker frontoamygdala FC between the right basolateral (BL) amygdala and the rostral anterior cingulate cortex (rACC). These findings extend prior work to a broader developmental range in ASD, and indicate ASD-related differences in frontoamygdala FC that may underlie core socioemotional impairments in children and adolescents with ASD.

Talking with teens about traffic safety: Initial feasibility, acceptability, and efficacy of a parent-targeted intervention for primary care settings.

INTRODUCTION: The aims of the current pilot study were to evaluate the feasibility, acceptability, and preliminary efficacy of the Talking with Teens about Traffic Safety Program. The program consists of a clinic-based health coaching session with parents of adolescents at their annual well-child visit to promote parent-teen communication about teen driver safety including: a Parent Handbook that is designed to serve as a primer on teen driver safety and facilitate parent-teen communication on a variety of teen driver topics; an interactive practice driving toolset; and an endorsement of the materials by the primary care provider. METHOD: Fifty-four parent-teen dyads (n = 108 total) were recruited from a primary care practice. Dyads were randomized (1:1) into a treatment group or a usual care group. Implementation fidelity was assessed using checklists completed by health coaches and parent interviews. After 6 months, parents reported how often they talked with their teen about 12 safe driving topics (e.g., state graduated driver licensing laws). RESULTS: Parents in the treatment group reported more frequent discussions than parents in the control group on 7 out of the 12 topics. Fidelity data indicate that 100% of sessions were implemented as designed and were acceptable to parents. CONCLUSIONS: The program was feasible to administer and there was evidence for preliminary efficacy. Generally, effects were larger for more infrequently discussed topics, which is to be expected due to the potential for ceiling effects on more commonly discussed topics (e.g., distracted driving). A larger multi-site study is warranted. PRACTICAL APPLICATIONS: The results from this pilot study provide support for implementation fidelity and establish a proof-of-concept for the Talking with Teens about Traffic Safety Program. The results provide guidance for developing partnerships with pediatricians and parents to develop parent-teen communication interventions on injury prevention topics.

Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2.

Early life stress increases risk for depression. Here we establish a "two-hit" stress model in mice wherein stress at a specific postnatal period increases susceptibility to adult social defeat stress and causes long-lasting transcriptional alterations that prime the ventral tegmental area (VTA)-a brain reward region-to be in a depression-like state. We identify a role for the developmental transcription factor orthodenticle homeobox 2 (Otx2) as an upstream mediator of these enduring effects. Transient juvenile-but not adult-knockdown of Otx2 in VTA mimics early life stress by increasing stress susceptibility, whereas its overexpression reverses the effects of early life stress. This work establishes a mechanism by which early life stress encodes lifelong susceptibility to stress via long-lasting transcriptional programming in VTA mediated by Otx2.

Families with children conceived by donor insemination: a follow-up at age twelve.

Growing public awareness of the use of donor insemination (DI) to enable infertile couples to become parents has been accompanied by increasing concern regarding the potentially negative consequences for family relationships and child development. Findings are presented from a prospective study of the quality of parenting and psychological adjustment of DI children at age 12. Thirty-seven DI families, 49 adoptive families, and 91 families with a naturally conceived child were compared on standardized interview and questionnaire measures administered to mothers, fathers, children, and teachers. The differences between DI families and the other family types reflected greater expressive warmth of DI mothers toward their children and less involvement in the discipline of their children by DI fathers. The DI children were well adjusted in terms of their social and emotional development. The findings are discussed with respect to the secrecy surrounding DI and the imbalance in genetic relatedness between the parents and the child.