The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell-Mediated Killing of AML Leukemic Stem Cells.

The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging designed ankyrin repeat protein (DARPin) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell-mediated killing of AML cells coexpressing at least two of the antigens. In vitro, MP0533 induced selective T cell-mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen-targeting T-cell engagers. In xenograft AML mice models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity toward LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with a high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).

The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19).

Patients' and therapists' experiences of general change mechanisms during bug-in-the-eye and delayed video-based supervised cognitive-behavioral therapy. A randomized controlled trial.

OBJECTIVE: This secondary analysis of a randomized controlled trial investigated whether bug-in-the-eye (BITE) supervision (live computer-based supervision during a psychotherapy session) affects the manner in which patients and therapists experience general change mechanisms (GCMs) during cognitive-behavioral therapy (CBT). METHOD: A total of 23 therapists were randomized either to the BITE condition or the control condition (delayed video-based [DVB] supervision). After each session, both patients (BITE: n = 19; DVB: n = 23) and therapists (BITE: n = 11; DVB: n = 12) completed the Helping Alliance Questionnaire (HAQ) and the Bernese Post Session Report (BPSR). The HAQ total score and the 3 secondary factors of the BPSR (interpersonal experiences, intrapersonal experiences, problem actuation) functioned as GCMs. Multilevel models were performed. RESULTS: For patients, GCMs did not develop differently between BITE and DVB during CBT. Therapists rated the alliance as well as interpersonal and intrapersonal experiences not significantly different between BITE and DVB during CBT, but they perceived problem actuation to increase significantly more in BITE than in DVB (p < .05). CONCLUSION: BITE supervision might be helpful in encouraging CBT therapists to apply interventions, which focus on the activation of relevant problems and related emotions.

Competence feedback improves CBT competence in trainee therapists: A randomized controlled pilot study.

OBJECTIVE: The development and improvement of therapeutic competencies are central aims in psychotherapy training; however, little is known about which training interventions are suitable for the improvement of competencies. METHOD: In the current pilot study, the efficacy of feedback regarding therapeutic competencies was investigated in cognitive behavioural therapy (CBT). Totally 19 trainee therapists and 19 patients were allocated randomly to a competence feedback group (CFG) or control group (CG). Two experienced clinicians and feedback providers who were blind to the treatment conditions independently evaluated therapeutic competencies on the Cognitive Therapy Scale at five treatment times (i.e., at Sessions 1, 5, 9, 13, and 17). Whereas CFG and CG included regular supervision, only therapists in the CFG additionally received written qualitative and quantitative feedback regarding their demonstrated competencies in conducting CBT during treatment. RESULTS: We found a significant Time × Group interaction effect (η² = .09), which indicates a larger competence increase in the CFG in comparison to the CG. CONCLUSIONS: Competence feedback was demonstrated to be suitable for the improvement of therapeutic competencies in CBT. These findings may have important implications for psychotherapy training, clinical practice, and psychotherapy research. However, further research is necessary to ensure the replicability and generalizability of the findings.