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Background: Epidemiologic studies suggest that Black, Asian, and minority ethnic (BAME) patients may be at risk of worse outcomes from coronavirus disease-2019 (COVID-19), but the pathophysiological drivers for this association are unknown. This study sought to investigate the relationship between findings on echocardiography, mortality, and race in COVID-19 pneumonia. Methods: This was a multicentre, retrospective, observational study including 164 adults (aged 61 ± 13 years; 78% male; 36% BAME) hospitalized with COVID-19 undergoing echocardiography between March 16 and May 9, 2020 at 3 days (interquartile range 2-5) from admission. The primary outcome was all-cause mortality. Results: After a median follow-up of 31 days (interquartile range 14-42 days), 66 (40%) patients had died. The right ventricle was dilated in 62 (38%) patients, and 58 (35%) patients had right ventricular (RV) systolic dysfunction. Only 2 (1%) patients had left ventricular (LV) dilatation, and 133 (81%) had normal or hyperdynamic LV systolic function. Reduced tricuspid annulus planar systolic excursion was associated with elevated D-dimer (ρ = −0.18, P = 0.025) and high-sensitivity cardiac Troponin (ρ = −0.30, P < 0.0001). Reduced RV systolic function (hazard ratio 1.80; 95% confidence interval, 1.05-3.09; P = 0.032) was an independent predictor of all-cause mortality after adjustment for demographic and clinical risk factors. Comparing white and BAME individuals, there were no differences in echocardiography findings, biomarkers, or mortality. Conclusions: In patients hospitalized with COVID-19 pneumonia, reduced RV systolic function is prevalent and associated with all-cause mortality. There is, however, no racial variation in the early findings on echocardiography, biomarkers, or mortality. Résumé: Contexte: Des études épidémiologiques suggèrent que les patients noirs, asiatiques et appartenant à des minorités ethniques (BAME) auraient un risque accru d'aggravation de la maladie à coronavirus 2019 (COVID-19), mais les facteurs physiopathologiques de cette association sont inconnus. Cette étude a cherché à étudier la relation entre les données d'échocardiographie, de mortalité, de l’origine ethnique avec la pneumonie associée à la COVID-19. Méthodes: Il s'agit d'une étude observationnelle rétrospective multicentrique portant sur 164 adultes (âgés de 61 ± 13 ans; 78 % d'hommes; 36 % de BAME) hospitalisés pour la COVID-19 et soumis à une échocardiographie entre le 16 mars et le 9 mai 2020, trois jours (écart interquartile 2-5) après leur admission. Le critère principal d’évaluation était la mortalité, toutes causes confondues. Résultats: Après un suivi médian de 31 jours (intervalle interquartile 14-42 jours), 66 (40 %) patients sont décédés. Le ventricule droit était dilaté chez 62 (38 %) des patients, et 58 (35 %) patients présentaient une dysfonction systolique du ventricule droit (VD). Seuls deux (1 %) patients présentaient une dilatation du ventricule gauche (VG), et 133 (81 %) avaient une fonction systolique VG normale ou en état hyperdynamique. Une réduction du déplacement systolique de l’anneau tricuspide a été associée à un taux de D-dimère élevé (ρ = -0,18, P = 0,025) et à une Troponine cardiaque de haute sensibilité (ρ = -0,30, P < 0,0001). Une fonction systolique VD réduite (rapport de risque de 1,80; intervalle de confiance à 95 %, 1,05-3,09 ; P = 0,032) était un facteur prédicteur indépendant pour la mortalité, toutes causes confondues, après ajustement pour les facteurs de risque démographiques et cliniques. En comparant les individus blancs et BAME, aucune différence n'a été constatée concernant les résultats d'échocardiographie, les biomarqueurs ou la mortalité. Conclusions: Chez les patients hospitalisés pour une pneumonie liée à la COVID-19, une réduction de la fonction systolique VD est apparue comme prévalente et associée à la mortalité, toutes causes confondues. Il n'y a cependant aucune influence de l’ethnicité en rapport avec les premiers résultats d'échocardiographie, des biomarqueurs ou de la mortalité.

Background In lymphoid malignancies, the introduction of chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) has achieved remarkable clinical success. However, such immunotherapeutic strategies are not yet established for acute myeloid leukemia (AML), the most common form of acute leukemia in adults. Common targets in AML such as CD33, CD123, and CLEC12A are highly expressed on both AML blasts and on normal myeloid cells and hematopoietic stem cells (HSCs), thereby raising toxicity concerns. In B-cell acute lymphoblastic leukemia (B-ALL), bsAbs and CAR-T therapy targeting CD19 and CD22 have demonstrated clinical success, but resistance via antigen loss is common, motivating the development of agents focused on alternative targets. An attractive emerging target is FLT3, a proto-oncogene expressed in both AML and B-ALL, with low and limited expression on myeloid dendritic cells and HSCs.Methods We developed and characterized CLN-049, a T cell-activating bsAb targeting CD3 and FLT3, constructed as an IgG heavy chain/scFv fusion. CLN-049 binds the membrane proximal extracellular domain of the FLT3 protein tyrosine kinase, which facilitates the targeting of leukemic blasts regardless of FLT3 mutational status. CLN-049 was evaluated for preclinical safety and efficacy in vitro and in vivo.Results CLN-049 induced target-restricted activation of CD4+ and CD8+ T cells. AML cell lines expressing a broad range of surface levels of FLT3 were efficiently lysed on treatment with subnanomolar concentrations of CLN-049, whereas FLT3-expressing hematopoietic progenitor cells and dendritic cells were not sensitive to CLN-049 killing. Treatment with CLN-049 also induced lysis of AML and B-ALL patient blasts by autologous T cells at the low effector-to-target ratios typically observed in patients with overt disease. Lysis of leukemic cells was not affected by supraphysiological levels of soluble FLT3 or FLT3 ligand. In mouse xenograft models, CLN-049 was highly active against human leukemic cell lines and patient-derived AML and B-ALL blasts.Conclusions CLN-049 has a favorable efficacy and safety profile in preclinical models, warranting evaluation of its antileukemic activity in the clinic.

Abstract The prostate‐specific membrane antigen (PSMA) has been demonstrated in numerous studies to be expressed specifically on prostate carcinoma cells and on the neovasculature of several other cancer entities. However, the simultaneous expression of PSMA on both, tumor cells as well as tumor vessels remains unclear, even if such “dual” expression would constitute an important asset to facilitate sufficient influx of effector cells to a given tumor site. We report here on the generation of a PSMA antibody, termed 10B3, which exerts superior dual reactivity on sections of prostate carcinoma and squamous cell carcinoma of the lung. 10B3 was used for the construction of T‐cell recruiting bispecific PSMAxCD3 antibodies in Fab‐ and IgG‐based formats, designated Fabsc and IgGsc, respectively. In vitro, both molecules exhibited comparable activity. In contrast, only the larger IgGsc molecule induced complete and durable elimination of established tumors in humanized mice due to favorable pharmacokinetic properties. Upon treatment of three patients with metastasized prostate carcinoma with the IgGsc reagent, marked activation of T cells and rapid reduction of elevated PSA levels were observed.