3 research outputs found
A Cell-Permeant Nanobody-Based Degrader That Induces Fetal Hemoglobin
Proximity-based strategies
to degrade proteins have enormous therapeutic
potential in medicine, but the technologies are limited to proteins
for which small molecule ligands exist. The identification of such
ligands for therapeutically relevant but “undruggable”
proteins remains challenging. Herein, we employed yeast surface display
of synthetic nanobodies to identify a protein ligand selective for
BCL11A, a critical repressor of fetal globin gene transcription. Fusion
of the nanobody to a cell-permeant miniature protein and an E3 adaptor
creates a degrader that depletes cellular BCL11A in differentiated
primary erythroid precursor cells, thereby inducing the expression
of fetal hemoglobin, a modifier of clinical severity of sickle cell
disease and β-thalassemia. Our strategy provides a means of
fetal hemoglobin induction through reversible, temporal modulation
of BCL11A. Additionally, it establishes a new paradigm for the targeted
degradation of previously intractable proteins
A Cell-Permeant Nanobody-Based Degrader That Induces Fetal Hemoglobin
Proximity-based strategies
to degrade proteins have enormous therapeutic
potential in medicine, but the technologies are limited to proteins
for which small molecule ligands exist. The identification of such
ligands for therapeutically relevant but “undruggable”
proteins remains challenging. Herein, we employed yeast surface display
of synthetic nanobodies to identify a protein ligand selective for
BCL11A, a critical repressor of fetal globin gene transcription. Fusion
of the nanobody to a cell-permeant miniature protein and an E3 adaptor
creates a degrader that depletes cellular BCL11A in differentiated
primary erythroid precursor cells, thereby inducing the expression
of fetal hemoglobin, a modifier of clinical severity of sickle cell
disease and β-thalassemia. Our strategy provides a means of
fetal hemoglobin induction through reversible, temporal modulation
of BCL11A. Additionally, it establishes a new paradigm for the targeted
degradation of previously intractable proteins
Clinical outcomes and medical resource utilization of toripalimab combination therapy versus bevacizumab plus chemotherapy in advanced non-squamous non-small cell lung cancer
This study aimed to evaluate the real-world clinical efficacy and safety, economic burdens and medical resource utilization (MRU) of toripalimab treatment patterns compared with bevacizumab plus chemotherapy (BCP) for patients with advanced non-squamous NSCLC in China. Progression-free survival (PFS), adverse drug reactions (ADR) and the costs of drugs, laboratory testing, imageology examinations (including CT, B ultrasound, MRI), medical service, nursing, treatment, genetic test and medical disposable material were compared between two groups. A retrospective observational study was conducted with electronic medical records from Fudan University Huashan hospital. Data was obtained from established electronic medical records (EMRs) and patient surveys. Survival time from the study enrollment to disease progression or death plus from 1st progression disease (PD) in the maintenance phase to 2nd PD (PFS II), adverse events (AE), direct medical costs, MRU and AE-related costs were collected and compared between toripalimab group and BCP group. A total of 246 patients were enrolled. Toripalimab combination therapy has significantly prolonged PFS comparing with BCP (13.8 months vs. 6.2 months, p p p p  Toripalimab combination therapy could significantly prolonged PFS for patients with advanced non-squamous NSCLC compared with BCP, but at the expense of more MRU, costs and AEs.</p