Biology subjects

Lebedeva, I. V.

Publications and source records attributed to Lebedeva, I. V..

3 recordsLinked to original sources

bioRxiv2026

CAR-T Targeting of Mutant Calreticulin Establishes a Potentially Curative Stem Cell-Directed Therapy for Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are sustained by mutated hematopoietic stem cells (HSCs). Existing therapies fail to eliminate this compartment, leaving allogeneic HSC transplantation as the only curative option. Recurrent MPN driver mutations in calreticulin (CALRmut) generate a C-terminal neopeptide that requires cell-surface expression for oncogenic signaling, making it an attractive immunologic target. However, it remains unknown if CALRmut is uniformly displayed on all MPN HSCs within hematopoietic microenvironments. We generated huAB2, a high-affinity CALRmut-specific humanized antibody, to use as the targeting domain for chimeric antigen receptor (CAR)-T cells. We show that CALRmut is consistently displayed on functional MPN HSCs and accessible in vivo. huAB2 CAR-T cells eradicate MPN-propagating CALRmut HSCs in patient-derived tumor xenograft models without antigen escape while preserving coexisting normal human and host hematopoiesis. These findings establish CALRmut display as an obligate feature of MPN HSC fitness and support the feasibility of curative, non-transplant immunotherapy for CALRmut MPNs. SignificanceTherapies that eradicate cancer stem cells enable cure, but their feasibility is unknown. We establish an approach to potentially cure MPNs by proving mutant calreticulin to be a MPN stem cell marker that can be targeted by CAR-T cells to selectively wipe out disease in preclinical models of human MPNs.

cancer biology↗

bioRxiv2022

Human anti-ACE2 monoclonal antibodies as pan-sarbecovirus prophylactic agents

Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, nearly all of these antibodies have been rendered obsolete by SARS-CoV-2 variants that evolved to resist similar, naturally occurring antibodies. Here, we describe the development of human monoclonal antibodies that bind the ACE2 receptor rather than the viral spike protein. These antibodies block infection by all ACE2 binding sarbecoviruses, including emergent SARS-CoV-2 variants. Structural and biochemical analyses revealed that the antibodies target an ACE2 epitope that engages SARS-CoV-2 spike. Importantly, the antibodies do not inhibit ACE2 enzymatic activity, nor do they induce ACE depletion from cell surfaces. The antibodies exhibit favorable pharmacology and protect human ACE2 knock-in mice against SARS-CoV-2 infection. Such antibodies should be useful prophylactic and treatment agents against any current and future SARS-CoV-2 variants, as well as ACE2-binding sarbecoviruses that might emerge as future pandemic threats.

microbiology↗

bioRxiv2020

Precision genetic cellular models identify therapies protective against endoplasmic reticulum stress

Congenital disorders of glycosylation (CDG) and deglycosylation (CDDG) are a collection of rare pediatric disorders with symptoms that range from mild to life threatening. They typically affect multiple organ systems and usually present with neurological abnormalities including hypotonia, cognitive impairment, and intractable seizures. Several genes have been implicated in the thirty-six types of CDG, but currently NGLY1 is the only known CDDG gene. A common biological mechanism among CDG types and in CDDG is endoplasmic reticulum (ER) stress. Here, we develop two isogenic human cellular models of CDG (PMM2, the most prevalent type of CDG, and DPAGT1) and of the only CDDG (NGLY1) in an effort to identify drugs that can alleviate ER stress. Systematic phenotyping identified elevated ER stress and autophagy levels among other cellular and morphological phenotypes in each of the cellular models. We screened a complex drug library for compounds able to correct aberrant morphological phenotypes in each of the models using an agnostic phenotypic cell painting assay based on >300 cellular features. The image-based screen identified multiple candidate compounds able to correct aberrant morphology, and we show a subset of these are able to correct cellular and molecular defects in each of the models. These results provide new directions for the treatment of rare diseases of glycosylation and deglycosylation and a framework for new drug screening paradigms for more common neurodegenerative diseases characterized by ER stress. Summary sentenceNovel drug screening modality identifies compounds that correct aberrant molecular phenotypes in precision cellular models of glycosylation defects.

neuroscience↗