Kermani, P. | Search bioRxiv

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↗

bioRxiv2025

Expression of the human immunomodulatory protein, human B7-1 (CD80), accelerates neuroinflammation, synaptic loss, microvascular instability and lethality in a murine model of Alzheimers Disease

Immune-mediated inflammatory processes play a pivotal role in the pathogenesis of Alzheimers disease (AD). However, immune loci exhibit significant sequence diversity, with human proteins sharing only [~]45-70% identity with their murine orthologs. This divergence contributes to the inability of many established mouse models to accurately capture key neuroinflammatory mechanisms relevant to human AD. We recently identified that the human, but not murine, immunomodulatory protein B7-1 (CD80) activates the p75 neurotrophin receptor (p75), a function arising from evolutionary divergence in human B7-1. This discovery provides an opportunity to directly interrogate the role of this interaction in disease progression using a well-characterized murine model of mutant A{beta} overexpression (CRND8). We generated a mouse line in which murine B7-1 was replaced with a chimeric human:murine B7-1 that retains normal interactions with CTLA-4 and CD28, while gaining the ability to bind p75, and evaluated its effects in CRND8 mice. Expression of human:murine B7-1 in vivo resulted in increased lethality, accelerated neuroinflammation of resident glia, more rapid synaptic and dendritic loss, and enhanced microvascular compromise in the subiculum compared to CRND8 mice expressing murine B7-1. Together, these findings identify the human B7-1:p75 interaction as a previously unrecognized contributor to AD pathogenesis and a potential therapeutic target in a brain region critical for learning and memory that is affected in early stages of disease.

neuroscience↗