Histone H3K27M neoantigen-specific B-cell receptor and antibody (H3K27M-specific BCR/Ab)

B-cell receptors (BCRs) and antibodies specific for the H3K27M neoantigen are specialized immune proteins designed to recognize a specific mutation in the histone H3 protein, where lysine 27 is replaced by methionine. This mutation is a hallmark of aggressive pediatric brain tumors, specifically diffuse midline gliomas (DMGs) and diffuse intrinsic pontine gliomas (DIPGs). Because this mutation is found exclusively in tumor cells and not in healthy tissue, it serves as an ideal neoantigen for targeted immunotherapy (https://www.nature.com/articles/s41467-020-18813-3). These BCRs and antibodies are being researched for their ability to mediate a targeted immune response against glioma cells. While histones are primarily intracellular, H3K27M fragments can be presented on the cell surface by HLA molecules or released into the tumor microenvironment, allowing for antibody-mediated recognition. Therapeutic strategies include using these sequences to develop chimeric antigen receptor (CAR) therapies or bispecific antibodies that bridge tumor cells and immune effectors. Their high specificity for the K27M mutation minimizes the risk of systemic toxicity, although delivering these large molecules across the blood-brain barrier remains a significant clinical hurdle (https://clinicaltrials.gov/ct2/show/NCT04749641).

Other names

H3K27M-specific antibodiesH3.3 K27M-specific B-cell receptorsAnti-H3K27M antibodiesH3K27M neoepitope-targeting B-cell receptors

These receptors and antibodies function by specifically binding to the H3K27M neoepitope, typically presented on the cell surface in the context of Major Histocompatibility Complex (MHC) molecules or released from necrotic tumor cells. In a therapeutic context, they can be used to engineer CAR-B or CAR-T cells, or as monoclonal antibodies to induce antibody-dependent cellular cytotoxicity (ADCC) or facilitate antigen presentation to T cells (https://pubmed.ncbi.nlm.nih.gov/33020650/).