AUTOANTIBODIES AS BIOMARKERS FOR LIPODYSTROPHY

AUTOANTIBODIES AS BIOMARKERS FOR LIPODYSTROPHY

Researchers at UCSF and the Chan Zuckerberg Biohub have developed methods to identify a subject that is at risk of developing autoimmune-related lipodystrophy.

Lipodystrophy is a clinical phenotype defined by a reduction in subcutaneous fat or adipose tissue. Excessive fat loss can lead to an imbalance of lipid metabolism, storage, and signaling, manifesting as several clinical pathologies (e.g., diabetes, dyslipidemia). Although the underlying mechanism of fat loss is not clear, it is hypothesized to be linked to autoimmune destruction of adipocytes; patients with acquired lipodystrophy often present with associated autoimmune diseases. Recently, lipodystrophy has been described as an immune-related adverse event (IRAE) in cancer immunotherapy patients that underwent immune checkpoint inhibitor (ICI) therapy. As the use of ICI therapy expands, it will become increasingly important to identify patients at risk for developing autoimmune-related lipodystrophy.

Stage of Research

The inventors have developed methods to detect a specific immunoglobulin G (IgG) autoantibody marker for early detection and risk assessment of autoimmune-related lipodystrophy. The target of the novel autoantibody marker is Perilipin 1 (PLIN1), which is expressed in adipocytes and has demonstrated roles in triacylglycerol storage and lipolysis. Antigenic PLIN1 polypeptides are used in various immunoassays to detect the presence of PLIN1 autoantibodies in a biological sample obtained from a subject. Detection of PLIN1 autoantibodies in the biological sample indicates that the subject has autoimmune-related lipodystrophy. The inventors validate their methods by detecting PLIN1 autoantibodies in a human patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy.

Applications

Identifying a subject at risk of developing acquired generalized lipodystrophy (AGL) or acquired partial lipodystrophy (APL)
Identifying early evidence or assessing the risk of autoimmune-related lipodystrophy in a subject that has been previously treated, or is being treated, with immune checkpoint inhibitor therapy
Monitoring immune response of seropositive patients in the course of ICI therapy
Treating a subject having early evidence of autoimmune-related lipodystrophy

Advantages

PLIN1 autoantibodies are not found in healthy subjects or in ICI-treated patients that do not develop lipodystrophy
Depending on the nature of the biological sample, either immunoassays or immunocytochemical staining techniques may be used to detect autoantibodies in complex with PLIN1 antigenic polypeptides.
Confirmation of lipodystrophy by PLIN1 autoantibodies can allow general (e.g., immunosuppressant drugs) or targeted (e.g., PPAR agonist) treatment of the condition, or alteration and/or termination of ICI therapy

Stage of Development

Research – in vitro

Publications

Mandel-Brehm C., et al. Autoantibodies to perilipin-1 define a subset of acquired generalized lipodystrophy. Diabetes. 2022. DOI: 10.2337/db21-1172

PCT Publication No. WO2022/146837

­AUTOANTIBODIES AS BIOMARKERS FOR LIPODYSTROPHY

AUTOANTIBODIES AS BIOMARKERS FOR LIPODYSTROPHY