ESPE Yearbook of Paediatric Endocrinology

In Brief: This case report describes the successful use of RZ358, a novel human anti–insulin receptor monoclonal antibody therapy, in a patient with severe, refractory hypoglycaemia due to metastatic insulinoma.

The tumour and resulting severe hypoglycaemia had been resistant to treatments with octreotide, lutetium Lu 177 dotatate radionuclide, diazoxide, everolimus, dexamethasone, pasireotide, and glucagon – and the patient, a 55-year old man with a pathogenic MEN1 gene mutation, was dependent on continuous high dose 50% dextrose infusion. So the authors, from the Beth Israel Deaconess Medical Center, Boston, obtained emergency use authorization from the US Food and Drug Administration to try RZ358 for the first time. Hypoglycaemia resolved after the second infusion of RZ358 (6 mg/kg) and all other therapies could be discontinued after an additional 4 infusions. Despite persisting high tumour size, severe hypoglycaemia remained controlled by ongoing monthly infusions (up to 9 months at the time of report).

As well as providing a future effective option for the treatment of resistant hyperinsulinism, this case report highlights the potential for therapeutic monoclonal antibodies (MAB) in metabolic conditions. In recent years, MABs have emerged as remarkably effective new treatments in oncology, and as immunotherapies for rheumatology and other inflammatory diseases. So far, endocrinologists have been mostly involved in ‘picking up the pieces’ of managing endocrine immune-related adverse events, e.g. thyroiditis (in up to 9%), hypophysitis (<1%) and more rarely primary adrenal insufficiency.

In Paediatric Endocrinology, we use denosumab, a MAB which inhibits osteoclast formation, function, and survival, as a treatment for rare (RANKL)-mediated disorders, and also emerging MAB immunotherapies to prevent or prolong beta-cell function in Type 1 diabetes. Other promising new endocrine targets include MABs that bind to and degrade stimulating thyrotropin receptor autoantibodies as new treatments for Graves’ Disease (1).

Reference: 1. Wolf J et al. A Novel Monoclonal Antibody Degrades the Thyrotropin Receptor Autoantibodies in Graves’ Disease. Endocrine Practice. Vol 29, 7; 553-559 (2023) 10.1016/j.eprac.2023.04.002