Targeting Bruton's Tyrosine Kinase: NX-5948's Anti-Inflammatory Impact in Autoimmune Disease Models

Autoimmune diseases like SLE and RA are characterized by abnormal B cell activation and autoantibody-induced tissue damage, making them a target for novel therapies that can prevent autoantibody production or antibody-mediated tissue damage. Bruton’s tyrosine kinase (BTK) plays a key role in signal transduction in B and myeloid cells, and its overexpression can lead to an SLE-like disease in mice. BTK inhibitors are being studied for the treatment of autoimmune diseases.

NX-5948 is a Chimeric Targeting Molecule (CTM) designed to degrade BTK, thereby eliminating both its kinase activity and scaffolding interactions. It is composed of a BTK binding element and a cereblon (CRBN) binding element. The molecule was tested for its ability to degrade BTK and inhibit BCR signaling in human peripheral blood mononuclear cells (PBMCs) using flow cytometry.

In a collagen-induced arthritis (CIA) model, NX-5948 was administered orally to mice before symptom onset. The treatment resulted in significant BTK degradation in circulating and splenic B cells and reduced arthritis clinical scores. It also decreased anti-type II collagen titers and serum IL-6 levels, showing superior anti-inflammatory effects compared to the BTK inhibitor ibrutinib and similar effects to dexamethasone. Importantly, NX-5948 was well-tolerated and did not cause body weight loss, unlike dexamethasone.

The study concludes that NX-5948 demonstrates potent activity in the CIA model and supports further investigation of the molecule in other autoimmune disease models, with the aim of informing clinical development plans. NX-5948's ability to degrade BTK without causing the degradation of other CRBN substrates, such as Aiolos and Ikaros, and its lack of IMiD activity associated with lenalidomide, suggests it may offer a unique therapeutic approach for autoimmune diseases.