Development of human B-lymphocyte targeted bi-specific DART® molecules for the treatment of autoimmune disorders (THER5P.830)

Abstract B-cell targeted immunotherapy for autoimmune disorders is often limited by general immune suppression caused by significantly altered B-cell homeostasis. To overcome this, we developed MGD010, a bi-specific Dual-Affinity Re-Targeting (DART) molecule that coligates the inhibitory Fcγ receptor IIb (CD32B) and the B-cell receptor component, CD79B, on B cells. Previous work has shown that CD32BxCD79B DARTs engage CD32B in a BCR-dependent manner and inhibit B-cell activation without B-cell depletion. MGD010, a CD32BxCD79B DART bearing an Fc domain to enhance pharmacokinetic (PK) properties, was generated to support potential clinical development. Favorable PK properties and lack of safety signals, including no cytokine release nor B-cell depletion, were observed in non-human primate dose-escalated with MGD010 to up to 10 mg/kg. Pharmacodynamic analysis demonstrated dose-correlated target binding to B cells and reduced B-cell calcium flux induced by ex vivo BCR-crosslinking. In addition, MGD010 blocked B-cell function ex vivo in samples from autoimmune patients. Repeat administration of MGD010 also inhibited both humoral immune responses and the development of chronic graft-versus-host disease in a humanized mouse model. Thus, MGD010, an Fc-bearing CD32BxCD79B DART with extended PK, may represent a promising B-cell intervention strategy for the treatment of autoimmune diseases, with limited impact on B-cell homeostasis.