Selective targeting of pathogenic auto-reactive VH4–34 B cells with a rationally developed anti-VH4–34 antibody offers a new therapeutic approach for autoimmune disorders

Abstract

Abstract B cells expressing B cell receptors (BCRs) specific for self-antigens are normally eliminated, or made anergic, through negative selection during B cell development. VH4–34 is an intrinsically autoreactive antibody (and BCR) heavy chain variable region that includes a germline encoded hydrophobic patch in framework region 1 (FR1). Autoantigens recognized by VH4–34 antibodies include N-acetyl lactosamine chains displayed on RBCs. In healthy individuals, <1% of B cells express VH4–34 encoded BCRs but during the loss of self-tolerance, characteristic of pathogenic disorders, the hydrophobic region of VH4–34 reacts to self-antigen, erroneously driving BCR activation and expansion. Expansion of VH4–34+ B cells and increased serum concentrations of VH4–34 antibodies has been implicated in systemic lupus erythematosus (50%) and virtually all cases of cold agglutinin disease. To date there have been no therapies against VH4–34 due to challenges of specifically targeting VH4–34 while avoiding other VH regions. We applied Hummingbird Bioscience’s Rational Antibody Discovery approach to develop anti-VH4–34 antibodies that bind to a computationally predicted and lineage conserved epitope in the hydrophobic FR1 region. The lead antibody, HMBD-011, demonstrates selective and high affinity binding to all tested VH4–34 antibodies, with no off-target binding. The binding epitope of HMBD-011 was confirmed by mutagenesis to be within the FR1 region of VH4–34. Further, HMBD-011 shows selective binding to cells that express VH4–34 BCRs. In vivo, HMBD-011 treatment resulted in rapid elimination of VH4–34+ antibodies and cells. In conclusion, HMBD-011 represents a promising precision therapy for VH4–34 driven autoimmune disorders.