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LSO-006 Targeting pathogenic auto-reactive VH4-34 B cells with a rationally developed and highly specific anti-VH4-34 antibody offers a new therapeutic approach for VH4-34 autoimmune disorders
  1. Shalini Paliwal,
  2. Dipti Thakkar,
  3. Wen Jie Chin,
  4. Warren Lee,
  5. Jie Ying Jacklyn Neo,
  6. Brendon Hanson,
  7. Konrad Paszkiewicz,
  8. Piers Ingram and
  9. Jerome Boyd-Kirkup
  1. Research, Hummingbird Bioscience, Singapore


Background 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 hydrophobic patch in framework region 1 (FR1). Autoantigens recognized by VH4-34-encoded antibodies include N-acetyl lactosamine chains displayed on red blood cells. In healthy individuals, <1% of B cells express VH4-34-encoded BCRs but during the loss of self-tolerance, the hydrophobic region in FR1 reacts to self-antigen, erroneously driving B-cell activation and expansion.

Expansion of VH4-34+ B cells and increased serum concentrations of auto-reactive VH4-34 antibodies have been reported in autoimmune disorders, including systemic lupus erythematosus (50%) and virtually all cases of cold agglutinin disease. To date, there have been no successful therapies against VH4-34 due to challenges of specifically targeting VH4-34 while avoiding other VH regions.

Methods 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 FR1 of VH4-34 antibodies. In vitro, the ability of HMBD-011 to specifically bind VH4-34+ cell lines was determined using flow cytometry. Potency of HMBD-011, to eliminate circulating VH4-34 antibodies and VH4-34+ cells in vivo, was measured using serum ELISA and IVIS Spectrum In Vivo Imaging System respectively.

Results The lead antibody, HMBD-011, demonstrates selective and high affinity binding to tested VH4-34 antibodies, with no off-target binding to a panel of other VH antibodies. The binding epitope of HMBD-011 was confirmed by mutagenesis to be within the FR1 of VH4-34. Further, HMBD-011 shows selective binding to cells that endogenously and exogenously express VH4-34 BCRs. In vivo, HMBD-011 treatment results in specific elimination of VH4-34 auto-antibodies and depletion of VH4-34+ B cells.

Conclusions HMBD-011 represents a promising new precision therapy for patients with VH4-34 autoimmune disorders.

  • VH4-34
  • systemic lupus erythematosus (SLE)
  • cold agglutinin disease (CAD)

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