Abstract: TH-PO044

Discovery and Engineering of VIS649, a First-in-Class Humanized IgG2 Targeting APRIL for the Treatment of IgA Nephropathy

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Myette, James R., Visterra, Inc., Cambridge, Massachusetts, United States
  • Adari, Hedy, Visterra, Inc., Cambridge, Massachusetts, United States
  • Deotale, Ketan, Visterra, Inc., Cambridge, Massachusetts, United States
  • Ramakrishnan, Boopathy -, Visterra, Inc., Cambridge, Massachusetts, United States
  • Robinson, Luke, Visterra, Inc., Cambridge, Massachusetts, United States
  • Szretter, Kristy J, Visterra, Inc., Cambridge, Massachusetts, United States
  • Wollacott, Andrew M., Visterra, Inc., Cambridge, Massachusetts, United States
  • Shriver, Zachary H, Visterra, Inc., Cambridge, Massachusetts, United States
  • Pereira, Brian J.G., Visterra, Inc., Cambridge, Massachusetts, United States
Background

IgA nephropathy (IgAN) is one of the most prevalent, chronic glomerular diseases worldwide. No disease-specific therapeutic modalities currently exist. APRIL (A PRoliferation Inducing Ligand; TNFSF13) has recently emerged as a potentially key immunobiological factor in disease pathogenesis and progression. We describe here the discovery and lead identification of VIS649, a highly potent, humanized IgG2κ antibody targeting human APRIL. A molecular description of the unique VIS649 epitope and correlation of its mode of target engagement to its potent neutralizing activity and pharmaceutical properties are described

Methods

VIS649 was derived from parental mouse antibody 2419 following immunization with recombinant APRIL. Parental mAb 2419 was humanized with conversion to an IgG2κ with full retention of in vitro activity. The VIS649 binding epitope on APRIL was mapped using an integrated platform approach that incorporated X-ray crystallography, deep mutational scanning with an APRIL yeast display library, and computationally driven structural modeling. Antibody effector function (ADCC, CDC) was assessed using recombinant human Fc receptor binding and cell-based assays.

Results

VIS649 binds to human APRIL with low picomolar affinity and possesses subnanomolar blocking potency of APRIL binding and signaling through both its receptors, BCMA and TACI. VIS649 also exhibits potent inhibition of relevant APRIL-mediated B-cell activities including B cell proliferation, IgA production, and terminal B-cell survival. VIS649 targets a critical quaternary epitope within APRIL that overlaps with the high affinity (CRD2) receptor binding site and spanning the interface between two monomers to effectively neutralize oligomeric APRIL, the biologically relevant form of APRIL. VIS649 engages with Fc receptors reflecting the expected canonical binding characteristics of a human IgG2 isotype and binds only minimally to complement (C1q).

Conclusion

This work highlights the integrated platform used for the discovery, lead optimization, and structure-activity characterization of VIS649, a first-in class anti-APRIL antibody currently in development for the treatment of IgA nephropathy.

Funding

  • Commercial Support