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Abstract: FR-OR105

Prevention of Proteinuria by a Novel, Subnanomolar ApoL1 Inhibitor

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Antonio, Brett M., OmniAb, Durham, North Carolina, United States
  • Zahler, Nathan, OmniAb, Durham, North Carolina, United States
  • Mechin, Ingrid, OmniAb, Durham, North Carolina, United States
  • Theile, Jonathan W., OmniAb, Durham, North Carolina, United States
  • Dow, Robert L., BioPharmaWorks, Groton, Connecticut, United States
  • Volkmann, Robert A., BioPharmaWorks, Groton, Connecticut, United States
  • Zellmer, Shannon Gail, OmniAb, Durham, North Carolina, United States
  • Chdid, Lhoucine, OmniAb, Durham, North Carolina, United States
  • Nair, Anil, OmniAb, Durham, North Carolina, United States
  • Krafte, Douglas, OmniAb, Durham, North Carolina, United States
Background

Genetic variants of human ApoL1, which have arisen under evolutionary pressure to target mutant trypanosomes, have also been associated with an increased risk of developing chronic kidney diseases (CKD) in people of African ancestry1. Recently reported clinical results suggest inhibition of ApoL1 ion channel function may produce clinical benefit in patients with ApoL1-induced nephropathies2.
1. doi: 10.2215/CJN.15161219
2. doi: 10.1056/NEJMoa2202396

Methods

We established stable HEK-TREx cell lines in the EIK haplotype expressing human G1 and G2 variants under control of an inducible promoter and identified compounds for evaluation via high throughput screening, in silico profiling and medicinal chemistry design.
Tl+ flux and electrophysiology assays were used to assess in vitro efficacy of compounds against ApoL1 function. A human transgenic mouse model expressing ApoL1-G1 EIK and exhibiting a significantly elevated urinary albumin/creatine ratio (uACR) following IFNγ challenge was used to assess in vivo efficacy. Compound efficacy was determined by assessing inhibition of proteinuria.

Results

Our lead compound, ICA-264 demonstrated concentration-dependent inhibition of ApoL1-G1 mediated Tl+ flux with an IC50 value of 4 nM (95% CI 3.5-4.4 nM, n=196). The potency was similar against ApoL1-G2 (IC50 = 5 nM, 95% CI 4.4-6.0 nM, n=77). Directly measuring ApoL1 current in electrophysiological experiments demonstrated potent inhibition with IC50 values at -80 mV and +60 mV of 0.6 nM and 0.4 nM (95% CI 0.35-0.47 and 0.49-0.65, respectively). Analogs of ICA-264 were identified with IC50 values as low as 0.26 nM in electrophysiological assays. In our in vivo model oral dosing of ICA-264 (BID) at 3, 10, and 30 mg/kg decreased the IFNγ-induced rise in uACR by 73%, 92%, and 91%, respectively (n=6) on day 2.

Conclusion

ICA-264 is a novel ApoL1 inhibitor with excellent drug-like properties and in vivo efficacy. This merits further consideration as a potential novel therapeutic for the treatment of ApoL1-induced nephropathies.

Funding

  • Commercial Support – OmniAb, Inc.