Pharmacokinetics, disease-modifying activity, and safety of an experimental therapeutic targeting an immunological isoform of macrophage migration inhibitory factor, in rat glomerulonephritis

Abstract

New therapeutic agents are needed to overcome the toxicity and suboptimal efficacy observed in current treatment of glomerulonephritis (GN). BaxB01 is a fully human monoclonal antibody targeting a disease-related immunologically distinct isoform of Macrophage migration Inhibitory Factor (MIF), designated oxidized MIF (oxMIF) and locally expressed in inflammatory conditions. We report the pharmacokinetic profile of BaxB01, and its dose and exposure-related disease-modifying activity in experimentally induced rat GN. BaxB01 bound to rat oxMIF with high affinity and reduced rat macrophage migration in vitro. After intravenous administration in rats, BaxB01 demonstrated favorable pharmacokinetics, with a half-life of up to nine days. Disease modification was dose-related (≥ 10mg/kg) as demonstrated by significantly reduced proteinuria and diminished histopathological glomerular crescent formation. Importantly, a single dose was sufficient to establish an exposure-related, anti-inflammatory milieu via amelioration of glomerular cellular inflammation. Pharmacodynamic modeling corroborated these findings, consistently predicting plasma exposures that were effective in attenuating both anti-inflammatory activity and reducing loss of kidney function. This pharmacologic benefit on glomerular function and structure was sustained during established disease, while correlation analyses confirmed a link between the antibody's anti-inflammatory activity and reduced crescent formation in individual rats. Finally, safety assessment in rats showed that the experimental therapeutic was well tolerated without signs of systemic toxicity or negative impact on kidney function. These data define therapeutically relevant exposures correlated with mechanism-based activity in GN, while toxicological evaluation suggests a large therapeutic index and provides evidence for achieving safe and effective exposure to a MIF isoform-directed therapeutic in nephritis-associated disease.

OxMIF: a druggable isoform of macrophage migration inhibitory factor in cancer and inflammatory diseases

“… 1 In vitro, immobilized anti-oxMIF antibody BaxB01 bound to rat oxMIF with high affinity and reduced rat macrophage migration. 109 In addition, treatment with BaxB01 in an experimentally induced rat glomerulonephritis model significantly reduced histopathological glomerular crescent formation, suggesting the anti-oxMIF antibodies altered immune cell function and/or migration. 109 Finally, oxMIF—by binding to CXCR2 on neutrophils and peripheral blood mononuclear cells—prolonged neutrophil survival by exerting anti-apoptotic effects.…”

“… 109 In addition, treatment with BaxB01 in an experimentally induced rat glomerulonephritis model significantly reduced histopathological glomerular crescent formation, suggesting the anti-oxMIF antibodies altered immune cell function and/or migration. 109 Finally, oxMIF—by binding to CXCR2 on neutrophils and peripheral blood mononuclear cells—prolonged neutrophil survival by exerting anti-apoptotic effects. 111 When evaluated in murine lungs, single-point mutations in redox-modifiable (Cys-80) and redox-sensitive (Lys-66) MIF residues reduced total immune cell recruitment compared with wild-type MIF.…”

“… 1 23 46 Finally, in the aforementioned rat glomerulonephritis model, one dose of BaxB01 created an exposure-related, anti-inflammatory environment by inhibiting glomerular cellular inflammation. 109 Treatment significantly reduced proteinuria and diminished histopathological glomerular crescent formation, indicating BaxB01 altered immune cell function and migration. 109 …”

“… 109 Treatment significantly reduced proteinuria and diminished histopathological glomerular crescent formation, indicating BaxB01 altered immune cell function and migration. 109 …”

Optimization of an Antibody Light Chain Framework Enhances Expression, Biophysical Properties and Pharmacokinetics

“…The affinity of the antibodies was determined by surface plasmon resonance as described [25]. In brief, 40 RU units of each antibody was immobilized onto a CM5 sensor chip (GE-Healthcare).…”