Anastasia Dmitrieva
R-Pharm JSC, Russia
Title: Nonclinical characterization of the novel IL-1 heterodimeric fusion protein RPH-104
Biography
Biography: Anastasia Dmitrieva
Abstract
Statement of the Problem: Interleukin-1 (IL-1), a central mediator of innate immunity and inflammation, plays a pivotal role in a broad spectrum of inflammatory diseases. RPH-104 is a novel IL-1 antagonist: a heterodimer comprised of human extracellular portions of IL-1RI and IL-1 receptor accessory protein, each linked to a mutant Fc portion of human IgG1.
Aim: The aim of the studies is preclinical characterization of RPH-104.
Methodology & Theoretical Orientation: A surface plasmon resonance methods were developed to measure the binding kinetics/affinity of RPH-104 to IL-1α, IL-1β, IL-1Ra and Fc receptor binding. U937 cells which express IL-1α were selected for use in the antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. Potential tissue cross-reactivity (TCR) was assessed with histologically prepared cryo-sections from a selected panel of human and cynomolgus monkey tissues. To facilitate immunohistochemical detection RPH-104 and human IgG1 were conjugated with biotin. To assess the toxicity, toxicokinetics and immunogenicity of RPH-104, a 4 weeks subcutaneous administrations toxicity study in cynomolgus monkey was performed.
Findings: RPH-104 binds to IL-1β in preference to IL-1α or IL-Ra. RPH-104 binds to Fc (FcγRI, FcγRIIa, FcγRIIb, FcRn, FcγIIIb) receptors overall with a lower affinity than human IgG1. No evidence of RPH-104 ADCC or CDC was shown. TCR study shows similar binding of RPH-104 to cynomolgus monkeys and human tissues. There are no safety issues evident from the cynomolgus monkey GLP (Good Laboratory Practice) 4-week toxicology study. No-observed-adverse-effects-level is considered to be 100 mg/kg RPH-104.
Conclusion & Significance: Overall RPH-104 has shown potent in vitro activity and no safety concerns. This makes RPH-104 a potent candidate as an anti-inflammatory therapeutic for a range of IL-1 mediated clinical indications.