Modification of the Fc Region of a Human Anti‐oncostatin M Monoclonal Antibody for Higher Affinity to FcRn Receptor and Extension of Half‐life in Cynomolgus Monkeys

Abstract

The purpose of this study was to evaluate the pharmacokinetics (PK) of anti-oncostatin M (OSM) IgG1 monoclonal antibodies, CNTO 1119 and its Fc variant (CNTO 8212), which incorporates the LS(Xtend) mutation to extend terminal half-life (T ), after a single intravenous (IV) or subcutaneous (SC) administration in cynomolgus monkeys, and to predict human PK. In study 1, single doses of CNTO 1119 and CNTO 8212 were administered IV or SC at 3 mg/kg to cynomolgus monkeys (n = 3 per group). In study 2, single doses of CNTO 8212 were administered IV at 1, 5 or 20 mg/kg, or SC at 5 mg/kg to cynomolgus monkeys (n = 5 per group). Serial blood samples were collected for assessment of serum concentrations of CNTO 1119 and/or CNTO 8212. A two-compartment population PK model with first-order elimination was utilized to simultaneously describe the serum concentrations of CNTO 1119 and CNTO 8212 over time after IV and SC administration in cynomolgus monkeys. The typical population PK parameter estimates for CNTO 1119 in cynomolgus monkeys were clearance (CL) = 2.81 mL/day/kg, volume of distribution of central compartment (V ) = 31.3 mL/kg, volume of distribution of peripheral compartment (V ) = 23.3 mL/kg, absolute bioavailability (F) = 0.84 and T = 13.4 days. In comparison, the typical population PK parameter estimates for CNTO 8212 in cynomolgus monkeys were CL = 1.41 mL/day/kg, V = 39.8 mL/kg, V = 32.6 mL/kg, F = 0.75 and T = 35.7 days. The mean CL of CNTO 8212 was ~50% lower compared with that for CNTO 1119 in cynomolgus monkeys. The overall volume of distribution (V +V ) for CNTO 8212 was about 32% larger compared with that for CNTO 1119, but generally similar to the vascular volume in cynomolgus monkeys. The T of CNTO 8212 was significantly (p < 0.05) longer by about 2.7-fold than that for CNTO 1119 in cynomolgus monkeys. Thus, the modification of the Fc portion of an anti-OSM IgG1 mAb for higher FcRn binding affinity resulted in lower systemic clearance and a longer terminal half-life in cynomolgus monkeys. CNTO 8212 demonstrated linear PK after a single IV dose (1-20 mg/kg) in cynomolgus monkeys. The predicted human PK parameters suggest that CNTO 8212 is likely to exhibit slow clearance and long terminal half-life in human beings and may likely allow less frequent dosing in the clinical setting.

Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life

“…For two different cancer immunotherapeutic antibodies the LS mutant IgG1 inhibited tumor growth significantly better than the wildtype IgG1 (112). Since the initial description of the LS mutations, multiple groups have shown these mutations boost antibody half-life in cynomolgus macaques (120, 121) and rhesus macaques (119, 122). The LS mutations have been helpful in sustaining protection against HIV-1 infection in animal models (119, 122, 123).…”

The oncostatin M‐stromal cell axis in health and disease

“…These two antibodies represent the sum of anti‐OSM therapeutic agents that have progressed into clinical investigation. However, evidence suggests that further OSM‐targeted assets are or were in preclinical development, including a fully human OSM‐targeting mAb (CNTO8212; Janssen) and two OSMR‐targeting mAbs (Biogen Idec, Patent WO2014/194274A2, 2014; and Raven Biotechnologies, Patent US7572896B2, 2009).…”

Targeting FcRn to Generate Antibody-Based Therapeutics

“…These mutated genes were used to produce a phage display library , from which Fc fragments with mutations that conferred higher affinity for FcRn at pH 6.0 (early endosomal pH) were selected [50]. Subsequently, similar approaches, or molecular modeling based on structural data, have been used to generate human IgG (IgG1 or IgG4) variants with increased affinity for human FcRn, resulting in 2–5-fold increases in half-life in monkeys and humans [51–58]. For example, the analysis of antibodies specific for Staphylococcal α-toxin with the ‘YTE’ half-life extending mutations (Met252 to Tyr, Ser254 to Thr, Thr256 to Glu that are all in proximity to the key residues of IgG that interact with FcRn (Figure 1B) [59]) during phase II clinical trials demonstrated half-lives ranging from 80–112 days, compared to around 20 days for wild type (WT) human IgG1 [52].…”