Purpose: Binding of high turnover soluble targets often leads to accumulation and/or increased CL of the antibody/target complex. Both negatively affect the PK/PD relationship of conventional mAbs against such targets. The SMART-Ig® (Sequential monoclonal antibody recycling technology) has been developed to overcome this challenge.
Chugai/Roche generated a novel SMART-Ig® against complement component C5. RO7112689 (SKY59) displays a significantly longer-lasting complement inhibition with longer half-life in NHP. The purpose of this study is to design an appropriately safe and efficacious dose for clinical trials from non-clinical studies.
Methods: To evaluate Pharmacokinetics/Pharmacodynamics (PK/PD) in NHP, designated assays to measure PK and total and free C5 were established, based on the ligand binding assay format. To prove the SMART-Ig® concepts, a comparative PK study in cynomolgsus monkeys was conducted with a conventional antibody. The conventional antibody was injected twice, on days 0 and 14, while RO7112689 was injected once, on day 0. To determine the efficacious concentration in NHP, a PK/PD study by 3 doses by IV and 1 dose by SC was conducted. Correlation between RO7112689 and PD values was investigated.
Results: In the comparative PK study, PK of the antibody was significantly improved by our antibody engineering, and pH dependent dissociation of antigen prevented C5 accumulation. Consistent with antibody and antigen PK profiles, RO7112689 suppressed the complement activity stably and for more than 8 weeks after 20 mg/kg one-shot injection. In the dose-ranging-study, above RO7112689 40 ug/mL completely suppressed free C5. In line with the results, when free C5 levels were lower than 2 ug/mL, complement activity inhibition was less than 20% of the baseline. Because there is little or no species difference between cyno and human in C5 level and affinity, these thresholds were also used to predict human PK/PD. Based on a comprehensive analysis of all NHP studies, the PK property of RO7112689 was predicted to be linear and have a wide dose range with low clearance. Using the PK/PD relationship established in NHP, an appropriate dose regimen was designed to ensure complete complement inhibition in patients (above 40 ug/mL at trough level). The first dose for healthy volunteers was also estimated in the same way, so as to avoid adverse effects by not inhibiting complement activity for more than 7 days.
Conclusion: The SMART-Ig® concept for an anti-C5 antibody was proved in preclinical study. A series of NHP studies increased the confidence of translatability to human PK/PD. The M&S approach successfully guided the design of the entry into human study design.
Michael Gertz– F. Hoffmann-La Roche Ltd.
Niels Janssen– F. Hoffmann-La Roche Ltd
Kenta Haraya– Chugai Pharmaceutical Co., Ltd.
Taku Fukuzawa– Chugai Pharmaceutical Co., Ltd.
Koji Yamaguchi– Chugai Pharmaceutical Co.,Ltd.
Mitsuko Shibuya– Chugai Pharmaceutical Co., Ltd.
Hiroo Watanabe– Chugai Pharmaceutical Co., Ltd.
Masahiko Nanami– Chugai Pharmaceutical Co., Ltd
Masaki Ishigai– Chugai Pharmaceutical Co., Ltd.