RT Journal Article
SR Electronic
T1 Dual blockade of interleukin 1β and interleukin 17A reduces murine arthritis pathogenesis but also leads to spontaneous skin infections in non-human primates
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.117.243493
DO 10.1124/jpet.117.243493
A1 Melanie C Ruzek
A1 Lili Huang
A1 Ting Ting Zhang
A1 Shaughn Bryant
A1 Peter F Slivka
A1 Carolyn A Cuff
A1 Catherine Tripp
A1 Guenter Blaich
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/01/08/jpet.117.243493.abstract
AB Despite the efficacy of biologics for treatment of rheumatoid arthritis (RA), many patients show inadequate responses and likely require neutralization of multiple mediators. Neutralization of both interleukin (IL)-1β and IL-17A with monoclonal antibodies showed greater efficacy than either agent alone in a mouse arthritis model with cooperative inhibition of key inflammatory factors, IL-6, granulocyte colony stimulating factor (G-CSF) and CXC chemokine ligand (CXCL)1. Given the potential clinical benefit in RA, we generated a human dual variable domain antibody (DVD-Ig), ABBV-615, capable of simultaneous binding and neutralization of IL-1β and IL-17A. ABBV-615 was characterized and evaluated in cynomolgus monkeys for pharmacokinetics and toxicity to enable clinical development. ABBV-615 exhibited affinities (KD) of 12 and 3 pM on human IL-1β and IL-17A, respectively, and potencies (IC50) of 3 and 58 pM, respectively, as well as excellent drug-like properties. ABBV-615 pharmacokinetics in cynomolgus monkeys was dose proportional from 20 to 100 mg/kg with a mean half-life of 16d. However, a 13-week repeat-dose toxicity study in cynomolgus monkeys revealed time-dependent spontaneous infections exclusively in skin at all doses tested and not historically seen with single agent anti-IL-1α/β or anti-IL-17A. Consistent with reduced resistance to skin infections, IL-1β and IL-17A-stimulated human keratinocytes demonstrate cooperative or compensatory production of key anti-bacterial and inflammatory mediators such as Lipocalin-2 (LCN2), G-CSF, CXCL1, IL-8, tumor necrosis factor (TNF) and IL-6, which aid in defense against skin bacterial infections. These results illustrate the skin-specific antimicrobial mechanisms of IL-1β and IL-17A and highlight the importance of understanding unique combinatorial effects of biological agents.