Anti-IL-6 Antibody Clazakizumab Is More Potent Than Tocilizumab In Blocking In Vitro and Ex Vivo IL-6-Induced Functions

Q Zhao, J Pang, D Shuster, C Hung, S Baglino, R Dodge, H Sun, W Trigona and L Salter-Cid, Bristol-Myers Squibb Research and Development, Princeton, NJ

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: IL-6 and IL-6R signaling

Session Information

Session Title: Rheumatoid Arthritis Treatment - Small Molecules, Biologics and Gene Therapy III

Session Type: Abstract Submissions (ACR)

Background/Purpose: Interleukin-6 (IL-6), a pleiotropic cytokine, drives cell functions by binding to membrane-bound IL-6 receptor (IL-6R, classical signaling) or to soluble IL-6R (sIL-6R, trans-signaling) and is a key player in the pathogenesis of chronic inflammatory diseases including RA. Tocilizumab, an antibody targeting the IL-6 pathway via the IL-6R, is the only agent currently available for the treatment of RA and juvenile idiopathic arthritis. The objective of this study was to compare the potency of clazakizumab (BMS-945429), an antibody against the IL-6 cytokine that is in clinical development for several auto-immune conditions, with that of tocilizumab in blocking IL-6-induced cell functions. Methods: Multiple in vitro assays for IL-6-induced functions (classical signaling) and IL-6/sIL-6R-mediated functions (trans-signaling) were used to compare the potential of clazakizumab and tocilizumab for inhibiting signaling, proliferation, activation, antibody production and secretion of acute phase protein (Table). Pharmacokinetic/pharmacodynamic (PK/PD) studies of clazakizumab and tocilizumab were also conducted using monkey and human IL-6R knock-in (hIL-6R KI) mouse models to examine pSTAT3 and serum amyloid A blockade, respectively. Results: In multiple cell function assays, clazakizumab and tocilizumab inhibited both classical signaling and trans-signaling; clazakizumab was between 3 and 120 times more potent than tocilizumab (Table). Furthermore, PK/PD studies confirmed that clazakizumab is a potent blocker of ex vivo IL-6-induced pSTAT3 in cynomolgus monkey and of serum amyloid A protein induction in hIL-6R KI mice injected with human IL-6.

Cell function assay		Stimulus	Clazakizumab IC50, nM (SD)	Tocilizumab IC50, nM (SD)	Fold tocilizumab/ clazakizumab
Signaling	pSTAT3 in human whole blood	IL-6 (0.7 nM)	0.07 (0.04)	4.8 (0.08)	~66
Proliferation	TF-1 erythroleukemic cell line (classical)	IL-6 (0.1 nM)	0.007 (0.007)	0.23 (0.23)	~33
Proliferation	PHA-activated blood T cell (classical)	IL-6 (0.1 nM)	0.005 (0.002)	0.6	120
Activation	Endothelial cell secretion of MCP-1 (trans)	IL-6 (1 nM) /sIL-6R (1 nM)	0.1 (0.05)	0.3 (0.2)	~3
Activation	JURKAT T-cell line expression of JAK3 (trans)	IL-6 (1 nM) /sIL-6R (10 nM)	0.1 (0.05)	4.8 (0.2)	~44
Antibody production	SKW B-cell line secretion of IgM (classical)	IL-6 (0.1 nM)	0.007 (0.005)	0.3 (0.1)	~43
Secretion of acute phase protein	PLC/PRF/5 hepatocyte line secretion of CRP (classical)	IL-6 (0.1 nM)	0.008 (0.004)	0.7 (0.5)	~88

Conclusion: Both in vitro and ex vivo/in vivo studies have shown that clazakizumab is a potent blocker of IL-6-induced functions. Evidence collected thus far has demonstrated that clazakizumab is more potent than tocilizumab in blocking IL-6-induced functions.

Disclosure:

Q. Zhao,

Bristol-Myers Squibb,

J. Pang,

Bristol-Myers Squibb,

D. Shuster,

Bristol-Myers Squibb,

C. Hung,

Bristol-Myers Squibb,

S. Baglino,

Bristol-Myers Squibb,

R. Dodge,

Bristol-Myers Squibb,

H. Sun,

Bristol-Myers Squibb,

W. Trigona,

Bristol-Myers Squibb,

L. Salter-Cid,

Bristol-Myers Squibb,

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