Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases

Table 1 Comparison of affinity to tumor necrosis factor by anti-tumor necrosis factor agents

Target	Method /source	Affinity	Ref.
sTNF	SPR	GOL = ETA > IFX > ADA	[40]
sTNF	SPR	ETA > ADA = IFX	[41]
mTNF	mTNF-expressing cells (Sp2/0-11A5-1 myeloma cells)	IFX = ADA = ETA	[41]
mTNF	mTNF-expressing cells (K2 murine myeloma cells)	IFX = GOL > ADA > ETA	[40]
mTNF	PBMCs (T cells)	IFX = ADA > Certo >> No binding of ETA	[42]
	Flow cytometry
mTNF	PBL	IFX >> No binding of ETA	[43]
	Flow cytometry
sTNF	Immunoassay	IFX > ETA (rapid dissociation)	[44]

ADA: Adalimumab; ETA: Etanercept; GOL: Golimumab; IFX: Infliximab; Certo: Certolizumab pegol; PBL: peripheral blood lymphocytes; TNF: Tumor necrosis factor; mTNF: Membrane-bound TNF; sTNF: Soluble TNF; SPR: Surface plasmon resonance.

Table 2 Comparison of avidity to tumor necrosis factor by anti-tumor necrosis factor agents

Target	Method/source	Avidity	Ref.
sTNF	KinExA®	ETA > ADA	[41]
	(automated flow immunoassay system)	IFX
mTNF	[44]	IFX > ETA	[44]

ADA: Adalimumab; ETA: Etanercept; IFX: Infliximab; TNF: Tumor necrosis factor; mTNF: Membrane-bound TNF; sTNF: Soluble TNF.

Table 3 Mechanism of action of anti-tumor necrosis factor agents

Agent	Cell type	Mechanism of action	Ref.
ADA	CHO cell line stably expressing mTNF cocultured with human PBMCs	Induction of ADCC	[75]
ADA	CHO cell line stably expressing mTNF with human normal serum	Induction of CDC	[75]
IFX, ADA, ETA, Certo	TNF6.5 cells (murine NSO cell line stably expressing human TNF) with baby rabbit complement	CDC: IFX, ADA, ETA ++; Certo -	[50]
IFX, ADA, ETA, Certo	TNF6.5 cells in coculture with CD14-depleted PBMCs	ADCC: IFX, ADA ++, ETA+, Certo -	[50]
IFX, ADA, ETA, Certo	Peripheral blood lymphocytes	Apoptosis: IFX, ADA ++; ETA+, Certo -	[50]
IFX, ADA, ETA, Certo	Peripheral blood monocytes	Apoptosis: IFX, ADA ++; ETA+, Certo -	[50]
IFX, ADA	mTNF transfected cell line (SP2/0-11A5-1, murine)	Induction of CDC	[41]
IFX, ADA	Activated human PBMCs	No induction of CDC	[41]
GOL, ADA, IFX, Certo	mTNF expressing Jurkat cells with PBMCs/human serum	ADCC, CDC: GOL, ADA, IFX ++; ETA+, Certo-	[77]
ADA, IFX, GOL, Certo	mTNF expressing Jurkat cells	Apoptosis: ADA, IFX ++,	[77]
		GOL+, Certo+
ADA, IFX, ETA	cultured monocytes	Caspase-dependent apoptosis: ADA, IFX ++; ETA -	[53]
IFX, ETA	Peripheral blood lymphocytes and lamina propria T cells	Caspase-3 activation and apoptosis: IFX +; ETA -	[43]
ADA, IFX, ETA, Certo	Intestinal CD4/CD14 cells from IBD patients	Apoptosis by targeting mTNF/TNFR2: ADA, IFX, Certo +; ETA -	[24]

Apoptosis induction of anti-TNF agents. ++: Strong effect; +: Effect visible; -: No effect; ADA: Adalimumab; ETA: Etanercept; IFX: Infliximab; Certo: Certolizumab pegol; GOL: Golimumab; TNF: Tumor necrosis factor; mTNF: Membrane-bound TNF; sTNF: Soluble TNF; PBMCs: Peripheral blood mononuclear cells; ADCC: Antibody-dependent cellular cytotoxicity.

Table 4 Prediction of response to anti-tumor necrosis factor therapy - possible biomarkers

Material/method	Predictor for response	Disease	Ref.
Intestinal biopsies	IL1B (upregulated in non-responders)	CD	[54]
	IL17A (upregulated in non-responders)
Intestinal biopsies	IL13RA2	CD and UC	[16]
	PTGS2
	WNT5A
Blood	high CAI	UC	[17]
	negative ANCA
	IL23R
Blood	High API	CD	[83]
Blood	C-reactive protein	CD and UC	[84]
Intestinal biopsies	TNFRSF11B (osteoprotegerin)	UC	[85]
	STC1 (stanniocalcin-1)
	PTGS2 (prostaglandin-endoperoxide synthase 2)
	IL13Ralpha2 (IL13R alpha 2)
	IL11 (IL-11)
SPECT	High apoptosis rate	CD	[80]
Endoscopic molecular imaging	High mucosal mTNF expression in vivo	CD	[18]

CD: Crohn’s disease; UC: Ulcerative colitis; SPECT: Single-photon emission computer tomography.