Use of the tumor necrosis factor-blockers for Crohn's disease

Table 2 Individual biological properties of tumor necrosis factor blockers

IFX

High sensitivity and specificity for binding to both sTNF and tmTNF

2-3 IFX molecules bind to each TNF trimer, preventing TNF binding to cellular receptors, and reversing the actions of TNF

The TNF trimer complexes are biologically inactive and are thought to be cleared by the hepatic reticuloendothelial system

Most IFX is in the vascular compartment

No systemic accumulation

Clearance of IFN is slowed by MTX and is ATI

The VOD at steady state is independent of dose

VOD and clearance are not affected by patient age or weight. The effect of liver or kidney disease is unknown

Does not produce a generalized suppression of the body’s immune system

Response to IFX is affected by CRP polymorphisms

Linear relationship between dose and serum concentration of IFX

Serum concentration is correlated with clinical response (in at least persons with rheumatoid arthritis)

Reductions in IL-10 levels also correlate with improvement in clinical activity, and FGF and improvement in perianal disease

For the 5 mg/kg dose, the median terminal half-life (t) is 10.9 d1

↓ Cells expressing TNF, IL-10, IFN-γ

↓ Cells staining for CD4, CD5, CD6, MMP-9

↓ TNF levels (that are ↑ in serum and diseased mucosa in CD)

↓ ICAM-1

↓ Lamina propria T-lymphocytes and peripheral blood monocytes

↓ Growth hormone resistance

↓ Markers of bone reabsorption, ↑ markers of bone formation

ADA

Forms high molecular weight complexes with human TNF (600-5000 kDa)

Linear relation between dose and serum concentration

Serum concentration is correlated with clinical response

Mean serum t is 10-20 d

Clearance is slowed by MTX, and is accelerated by ATA

Certolizumab pegol

Lacks IgG Fc domain, and thus does not fix lysed cells or complement

The Fab’ component of CER contains a free cysteine residue to the hinge region, which provides site-specific attachment of the PEG to the Fab’ at a site well removed from the antigen binding site

The retention time of protein conjugates in the blood is increased by pegylation, and immunogenicity is reduced. Pegylation increases in the half-life (t½) of the antibody fragment, so dosing may be less frequent

The half-life of CER in healthy volunteers is 313 h

Site-specific pegylation of the Fab’ fragment of CER is directed to a site well away from the antigen-binding region. In this way, the conjugate has the same high affinity of the TNF as the tmTNF and sTNF without the pegylation

Does not cause apoptosis of lymphocytes and monocytes, and antibodies to IFX (ATI) do not cross-react with CER

Accumulates preferentially in inflamed rather than in non-inflamed tissue

Has a greater affinity for sTNFs than do IFX or ADA

Has twice the neutralizing potency as IFX or ADA for sTNFα

Has the same neutralizing potency as IFX and ADA for tnTNFα, and occurs through p55/p75 TNFR

Anti-CER antibodies levels are low, and do not affect the efficacy of CER

Does not cross-react with ATI (antibodies to IFX)

Has a linear pharmacokinetic profile

Bioavailability of subcutaneously administered CER is almost 100%

Does not lyse cells, cause compliment-dependant cytotoxicity, antibody-dependant cell-mediated cytotoxicity, apoptosis of activated monocytes or lymphocytes or necrosis of neutrophils

¹Represent the counts or concentration is decreased. IFX: Infliximab; TNF: Tumor necrosis factor; MTX: Methotrexate; ATI: Accelerated by antibodies to IFX; VOD: Volume of distribution; CRP: C-reactive protein; FGF: Fibroblast growth factor; IFN-γ: Intracellular interferon-γ; IL: Interleukin; MMP-9: Metalloproteinases; ADA: Adalimumab; ATA: Antibodies to ADA; ICAM-1: Intracellular adhesion molecule-1; PEG: Polyethylene glycol; CER: Certolizumab; CD: Crohn’s disease; TNFR: TNF receptor.