Biological Therapies for Inflammatory Bowel Diseases

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Biological Therapies for Inflammatory Bowel Diseases Paul Rutgeerts, Severine Vermeire, Gert Van Assche  Gastroenterology  Volume 136, Issue 4, Pages 1182-1197 (April 2009) DOI: 10.1053/j.gastro.2009.02.001 Copyright © 2009 AGA Institute Terms and Conditions

Figure 1 Humanization of therapeutic antibodies illustrated with the anti-TNF agents used in clinical practice. Original mouse IgG1 monoclonal antibodies (mAbs) contain mouse sequences only in every part of the variable (v) and constant (c) regions of both light (l) and heavy (h) chains. The 2 heavy chains are connected by the glycosylated hinge region, which separates the antibody binding Fab region from the effector, or complement binding, Fc portion. Mouse mAb are by convention called momabs, and induce anti-mouse antibodies in most if not all patients. Chimeric mAb (ximabs), such as infliximab, are only murine in the variable regions (VH + VL) and the antidrug antibodies they induce are called human antichimeric antibodies (haca). Humanized antibodies (zumabs) contain mouse sequences in only the complementarity-determining regions (cdr) and contain 95% human peptide sequences. Certolizumab-pegol is a humanized Fab fragment linked to 2 polyethylene glycol (peg) molecules, which improve pharmacokinetics. Removal of all murine peptide sequences results in fully human antibodies (mumabs) such as adalimumab. They can induce human anti-human antibodies (haha), but these mAbs have the lowest potential for antigenicity. Etanercept is a fully human TNF receptor/Fc fragment fusion protein containing 2 receptor units and 1 Fc fragment. Gastroenterology 2009 136, 1182-1197DOI: (10.1053/j.gastro.2009.02.001) Copyright © 2009 AGA Institute Terms and Conditions

Figure 2 (A) Leukocyte adhesion in high endothelial venules of the gut is a multistep process. Fast-moving immune cells are first slowed down by interaction of selectins and nonactivated integrins with their respective ligands expressed by endothelial cells. This causes tethering and rolling of leukocytes close to the endothelial surface. Chemokines secreted from sites of inflammation diffuse through the endothelial layer, bind to chemokine receptors, and activate integrins. Integrin activation is inhibited by CCX-282B, an oral CCR9 inhibitor. Firm adhesion is the last step before leukocyte diapedesis through endothelial pores and results from strong binding between activated α4β7-integrins with their ligand, mucosal addressin cellular adhesion molecule-1 (MadCAM-1). (B) Because MadCAM-1 is expressed specifically in gut lymphoid tissue and interacts with α4β7 integrins but not with other integrins, this crucial interaction can be targeted selectively by the anti–-MadCAM-1 mAb PF00547659 and by anti–β7-integrin mAbs such as MLN-0002 and rhuMab-β7. Endothelial cells in other organs such as the brain, bone marrow, and kidney express α4β1 integrins, which interact with their respective ligand, vascular cell adhesion molecule-1 (vcam-1). The anti–α4 -integrin mAb natalizumab blocks both α4β1-integrin/VCAM-1 and α4β7-integrin/MadCAM-1 interactions. Therefore, it does not selectively inhibit leukocyte trafficking to the gut. Gastroenterology 2009 136, 1182-1197DOI: (10.1053/j.gastro.2009.02.001) Copyright © 2009 AGA Institute Terms and Conditions

Figure 3 Compounds such as ustekinumab that interrupt the IL-12/IL-23 pathway and are currently in development for IBD are targeted at the common p40 subunit of both cytokines. Therefore, they inhibit the interaction of the p40 subunit with the IL-23 or the IL-12 receptor, which again share a common subunit (IL-12 receptor β1). Inhibiting IL-23 signaling interferes with proliferation and activation of IL-17 and TNF-secreting Th17 cells, whereas blocking the IL-12 receptor down-regulates the Th1 response. The relative role of inhibiting both pathways in the therapeutic effects of anti–IL-12/IL-23 p40 mAb is controversial. Gastroenterology 2009 136, 1182-1197DOI: (10.1053/j.gastro.2009.02.001) Copyright © 2009 AGA Institute Terms and Conditions

Figure 4 Therapeutic proteins that affect T-cell proliferation and activation can act at different molecular levels. Visilizumab blocks the binding of antigen presenting cell major histocompatibility complex–II molecules with the T-cell receptor or CD-3, resulting in apoptosis of T cells. The co-stimulatory molecules B7 and CD-28 also are essential for T-cell activation; blocking their interaction with the CLTA-4/Fc-fusion protein abatacept results in T-cell anergy. The anti-CD25 (α-chain of the activated IL-2 receptor) mAbs basiliximab and daclizumab prevent IL-2 receptor signaling and downstream T-cell activation and proliferation. Gastroenterology 2009 136, 1182-1197DOI: (10.1053/j.gastro.2009.02.001) Copyright © 2009 AGA Institute Terms and Conditions