Graft versus host disease

Disease ID:1220
Name:Graft versus host disease
Associated with:1 target
1 immuno-relevant target
11 immuno-relevant ligands
Synonyms
graft-versus-host disease | GvHD
Description
Rejection of non-self transplanted tissue. GvHD is a possible complication of a bone marrow or stem cell transplant but the term is also used to describe rejection of other types of tissue graft.

Targets

CD86
Comments:  CD86 is a primary target of the approved anti-rejection drug belatacept.
Ligand interactions: 
Ligand Comments
belatacept
Approved for prophylaxis of organ rejection after kidney transplant.

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
alvelestat
Immuno Disease Comments: A Phase 2 clinical candidate for bronchiolitis obliterans syndrome resulting from chronic GVHD.
Clinical Use: A series of Phase I and Phase II results are reported in clinicaltrials.gov entries | View clinical data
Bioactivity Comments: In contrast with ONO6818, an inhibitor that binds covalently to NE, AZD9668 exhibited a more rapid association and dissociation rate, and its interaction with NE was fully reversible. It also generally showed greater specificity than ONO6818 or for NE over other neutrophil-derived serine proteases, particularly Pr-3 and pancreatic elastase [8]. Approximately 90 analogues are listed in a patent [2] where this is example 94, but only limited SAR data is included. | View biological activity
itacitinib
Immuno Disease Comments: Phase 3 clinical candidate for acute GvHD (see NCT03139604).
Clinical Use: INCB039110 is being assessed in Phase II clinical trial as a potential treatment for indications such as rheumatoid arthritis (RA), post essential thrombocythemia myelofibrosis, chronic plaque psoriasis and non-small cell lung cancer (NSCLC). | View clinical data
ibrutinib
Immuno Disease Comments: Approved drug for chronic GvHD.
Clinical Use: Ibrutinib is approved to treat patients with mantle cell lymphoma (MCL), a rare and aggressive type of leukemia, especially patients with MCL who have received at least one prior therapy. In Feb 2014 ibrutinib was granted US FDA approval for treating chronic lymphocytic leukemia (CLL), as with MCL, this is only indicated for patients who have received at least one prior therapy. In February 2015, the US FDA expanded approval to include the treatment of Waldenström's macroglobulinemia (WM), which is a form of type of non-Hodgkin's lymphoma. Approval was granted based on the outcome of clinical trial NCT01614821 which indicated that the drug can offer a substantial improvement over contemporary therapies.
In August 2017, the FDA expanded approval to include treatment of chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy (e.g. first-line corticosteroid therapy). This approval followed results from clinical trial NCT02195869. The recommended dose of ibrutinib for cGVHD is 420 mg, orally once daily. | View clinical data
begelomab
Immuno Disease Comments: Ex Phase 3 clinical candidate for steroid-resistant GvHD- see NCT02411084.
Clinical Use: Begelomab reached Phase clinical trial as a potential therapy for steroid-resistant acute graft versus host disease (GvHD). | View clinical data
Bioactivity Comments: EP2767549 A1 [4] does not provide a precise dissociation constant value for any preferred antibodies. In the table below, we present a value which the author suggests would be the desireable affinity of a preferred antibody. | View biological activity
galectin-1 3
Immuno Disease Comments: Gal-1 reduces host alloreactivity and suppresses the graft versus host immune response in animal GvHD models, leading to increased survival.
cyclosporin A
Immuno Disease Comments: Cyclosporin A is approved as an anti-rejection drug.
Clinical Use: Cyclosporine is a powerful immunosupressant. Its inhibitory action on T-lymphocyte activation is used to circumvent graft rejection following autologous organ and tissue transplant. It can also be used to treat severe active, refractory rheumatoid arthritis and severe recalcitrant plaque psoriasis. Across the European Union ophthalmic solutions of cyclosporin are fully approved for the treatment of severe keratitis (corneal inflammation) and severe vernal keratoconjunctivitis (a form of chronic eye allergy that can lead to corneal ulcers and loss of sight; in patients aged 4yrs- adolescent), and it has current orphan designation for 8 indications (click here to link to the EMA's list of orphan designations for cyclosporin).
In August 2018 the FDA approved a 0.09% cyclosporine ophthalmic solution called Cequa® as a topical treatment for keratoconjunctivitis sicca (dry eye). | View clinical data
sirolimus
Immuno Disease Comments: Approved specifically as prophylaxis of renal transplant rejection.
Clinical Use: Sirolimus is used for prophylaxis of renal transplant rejection [5,9], and may be used in combination with . In June 2015 the US FDA approved sirolimus for the treatment of lymphangioleiomyomatosis, a rare proliferative but benign lung disease [7]. | View clinical data
basiliximab
Immuno Disease Comments: Used in combination with other anti-rejection drugs (cyclosporin A, corticosteroids, azathioprine and mycophenolate mofetil) to prevent renal allograft rejection.
Clinical Use: Prophylaxis of acute organ rejection in adults following cadaveric- or living-donor renal transplantation | View clinical data
Bioactivity Comments: Peptide sequence analysis reveals that patent US6383487 [1] covers the design and uses of basiliximab. However, this patent does not provide affinity data for the interaction between the antibody and its target, IL-2, and we have been unable to find accessible data elsewhere. | View biological activity
muromonab-CD3
Immuno Disease Comments: Approved to prevent renal, cardiac and hepatic allograft rejection. Withdrawn from the US market.
Clinical Use: Used to prevent renal, cardiac and hepatic allograft rejection. Due to reduced demand and use in the US, the manufacturer has withdrawn muromonab-CD3 from the US market. | View clinical data
Bioactivity Comments: We have been unable to find affinity data for this antibody from any open access source. | View biological activity
belatacept
Immuno Disease Comments: Approved for prophylaxis of organ rejection after kidney transplant.
Clinical Use: Approved for prophylaxis of organ rejection after kidney transplant.
The first analysis of long-term outcomes (7 years post-transplant) for belatacept-induced immunosuppression compared to cyclosporine treatment are reported by Vincenti et al. (2016) [10]. These results, from clinical trial NCT00256750, show a clear and significant benefit from treating with belatacept rather than cyclosporine. The authors suggest that the improvement is likely due to the alternative mechanism of action of belatacept (blocks T-cell costimulation) and its non-nephrotoxic nature, in comparison to cyclosporine which is often the cause of failure of transplanted kidneys over time. | View clinical data
Bioactivity Comments: Belatacept binds to human CD86 with an IC50 of 0.102µg/mL and to CD80 with an IC50 of 0.009µg/mL [6]. | View biological activity
KD025
Immuno Disease Comments: Phase 2 clinical candidate for chronic graft vs. host disease (NCT02841995).
Clinical Use: KD025 is in Phase 2 clinical trials evaluating its anti-inflammatory and anti-fibrotic activity. | View clinical data

References

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1. Amlot PL, Akbar AN, Heinrich G, Cammisuli S. (2002) Methods Of Treatment Using Cd25 Binding Molecules. Patent number: US6383487. Assignee: Novartis Ag, University College London. Priority date: 16/03/1990. Publication date: 07/05/2002.

2. Andersson, Marjana et al.. (2007) 2-Pyridone Derivatives As Neutrophil Elastase Inhibitors And Their Use. Patent number: US20070203129. Assignee: AstraZeneca. Priority date: 15/09/2004. Publication date: 30/08/2007.

3. Baum LG, Blackall DP, Arias-Magallano S, Nanigian D, Uh SY, Browne JM, Hoffmann D, Emmanouilides CE, Territo MC, Baldwin GC. (2003) Amelioration of graft versus host disease by galectin-1. Clin. Immunol., 109 (3): 295-307. [PMID:14697744]

4. Di Naro AF. (2014) Anti-CD26 Antibodies and Uses Thereof. Patent number: EP2767549 A1. Assignee: Adienne S.A.. Priority date: 19/02/2013. Publication date: 20/08/2014.

5. Kelly PA, Gruber SA, Behbod F, Kahan BD. (1997) Sirolimus, a new, potent immunosuppressive agent. Pharmacotherapy, 17 (6): 1148-56. [PMID:9399599]

6. Latek R, Fleener C, Lamian V, Kulbokas 3rd E, Davis PM, Suchard SJ, Curran M, Vincenti F, Townsend R. (2009) Assessment of belatacept-mediated costimulation blockade through evaluation of CD80/86-receptor saturation. Transplantation, 87 (6): 926-33. [PMID:19300198]

7. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM et al.. (2011) Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N. Engl. J. Med., 364 (17): 1595-606. [PMID:21410393]

8. Stevens T, Ekholm K, Gränse M, Lindahl M, Kozma V, Jungar C, Ottosson T, Falk-Håkansson H, Churg A, Wright JL et al.. (2011) AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase. J. Pharmacol. Exp. Ther., 339 (1): 313-20. [PMID:21791628]

9. Vasquez EM. (2000) Sirolimus: a new agent for prevention of renal allograft rejection. Am J Health Syst Pharm, 57 (5): 437-48; quiz 449-51. [PMID:10711524]

10. Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, Moal MC, Mondragon-Ramirez GA, Kothari J, Polinsky MS et al.. (2016) Belatacept and Long-Term Outcomes in Kidney Transplantation. N. Engl. J. Med., 374 (4): 333-43. [PMID:26816011]