Table 2.

The outcome of targeting co-stimulatory receptor-ligand pairs in preclinical animal models as well as in human diseases.

Receptor/ligand targeted	Human/animal studies reported	Outcome
CD28:CTLA-4/CD80:CD86	Anti-CD28 antibody. Phase I trial in healthy volunteers	Infusion was associated with acute onset, severe cytokine storm and multiorgan failure. Trial suspended and drug withdrawn.
	CTLA-4Ig (Abatacept) Preclinical studies in animals and several clinical trials in patients with RA	Significant therapeutic response and acceptable risk profile. FDA approved for treatment of RA.
	Modified CTLA-4Ig (Belatacept) Phase II trial in patients with RA.	Trial completed. Results pending.
OX40/OX40L	OX40 expression is enhanced during arthritis in animal models. OX40 and OX40L expression on synovial T cells is increased in RA. Anti OX40 and anti-OX40L antibody has been tested in the animal model of RA.	Anti-OX40L antibody and liposome coated with anti-OX40 antibody has been shown to reduce severity of arthritis in animal models of RA.
ICOS/ICOSL	ICOS deficient mice have reduced arthritis. Expression of ICOS/ICOSL is increased in the RA synovium and synovial fluid. Anti ICOSL antibody has been tested in an animal model of RA. A phase I trial with anti ICOSL antibody is underway in patients with RA.	Anti-ICOSL antibody resulted in reduced severity of arthritis in animal models.
4-1BB/4-1BBL	Increased expression of 4-1BB in the RA synovium. Increased levels of s4-1BB and s4-1BB L in RA synovium and synovial fluid. An agonistic anti-4-1BB antibody was tested in an animal model of RA.	Administration of agonistic anti 4-1BB antibody was associated with reduced severity of arthritis in animal models of RA.
CD4/MHC Class II	Phase I and II clinical trials in patients with RA.	Failed to show therapeutic response in patients with RA.
CD5/CD72	Tested in animal model	A partial therapeutic effect in was seen in the mouse model of RA.
CD40/CD40L	Anti CD40L antibody -- BG9588 and IDEC 131 Clinical trials have been done in patients with systemic lupus erythematosus.	Failed to show response in patients with systemic lupus erythematosus.
CD2/CD58	Alefacept is a fusion protein with 1-92-LFA-3 (CD58) fused with an immunoglobulin IgG1 dimer. Clinical trials have been done in patients with psoriasis.	Significant therapeutic improvement. Alefacept is FDA approved for treatment of moderate to severe chronic plaque psoriasis.
CD11a-CD18/CD54 (ICAM-1), CD102 (ICAM-2), CD50 (ICAM-3), CD242 (ICAM-4), ICAM-5, CD321 (JAM-1)	Efalizumab is a recombinant humanized IgG1 monoclonal antibody that binds to CD11a. Clinical trials have been done in patients with psoriasis.	Efalizumab was approved for moderate to severe plaque psoriasis in 2003. Withdrawn from the market in 2009.
CD49d -CD29, CD49d-β7 integrin/VCAM-1, MAdCAM-1	Natalizumab is a humanized IgG4 monoclonal antibody that binds to the α4 subunit of α4β1 and α4β7 integrins. Clinical trials have been done in patients with multiple sclerosis, Crohn’s disease, and RA.	Natalizumab is FDA approved for the treatment of relapsing multiple sclerosis and Crohn’s disease. Failed to show response in patients with RA.
CD97/CD55 and chondroitin sulfate	Soluble CD97 found in synovial fluid of rheumatoid arthritis patients and binding of CD97 to CD55 has been observed in synovial tissue of patients with RA. Tested in animal model of RA	A monoclonal, neutralizing antibody to CD97, mAb 1B2, was effective in preventing joint inflammation in an animal model of RA.
CD52 (Campath-1H)	Alemtuzumab is a humanized IgG1 kappa monoclonal antibody to CD52. Clinical trials have been done in patients with hematologic malignancies and RA.	Alemtuzumab is FDA approved for the treatment of B-cell chronic lymphocytic leukemia. Alemtuzumab caused dose-dependent toxicity in a trial in RA, and is not FDA approved for use in RA.
CD27/CD70	Tested in animal model	A murine anti-CD70 antibody resulted in improvement in disease severity and reduction of autoantibodies in the animal model of RA.