Full activation and differentiation of resting T cells into effector T cells requires at least two signals, the first through engagement of the T cell antigen receptor (TCR) by the antigen-major histocompatibility complex (MHC) on antigen-presenting cells (APCs), and the second by engagement of co-stimulatory molecules such as CD28, on T cells by ligands such as CD80/86 on APCs. Effector T cell differentiation is associated with proliferation, secretion of cytokines and expression of additional surface molecules. These inducible structures may have stimulatory (ICOS, OX40 and 4-1BB) or inhibitory (cytotoxic T-lymphocyte antigen (CTLA)-4) potential. To the extent that T cells have a role in particular immune-mediated diseases, interruption of T cell co-stimulation is a potentially worthwhile approach to the treatment of those conditions. This article summarises the experience in treating rheumatological disease by perturbation of T cell co-stimulation, and also describes structures that could be future targets for this type of therapeutic approach.
CD28:cytotoxic T-lymphocyte antigen (CTLA)-4 (CD152)/CD80:CD86
CD28 is the prototypic T cell receptor for co-stimulatory signals. CTLA-4, which is up-regulated on activated T cells, also binds to the CD28 ligands CD80/86 (B7.1 and B7.2), and this interaction inhibits further T cell activation .
The ligation of CD28 by CD80/86 not only sends co-stimulatory signals into the T cell but can also send activating signals into the antigen-presenting cells (APCs) . Maturation and activation of APCs are accompanied by expression of other co-stimulatory molecules [ Fig. 1 ; Table 1 ], as well as secretion of cytokines such as interleukin (IL)-6. The induction of IL-6 secretion from APCs via CD80/86 is of interest since IL-6 is one of the cytokines associated with the pathogenesis of rheumatoid arthritis (RA). IL-6 is necessary for the development of Th17 cells, which contribute to several auto-immune diseases including RA, and also has downstream roles in tissue damage. This is only one example of the many ways in which co-stimulatory receptor–ligand engagement is linked to cytokine pathways in RA and other diseases. Therapeutic blockade of such interactions would be expected, therefore, to have secondary effects on key disease-related cytokines.
| Costimulatory molecule on T cells. | Expression profile of molecule on T cell surface | Corresponding ligand/receptor | Cells which express the corresponding ligand/receptor | Expression profile of corresponding receptor/ligand |
|---|---|---|---|---|
| CD28/CTLA-4 (resting activated, and memory T cells) | Constitutive/ CTLA-4 only induced after activation | CD80/86 | Antigen presenting cells, and on some activated T cells | Constitutive, further upregulated after activation/maturation. |
| OX40 (activated T cells, memory T cells) | Expressed following activation via TCR and CD28 | OX40L | Dendritic cells, macrophages, and B cells | Expressed following activation and maturation. |
| ICOS (activated T cells, and CD4 memory T cells in RA) | Induced following activation via TCR and CD28 | ICOSL | B cells and monocytes | Constitutive and further augmented following activation and maturation. |
| 4-1BB (activated CD4 and CD8 T cells) | Induced following activation via TCR and CD28 | 4-1BBL | B cells, dendritic cells, and macrophages | Expressed following activation and maturation. |
| CD4 (T helper cells) | Constitutive | MHC II | Antigen presenting cells | Constitutive, further upregulated after activation |
| CD5 (thymocytes, T cells) | Constitutive | CD72 | Antigen presenting cells | Constitutive |
| CD154 (CD40L) (activated T cells) | Upregulated after activation | CD40 | B cells, monocytes, dendritic cells, epithelial cells, endothelial cells, fibroblasts, keratinocytes | Constitutive and upregulated following activation. |
| CD2 (thymocytes, T cells) | Constitutive | CD58 | Leukocytes, erythrocytes, endothelial and epithelial cells, fibroblasts and smooth muscle | Constitutive, further upregulated by activation |
| CD11a-CD18 (LFA-1) (memory T cells) | Constitutive | CD54 (ICAM-1), CD102 (ICAM-2), CD50 (ICAM-3), CD242 (ICAM-4), ICAM-5, CD321 (JAM-1) | Activated T cells, activated B cells, monocytes, epithelial cells, endothelial cells and fibroblasts | Constitutive and further upregulated after activation |
| CD49d -CD29/ CD49d-β7 integrin (activated T cells) | Constitutive, upregulated after activation | VCAM-1/ VCAM-1, MadCAM-1 | Endothelial cells | Upregulated upon activation |
| CD97 (T cells) | Upregulated by activation | CD55 | Wide expression including erythrocytes | Constitutive |
| CD27 (thymocytes, T cells) | Constitutive, upregulated after activation. | CD70 | T cells, B cells, NK cells | Upregulated after activation |
In addition to interfering with the binding of CD28 to CD80/86, thereby interrupting the co-stimulatory signal into T cells via CD28, CTLA-4 can also send inhibitory signals directly into the T cell that further limit T-cell activation .Similarly, the ligation of CD80/86 by CTLA-4 can also deliver regulatory signals to the APC. The interaction of CD80/86 with CTLA-4 leads to the induction of indoleamine dioxygenase (IDO) in APCs. IDO is thought to be critical in inducing anergy in T cells, during the T cell–APC interaction, via the depletion of tryptophan, which is necessary for full T-cell activation . These findings suggest that CTLA-4 can actively dampen T-cell activation both by direct effects on the T cell and also by effects on APCs.
Thus, the interaction of CD28 with CD80/CD86 is critical in the regulation of T-cell activation and is an important target in auto-immune diseases associated with aberrant activation of T cells such as in RA. However, use of antibodies against CD28 itself would be hazardous if agonistic effects occurred. Indeed, administration of TGN1412, an anti-CD28 monoclonal antibody, to healthy human volunteers resulted in acute onset of cytokine storm and associated multi-organ failure ( Table 2 ). This led to the suspension of further development of this drug or of other antibodies directly targeting CD28.
| Receptor/ligand targeted | Human/animal studies reported | Outcome |
|---|---|---|
| CD28:CTLA-4/CD80:CD86 | • Anti-CD28 antibody. | • Infusion was associated with acute onset, severe cytokine storm and multiorgan failure. Trial suspended and drug withdrawn. |
| • Phase I trial in healthy volunteers | ||
| • 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) | • Trial completed. Results pending. | |
| • Phase II trial in patients with RA. | ||
| OX40/OX40L | • OX40 expression is enhanced during arthritis in animal models. | • Anti-OX40L antibody and liposome coated with anti- OX40 antibody has been shown to reduce severity of arthritis in animal models of RA. |
| • OX40 and OX40L expression on synovial T cells is increased in RA. | ||
| • Anti-OX40 and anti-OX40L antibody have been tested in an animal model of RA. | ||
| ICOS/ICOSL | • ICOS deficient mice have reduced arthritis. | • Anti-ICOSL antibody resulted in reduced severity of arthritis in animal models |
| • 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. | ||
| 4-1BB/4-1BBL | • Increased expression of 4-1BB in the RA synovium. | • Administration of agonistic anti 4-1BB antibody was associated with reduced severity of arthritis in animal models of RA. |
| • 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. | ||
| 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 an animal model | • A partial therapeutic effect in was seen in an animal 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. | • Significant therapeutic improvement. Alefacept is FDA approved for treatment of moderate to severe chronic plaque psoriasis. |
| • Clinical trials have been done in patients with 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 IgG 1 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 IgG 4 monoclonal antibody that binds to the α4 subunit of α4β1 and α4β7 integrins. | • Natalizumab is FDA approved for the treatment of relapsing multiple sclerosis and Crohn’s disease. |
| • Clinical trials have been done in patients with multiple sclerosis, Crohn’s disease, and RA. | • 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. | • A monoclonal, neutralizing antibody to CD97, mAb 1B2, was effective in preventing joint inflammation in an animal model of RA. |
| • Tested in an animal model of RA | ||
| CD52 (Campath-1H) | • Alemtuzumab is a humanized IgG 1 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 an animal model of RA | • A murine anti-CD70 antibody resulted in improvement in disease severity and reduction of autoantibodies in an animal model of RA. |
CTLA-4Ig (abatacept), which is composed of CTLA-4 fused with the constant portion of the human IgG, binds to CD80/CD86 on APCs and thereby interferes with the co-stimulation of T cells induced by the interaction of CD80/CD86 with CD28. Abatacept was developed as a therapeutic intervention for RA and transplant rejection, two diseases associated with T cell activation. Preclinical studies with abatacept showed promise in an animal model of RA . Abatacept was approved for treatment of RA in 2007.
Clinical studies of abatacept in RA
After a successful Phase I study in which 50% of the patients achieved American College of Rheumatology (ACR) 20 responses without any significant adverse events, a phase II study was done in patients with active disease despite standard doses of methotrexate. In this study, abatacept was administered concurrently with stable doses of methotrexate for 6 months. The ACR20/50/70 responses were 60%, 36% and 16% in the group receiving abatacept plus methotrexate compared with 25%, 12% and 2% in the placebo plus methotrexate arm . The patients in this trial continued to improve beyond the initial 6-month period, in an open-label extension trial with abatacept and methotrexate for an additional 6 months. The percentage of patients achieving ACR50 and ACR70 increased to 41.7% and 20.9% respectively . The same cohort of patients continued to show improvement in clinical efficacy with an acceptable safety profile in a 5-year extension study. The ACR20/50/70 responses at 5 years were 82.7%, 65.4% and 40%, respectively .
The Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN), a 6-month phase III trial, was carried out in patients with RA who had inadequate clinical response or adverse effects on anti-tumour necrosis factor (TNF) agents . A significant proportion of patients demonstrated a favourable therapeutic response at 6 months. The percentages of patients achieving ACR20/50/70 responses were 50%, 20.3% and 10.2% in the study arm, in comparison to 19.5%, 3.8% and 1.5% in the placebo arm. This study was then continued as an open-label extension for an additional 18 months with continued improvement, with 56% achieving ACR20, 33% achieving ACR50 and 16% achieving ACR70 responses . These findings were confirmed in another trial involving patients with inadequate responses to anti-TNF agents. This study showed that a washout period, in previous anti-TNF non-responders, was not necessary for subsequent improvement with abatacept .
The sustained clinical efficacy of abatacept was shown in another trial – Abatacept in Inadequate Responders to Methotrexate (AIM) – in which abatacept was administered to patients who had inadequate responses to methotrexate . This study was designed to evaluate clinical improvement as well as radiographic progression. In this 1-year study, patients continued to show clinical improvement similar to previous studies, with ACR20/50/70 responses being 73%/48.3%/28.8%, in comparison to 39.7%/18.2%/6.1% in the placebo group, respectively. Further, there was a 50% reduction in the progression of the Genant Modified Sharp scores in the abatacept group. As in the previous studies, patients in this study were continued for an additional 12 months in an open-label extension study. There was continued clinical and radiographic improvement into the end of the second year.
Abatacept was directly compared with infliximab or placebo in the Tolerability, Efficacy and Safety in Treating Rheumatoid Arthritis (ATTEST) trial. This 12-month study demonstrated that patients treated with infliximab had more rapid clinical improvement than patients on abatacept during the initial 6 months, but patients on abatacept continued to have the same rate of clinical response throughout the 1-year period of the study and the clinical response at 1 year was therefore significantly greater than in the infliximab group (DAS28 scores changed by −2.88 in the abatacept group vs. −2.25 in the infliximab group) . It is important to point out that while abatacept was used at 10 mg kg −1 , which is the optimal dosage used in clinical practice, infliximab was used at 3 mg kg −1 , which is on the lower end of the recommended dose range. The therapeutic efficacy of abatacept in comparison to higher dosages of infliximab or to other anti-TNF agents remains to be evaluated. In a recent study, involving patients with early RA, administration of abatacept in combination with methotrexate was associated with a significantly increased rate of remission than administration of methotrexate alone. At 1 year of follow-up, 41.4% in the abatacept plus methotrexate group achieved DAS28 defined remission (DAS28 < 2.6) compared with 23.3% in the methotrexate only group .
Abatacept demonstrated a favourable safety profile in all of the above trials ( Table 3 ). Two trials were designed to assess the safety of abatacept in combination with other agents. The Abatacept Study of Safety in Use with other RA Therapies (ASSURE) trial was designed to evaluate the safety of abatacept for use in patients receiving disease-modifying anti-rheumatic drugs (DMARDs), as well as biologics . On the one hand, patients receiving abatacept along with other non-biologic DMARDs demonstrated a favourable safety profile. On the other hand, combination of abatacept with other biologics was associated with an increased rate of infections . In another trial, abatacept was administered along with etanercept . Patients on the combination did not show significant clinical improvement over and above those treated with a single biologic agent, but had more infections. These studies demonstrate that abatacept has a favourable safety profile when administered with non-biologic DMARDs, but the combination of abatacept with another biologic agent is not recommended.
| Receptor/ligand targeted | Agent | Observed or anticipated toxicities |
|---|---|---|
| CD28:CTLA-4/CD80:CD86 | TGN1412 (anti CD28 antibody) | Cytokine storm and multiorgan failure. |
| Abatacept | Minimal side effect profile. Increased risk of infections in combination with anti-TNF agents. | |
| Belatacept | Minimal side effect profile. | |
| CD4/MHC Class II | Zanolimab | Infusion reactions with low-grade fever, flu-like symptoms, unpredictable occurrence of a skin rash and/or vasculitis, and rapid, prolonged decline of CD4+ T cells |
| CD40/CD40L | BG9588 | Thromboembolic events in early trials. Further development of this drug is halted. |
| CD2/CD58 | Alefacept | Lymphopenia, possible increased risk of malignancies, infections, and liver injury. |
| CD11a-CD18/ CD54 (ICAM-1), CD102 (ICAM-2), CD50 (ICAM-3), CD242 (ICAM-4), ICAM-5, CD321 (JAM-1) | Efalizumab | Infections, thrombocytopenia, hemolytic anemia, and progressive multifocal leukoencephalopathy. Withdrawn from the market. |
| CD49d -CD29, CD49d-β7 integrin/VCAM-1, MadCAM-1 | Natalizumab | Progressive multifocal leukoencephalopathy, liver injury, infections, and hypersensitivity reactions. Withdrawn and reintroduced under a special risk management plan in patients with MS. |
| CD52 | Alemtuzumab | Cytopenias: serious, including fatal pancytopenia/marrow hypoplasia, autoimmune idiopathic thrombocytopenia, autoimmune hemolytic anemia, infusion reactions, and infections during trials done in RA and multiple sclerosis. Did not receive FDA approval for RA. |
The above studies illustrate the efficacy of abatacept in the treatment of RA, in various scenarios including early RA, methotrexate non-responders and anti-TNF failures. In addition, it has been shown to be consistently safe in multiple studies, except in combination with other biologic agents.
Although abatacept was developed to reduce the activating signal into the T cell via CD28, the precise mechanisms of action underlying the therapeutic response in RA remain to be elucidated. In one study, serum IL-6 was reduced in RA patients on abatacept, suggesting that interruption of the activation/maturation signal into APCs via CD80/86 might be important . In another study, levels of interferon (IFN)-γ, IL-6, IL-1β and matrix metalloproteinases (MMPs) were reduced in the RA synovium of patients receiving abatacept. In the same patients, the levels of receptor activator for nuclear factor κ B (ligand) (RANK/RANKL), which interact to induce osteoclastogenesis, were lowered, while osteoprotegerin (OPG), a decoy receptor which inhibits bone damage by interfering with RANK/RANKL, tended to increase . Thus, it is possible that abatacept has direct as well as indirect effect on both T cells and other immune system cells in RA.
Clinical studies of abatacept in RA
After a successful Phase I study in which 50% of the patients achieved American College of Rheumatology (ACR) 20 responses without any significant adverse events, a phase II study was done in patients with active disease despite standard doses of methotrexate. In this study, abatacept was administered concurrently with stable doses of methotrexate for 6 months. The ACR20/50/70 responses were 60%, 36% and 16% in the group receiving abatacept plus methotrexate compared with 25%, 12% and 2% in the placebo plus methotrexate arm . The patients in this trial continued to improve beyond the initial 6-month period, in an open-label extension trial with abatacept and methotrexate for an additional 6 months. The percentage of patients achieving ACR50 and ACR70 increased to 41.7% and 20.9% respectively . The same cohort of patients continued to show improvement in clinical efficacy with an acceptable safety profile in a 5-year extension study. The ACR20/50/70 responses at 5 years were 82.7%, 65.4% and 40%, respectively .
The Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN), a 6-month phase III trial, was carried out in patients with RA who had inadequate clinical response or adverse effects on anti-tumour necrosis factor (TNF) agents . A significant proportion of patients demonstrated a favourable therapeutic response at 6 months. The percentages of patients achieving ACR20/50/70 responses were 50%, 20.3% and 10.2% in the study arm, in comparison to 19.5%, 3.8% and 1.5% in the placebo arm. This study was then continued as an open-label extension for an additional 18 months with continued improvement, with 56% achieving ACR20, 33% achieving ACR50 and 16% achieving ACR70 responses . These findings were confirmed in another trial involving patients with inadequate responses to anti-TNF agents. This study showed that a washout period, in previous anti-TNF non-responders, was not necessary for subsequent improvement with abatacept .
The sustained clinical efficacy of abatacept was shown in another trial – Abatacept in Inadequate Responders to Methotrexate (AIM) – in which abatacept was administered to patients who had inadequate responses to methotrexate . This study was designed to evaluate clinical improvement as well as radiographic progression. In this 1-year study, patients continued to show clinical improvement similar to previous studies, with ACR20/50/70 responses being 73%/48.3%/28.8%, in comparison to 39.7%/18.2%/6.1% in the placebo group, respectively. Further, there was a 50% reduction in the progression of the Genant Modified Sharp scores in the abatacept group. As in the previous studies, patients in this study were continued for an additional 12 months in an open-label extension study. There was continued clinical and radiographic improvement into the end of the second year.
Abatacept was directly compared with infliximab or placebo in the Tolerability, Efficacy and Safety in Treating Rheumatoid Arthritis (ATTEST) trial. This 12-month study demonstrated that patients treated with infliximab had more rapid clinical improvement than patients on abatacept during the initial 6 months, but patients on abatacept continued to have the same rate of clinical response throughout the 1-year period of the study and the clinical response at 1 year was therefore significantly greater than in the infliximab group (DAS28 scores changed by −2.88 in the abatacept group vs. −2.25 in the infliximab group) . It is important to point out that while abatacept was used at 10 mg kg −1 , which is the optimal dosage used in clinical practice, infliximab was used at 3 mg kg −1 , which is on the lower end of the recommended dose range. The therapeutic efficacy of abatacept in comparison to higher dosages of infliximab or to other anti-TNF agents remains to be evaluated. In a recent study, involving patients with early RA, administration of abatacept in combination with methotrexate was associated with a significantly increased rate of remission than administration of methotrexate alone. At 1 year of follow-up, 41.4% in the abatacept plus methotrexate group achieved DAS28 defined remission (DAS28 < 2.6) compared with 23.3% in the methotrexate only group .
Abatacept demonstrated a favourable safety profile in all of the above trials ( Table 3 ). Two trials were designed to assess the safety of abatacept in combination with other agents. The Abatacept Study of Safety in Use with other RA Therapies (ASSURE) trial was designed to evaluate the safety of abatacept for use in patients receiving disease-modifying anti-rheumatic drugs (DMARDs), as well as biologics . On the one hand, patients receiving abatacept along with other non-biologic DMARDs demonstrated a favourable safety profile. On the other hand, combination of abatacept with other biologics was associated with an increased rate of infections . In another trial, abatacept was administered along with etanercept . Patients on the combination did not show significant clinical improvement over and above those treated with a single biologic agent, but had more infections. These studies demonstrate that abatacept has a favourable safety profile when administered with non-biologic DMARDs, but the combination of abatacept with another biologic agent is not recommended.
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