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Selective Costimulation Modulators: Addressing Unmet Needs in Rheumatoid Arthritis Management: Targeting T-Cell Activation Through Selective Costimulation Modulation


Targeting T-Cell Activation Through Selective Costimulation Modulation

As T cells activate and coordinate a number of biological pathways that cause synovial inflammation and joint destruction in patients with RA, therapeutic strategies that specifically modulate T-cell function may reduce the severity of symptoms or slow the progression of the disease more effectively than the currently available treatment options.[57]

A Novel Costimulation Modulator

Abatacept (CTLA4Ig), the first in a new class of agents known as costimulation modulators, is in development for the treatment of RA. Abatacept is a chimeric fusion protein that consists of the extracellular domain of the human CTLA4 molecule and the heavy-chain constant region of human IgG1 (Figure 8).[58,59] Abatacept binds to CD80 and CD86 on APCs, with its extracellular CTLA4 portion, preventing them from making contact with CD28 on T cells. By blocking engagement of CD28, abatacept, like CTLA4, prevents positive costimulation signals required for optimal T-cell activation (Figure 9). In RA, this may prevent the stimulation of T-cell effector functions in response to autoantigen exposure and may suppress the proliferation of autoreactive T cells, restoring the balance between self-tolerance and autoimmunity.

Figure 8. (click image to zoom) Abatacept is a chimeric fusion protein that consists of the extracellular domain of the human CTLA4 molecule and the heavy-chain constant region of human IgG1.

Figure 9. (click image to zoom) Abatacept selectively modulates T-cell activation by preventing the costimulation signal generated by binding of CD28 with CD80/86.

Abatacept Attenuates T-Cell-Mediated Immune Responses

The immunologic effects of abatacept offer a unique mechanism of action for the treatment of patients with RA. By preventing positive costimulation signals normally generated through engagement of CD28, abatacept can block the release of T-cell cytokines that stimulate other immune cells, while it simultaneously suppresses T-cell proliferation -- with cytokine release and T-cell proliferation being the hallmarks of optimal T-cell activation. This was demonstrated in an in vitro lymphocyte activation model in which human T cells were stimulated with APCs and antigen.[60] Abatacept exposure produced a clear, dose-related inhibition of T-cell proliferation, attaining approximately 80% suppression of proliferation at concentrations of 10 mcg/mL or higher. It also significantly reduced the release of IL-2, TNF-alpha, and IFN-gamma from the T cells during the 72 hours after antigen exposure. Thus, the results of this in vitro study confirmed that abatacept suppresses T-cell responses (both the release of inflammatory cytokines and proliferation) to stimulation by APCs and antigen and does so at concentrations that are similar to the serum concentration produced by abatacept doses evaluated in clinical trials of patients with RA (described below).

Abatacept has also been shown to reduce serum markers of joint inflammation in patients with RA after 6 months of treatment.[61] Blood samples obtained from patients treated with abatacept exhibited reductions from baseline levels of several inflammatory biomarkers, including C-reactive protein, E-selectin, soluble IL-2 receptor, and the macrophage-derived cytokine IL-6. Blood samples from patients treated with abatacept also demonstrated reductions from baseline levels of autoantibodies (RF) produced by B cells. Abatacept has also been shown to have a direct inhibitory effect on dendritic cells.[62] Taken together, these studies suggest that abatacept may act to decrease joint inflammation in RA.

Preclinical Studies With Abatacept

Preclinical studies provided the proof of concept for abatacept in RA. Data from several animal model studies of T-cell-mediated disease have demonstrated that targeting T cells may decrease the severity of autoimmune diseases, including RA. In systemic lupus erythematosus-prone mice (NZBxW strain), abatacept blocked the production of autoantibodies, inhibited T-cell-dependent B-cell maturation, and increased life span.[63,64] Webb and colleagues[65] examined the effects of CTLA4Ig in a mouse model of collagen-induced arthritis, in which exposure of genetically susceptible mice to type II collagen results in cell-mediated and humoral immune responses, synovial inflammation, infiltration of immune cells into the joint, and destruction of bone and cartilage. In 2 experiments, pretreatment with CTLA4Ig markedly reduced the number of mice that developed arthritis following collagen exposure. In the first study, 9 of 10 control mice and 1 of 10 mice treated with CTLA4Ig developed arthritis; in the second study, 9 of 10 control mice and 0 of 10 CTLA4Ig mice developed arthritis (P < .001 for both comparisons). When administered after arthritis was already established, CTLA4Ig significantly reduced the number of arthritic joints and improved other clinical signs of arthritis over 10 days following treatment. CTLA4Ig also significantly reduced lymphocyte proliferation in the lymph nodes.

Pilot and Clinical Studies With Abatacept

Abatacept has recently been evaluated in a series of clinical trials in patients with autoimmune T-cell-mediated diseases. The first study to examine abatacept in humans was a phase 1 clinical trial of 43 patients with psoriasis.[66] Patients received abatacept at doses of .5, 1, 2, 4, 8, 16, 25, and 50 mg/kg, administered at study days 1, 3, 16, and 29, with 4-6 patients enrolled at each dose. Abatacept treatment produced clinically significant improvement in psoriasis symptoms (defined as a decrease of at least 50% in disease activity) in 46% of patients, with a clear relationship between improvement and abatacept dose. All doses studied were well tolerated by the patients.

In a clinical trial that was primarily intended to evaluate safety and tolerability, patients with RA were treated with abatacept at doses of .5, 2, or 10 mg/kg.[67] Abatacept appeared to be safe and well tolerated, with no change in abatacept antibody levels from baseline. Serious adverse events (in most cases, worsening of RA requiring hospitalization) occurred in 4 of 32 patients who received placebo and 4 of 90 patients who received abatacept. The 10-mg/kg dose provided optimal efficacy compared with placebo, in the proportion of patients who attained ACR 20, 50, or 70 responses. This study provided the initial confirmation that monotherapy with abatacept is safe and effective for the treatment of RA.

Phase 2, Efficacy and Safety Clinical Trial of Abatacept

Combination treatment with abatacept and MTX was recently evaluated in a phase 2, randomized, double-blind, placebo-controlled efficacy and safety study.[68] A total of 339 patients with active RA and an inadequate response to MTX were randomized to treatment with MTX in combination with 1 of 2 abatacept dosages (2.0 mg/kg or 10 mg/kg administered as a 30-minute infusion every 2 weeks for the first month, and every month thereafter, for a total of 6 months) or MTX and placebo. All other DMARDs were discontinued at least 28 days before randomization. The patients had a mean duration of disease activity of 8.9-9.7 years, and more than 96% of the patients had no prior biological therapy.

The effects of abatacept on the study primary end point (the proportion of patients with ACR 20 response after 6 months of treatment) were analyzed for the 3 treatment groups. Beginning at day 60, patients who received high-dose abatacept and MTX (n = 115) were significantly more likely to have an ACR 20 response than patients who received placebo and MTX (n = 119; P < .001).[68] This improvement was sustained throughout the 6-month study. Patients who received low-dose abatacept (n = 105) tended to have an increased likelihood of an ACR 20 response, although the difference between the low-dose and placebo groups was not statistically significant. Both abatacept treatments were associated with significant increases in the number of patients who attained ACR 50 or ACR 70 responses, compared with placebo, as well as significantly improved patient quality-of-life ratings, which were measured with the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36).

Additional 1-year follow-up results from this study showed a sustained increase in the ACR 20 score in the abatacept 10-mg/kg group compared with placebo (Figure 10).[69] Clinical outcomes after 12 months reported at the recent European League Against Rheumatism (EULAR) 2004 annual meeting were similar to the results observed after 6 months, with significantly more patients in the abatacept 10-mg/kg group attaining ACR 20, 50, and 70 responses (Figure 11).[70] Adverse events were reported by 16.0% of patients in the placebo group and 12.2% of those who received abatacept. Reports of serious adverse events, or of the most common adverse events (nasopharyngitis, headache, nausea, cough, diarrhea, and upper respiratory tract infection), were similar for the MTX-plus-placebo and MTX-plus-abatacept treatment groups. The treatment response was sustained after 1 year in patients with early ( ≤ 3 years) and established (> 3 years) RA, although treatment with abatacept produced a trend toward a greater improvement in ACR response rates in patients with a shorter disease duration.[70] One year of treatment with abatacept was also associated with significant improvements in physical function and patient-reported pain, with improvements occurring before clinically evident improvement in ACR scores.[71,72] Finally, abatacept significantly increased the number of patients who exhibited disease remission (measured with the Disease Activity Score-28 [DAS28] rating scale, with remission defined as a DAS28 score < 2.6) compared with placebo (Figure 12).[73]

Figure 10. (click image to zoom) The combination of abatacept with MTX promotes a sustained increase in the ACR 20 response rate in patients with RA who have inadequate responses to MTX (reprinted with permission from Westhovens et al.[69]). *P < .001 vs placebo + MTX. Placebo + MTX: n = 119; abatacept 10 mg/kg + MTX: n = 115.

Figure 11. (click image to zoom) At 12 months, the combination of abatacept with MTX significantly increases the ACR 20, 50, and 70 response rates in patients with RA who have inadequate responses to MTX (data from Keystone et al.[70]). *P < .001; P < .05 vs placebo + MTX. Placebo + MTX: n = 119; abatacept 10 mg/kg + MTX: n = 115.

Figure 12. (click image to zoom) The combination of abatacept with MTX significantly increases the remission rate, defined as a DAS28 < 2.6, in patients with RA who have inadequate responses to MTX (reprinted with permission from Dougados et al.[73]). *P < .05 vs placebo + MTX. Placebo + MTX: n = 119; abatacept 10 mg/kg + MTX: n = 115.

Phase 3 Clinical Trials of Abatacept

Several ongoing phase 3 trials are currently examining the efficacy and safety of abatacept, including the effects of abatacept treatment on radiographic measures of disease progression. The Abatacept in Inadequate Responders to Methotrexate (AIM) clinical trial is evaluating abatacept safety and efficacy in patients who have exhibited incomplete responses to 12 months of MTX treatment. The Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) is evaluating the safety and efficacy of abatacept treatment in patients for whom 6 months of treatment with TNF-alpha inhibitors has failed. The Abatacept Study of Safety in Use With Other RA Therapies (ASSURE) is a large clinical trial that is evaluating the safety of abatacept after 12 months.

Targeting Costimulation and Normal Immune Function

One of the concerns associated with the use of biological DMARDs in the treatment of RA is that normal immune responses against infectious agents, for instance, may be compromised. In the case of costimulation modulators, such as abatacept, this may be less of a worry, because the selective targeting of only 1 costimulation pathway most likely leaves the multiple other pathways involved in T-cell activation intact. This hypothesis of selectivity is supported by animal model studies, in which CD28-deficient mice display normal infectious immunity both before and after treatment with abatacept.[74] In this study, abatacept did not block cytokine production or proliferation of lymph node T cells in response to challenge with the infectious antigen.[74]

Further, abatacept specifically targets a T-cell signaling pathway that has recently been associated with autoimmunity.[75] An autoimmune disease-susceptible haplotype of CTLA4, which most likely results in reduced blocking of CD80/86, has been identified. It is interesting to hypothesize that abatacept could potentially compensate for this reduction in CD80/86 binding in patients who carry the CTLA4 risk haplotype.

Also, it is likely that abatacept primarily prevents the activation of naive T cells, with less effect on the reactivation of memory T cells, as memory T cells are thought to be less dependent on CD28 costimulation.[23]