Still need to dig in on this molecule…
Clinical trials with intravenous anti-CD3 mAb
Two Phase I safety trials in renal allograft recipients with acute rejection episodes demonstrated that otelixizumab [93] and teplizumab [94] do not elicit major side-effects. In the year 2000 the first clinical trials with humanized anti-CD3 mAb were launched to test the tolerogenic activity of anti-CD3 mAb in T1D. In an American Phase I/II trial, teplizumab treatment of patients with recent onset T1D improved insulin production and metabolic control [95,96]. Similarly, a European Phase II/III study giving up to a total of 64 mg of the anti-CD3 mAb otelixizumab over 6 consecutive days reported a long-lasting therapeutic effect in terms of ß-cell preservation, as measured by C-peptide levels [97,98]. The effect was most significant in patients that had good C-peptide levels at the beginning of the treatment [97,98]. Follow-up studies were designed to test whether a lower dose of teplizumab (two courses of 14 days treatments, each cumulating 5, 6 or 17 mg) [9] or otelixizumab (3.1 mg cumulated during 8 days) could preserve C-peptide secretion in new-onset T1D patients while decreasing the side effects that were observed in the previous studies. However, the low dose of otelixizumab was nonefficacious [99–101] and the choice of endpoints of the Protégé study testing teplizumab was highly controversial [9]. A post hoc analysis using conventional endpoints found a treatment benefit in patients with higher baseline levels of C-peptide [102]. Also the AbATE study reported that patients with new onset diabetes benefit from treatment with teplizumab for at least 2 years and identified immunologic features at baseline that were significantly different between responders and nonresponders [103]. Teplizumab is currently being tested in preventing onset of T1D in a population ‘at-risk’ (ClinicalTrials.gov; NCT01030861). A new study on otelixizumab is recruiting T1D patients to identify the concentration with maximal therapeutic effect and minimal side effects (NCT02000817, clinicaltrials.gov). While otelixizumab and teplizumab were foremost tested in patients with T1D, visilizumab and foralumab were mostly studied in IBD [92]. A first Phase I trial, assessing safety and efficacy of visilizumab in patients with severe corticosteroid-refractory ulcerative colitis gave promising results [104]. After reducing the original dose of 15 µg/kg/day for 2 days due to occurring side effects (prolonged lymphopenia) to 10 µg/kg/day the safety profile was considered acceptable. 84% of patients showed a clinical response, with 41% entering clinical remission and 44% endoscopic remission [104]. A follow-up randomized, double-blind, placebo-controlled trial that was intended to confirm the efficacy of visilizumab for the treatment of IBD (but used only half of the original dose, i.e., 5 µg/kg) was terminated prematurely because of safety and efficacy concerns [105]. Treatment with a cumulated dose of only 0.7 mg (for a patient weighing 70 kg), was not only associated with a cytokine release syndrome but also with an increased rate of infection as well as vascular and cardiac symptoms. This was surprising as administration of 48 mg otelixizumab to patients with T1D provoked less side-effects [97]. It was hypothesized that visilizumab's low tolerability as compared with other Fc modified anti-CD3 mAb might be due to a stronger activation of CD3/TCR signaling [92]. As a consequence the clinical development of visilizumab was halted. Foralumab, the only completely human anti-CD3 mAb, was assessed in a Phase I/II clinical trial in patients with moderate to severe active Crohn's Disease [106]. Intravenous administration of up to 1 mg for 5 days was considered safe with manageable side effects. Even though the power of this study was too limited to assess clinical efficacy, the dose of 1 mg seemed to ameliorate the endoscopic index score while no significant improvement of clinical symptoms as assessed by the Crohn's disease activity index was reported [106].
Clinical trials with oral anti-CD3 mAb
A Phase I study with healthy subjects showed that repeated oral administration of the anti-CD3 mAb OKT3 was safe and induced immunological effects [107]. When given orally, this FcR binding antibody did not trigger systemic proinflammatory cytokines, immunogenicity, depletion of T cells or modulation of the CD3/TCR complex. Oral OKT3 enhanced T-cell proliferation, suppressed Th1 and Th17 responses and led to increased TGF-ß/IL-10 expression and decreased IL-23/IL-6 expression by dendritic cells [107]. A treatment regime of five-times 1 mg was considered superior to 0.2 or 5 mg [107]. Two single blind randomized placebo controlled Phase IIa studies in patients with treatment resistant chronic hepatitis C infection (HCV) [108] or nonalcoholic steatohepatitis (NASH) and altered glucose metabolism that included subjects with Type 2 diabetes [109], demonstrated that oral CD3 was safe and well tolerated, as measured by blood hematology, chemistry, immunological safety markers and physical signs [108,109]. Both studies reported positive effects on disease and immunological markers including an increase of Tregs [108,109].
Thus, mucosal anti-CD3 mAb therapy is an attractive approach for the treatment of inflammatory and autoimmune diseases. Further studies are now required to investigate the therapeutic effect of oral anti-CD3 mAb and to test nasal administration.
https://www.futuremedicine.com/doi/full/10.2217/imt-2016-0049?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org
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