Table 1.
Consensus priority ranking of combination immune-based therapies for type 1 diabetes
| Combination |
Commentary on: |
||
|---|---|---|---|
| Drug no. 1 | Drug no. 2 | Evidence for tolerance and other (dis)advantages | Drug availability |
| Anti-CD3 •Teplizumab (MacroGenics/Eli Lilly) •Otelixizumab (TolerX/GSK) | Antigen •Oral insulin •GAD-Alum (Diamyd) •Proinsulin DNA (BHT-3021, Genentech) •Proinsulin peptide | –Extended benefit of anti-CD3 monotherapy in Phase II –Long-term induction of Tregs by anti-CD3 in preclinical models –Synergy of anti-CD3 and antigen demonstrated in preclinical models –Antigen-specific suppression shown in preclinical models for antigens | Availability will require negotiations between companies |
| T cell modulation (anti-CD3) •Teplizumab (MacroGenics/Eli Lilly) •Otelixizumab (TolerX/GSK) | Anti-inflammatory •IL-1RA Anakinra (Amgen) •IL-1 Trap Rilonacept (Regeneron) | –See above | Availability will require negotiations between companies |
| B cell depletion (anti-CD20) •Rituximab (Genentech) | Antigen •ral insulin •GAD-Alum (Diamyd) •Proinsulin DNA (BHT-3021, Genentech) •Proinsulin peptide | –Clinical and preclinical studies on all agents show potential effects as monotherapies (and for antigens see above) | Availability will require negotiations between companies |
| Immune depletion/modulation •Anti-thymocyte globulin (ATG; thymoglobulin, Genzyme) | Immune modulation •GM-CSF (Neulasta, Amgen) | –Encouraging preclinical results of combination in NOD mice | Good for all agents |
| Antigen •GAD-Alum (Diamyd) | Antigen •Oral insulin •Proinsulin DNA •Proinsulin peptide | –Encouraging preclinical results of antigen combinations in NOD mice –Induction of Tregs across diverse genetic backgrounds –Specific combinations not tested preclinically or clinically | All early development phase and will therefore require negotiation |
| T cell modulation (anti-CD3) •See above | Incretin mimetic •Exendin-4 (Exenatide, Amylin/Lily) | –Efficacy of combination in animal models | Availability will require negotiations between companies |
| T cell modulation (anti-CD3) or B cell depletion (anti-CD20) | Anti-inflammatory •Anti-TNF-α (Enbrel, Amgen) | –All agents show success in monotherapy trials and target different pathways –No data on combinations in preclinical setting | Availability will require negotiations between companies |
| Other possible combinations with minimal supporting data: | |||
| Anti-inflammatory •e.g. see above or •anti-IL-6 (Tocilizumab, Roche) | Antigen | ||
| B cell depletion (anti-CD20) | IL-2 pathway blockade •Rapamycin (Rapamune, Wyeth) | ||
| B cell depletion (anti-CD20) | Incretin mimetic | ||
| B cell depletion (anti-CD20) | Anti-inflammatory | ||
| T cell modulation (anti-CD3) | Anti-inflammatory •α-1 anti-trypsin (Aralast, Baxter) | ||
| Immune modulation •Anti-IL-12/23 (Stelara, J&J) | Antigen | ||
| Antigen •CTB-Ins plasmid | Antigen | ||
| Antigen •CTB-Ins plasmid | Immune modulation •IL-10 plasmid | ||
GM-CSF: granulocyte–macrophage colony-stimulating factor; IL: interleukin; NOD: non-obese diabetic; TNF: tumour necrosis factor; Treg: regulated T cell.