Introduction

There is a need for more effective treatments for IBD, with advanced therapies having placebo-adjusted clinical remission rates of only 10 to 25%. The combined use of targeted biologic agents could break through this efficacy ceiling while avoiding the risks associated with broad immunosuppression. Towards this end, Spyre Therapeutics is developing half-life extended antibody drug candidates that can be administered in combination, inhibiting the clinically validated IBD targets α4β7 integrin (SPY001), TL1A (SPY002), and IL-23 (SPY003). The efficacy of combined inhibition of integrin β7 and TL1A, integrin β7 and IL-23, and TL1A and IL-23 was evaluated in proof-of-concept studies utilizing the TNBS-induced murine colitis model.

Aims & Methods

Mice were dosed intravenously with surrogate antibodies targeting mouse integrin β7 (25 mg/kg), mouse TL1A (25 mg/kg), mouse IL-23 (25 or 1 mg/kg), pairwise combinations of these three antibodies (integrin β7 + TL1A, integrin β7 + IL-23, TL1A + IL-23), an isotype control antibody, or vehicle on Day -1 and Day 2. TNBS was administered intrarectally (IR) on day 0 to induce colitis in all mice except the non-disease control group, which received IR vehicle. Body weight and disease activity score were recorded daily until the end of the study on Day 6. Colon weight and length were measured at the conclusion of the study. Colon histopathology was scored by a blinded pathologist.

Results

Monotherapy treatment with 25 mg/kg anti-β7 or 25 mg/kg anti-TL1A antibodies resulted in low magnitude, directional improvements in colitis outcome measurements, while treatment with 25 mg/kg anti-IL-23 antibody resulted in significant improvements relative to the vehicle and isotype control groups. Combinations of anti-β7 + anti-TL1A, anti-β7 + anti-IL-23, and anti-TL1A + anti-IL-23 resulted in superior efficacy compared to their constituent monotherapies based upon disease activity scoring. To further explore combination therapy benefit, a lower dose (1 mg/kg) of anti-IL-23 alone or in combination with anti-β7 or anti-TL1A was evaluated. Low dose anti-IL-23 showed minimal activity as a monotherapy, but low dose anti-IL-23 + anti-β7 maintained efficacy similar to the high dose combination. The combination of low dose anti-IL-23 + anti-TL1A was more effective than either monotherapy alone.

Conclusion

Combination therapy with anti-β7 + anti-TL1A, anti-β7 + anti-IL-23 or anti-TL1A + anti-IL-23 resulted in efficacy superior to their constituent monotherapies in the murine TNBS model of colitis. These data support and provide biologic rationale for the advancement of antibody combinations into human clinical trials for inflammatory bowel disease.

Disclosure

All authors are employees and shareholders in Spyre Therapeutics, Inc.