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Aims/hypothesis <p>Uncertainty exists regarding the effectiveness of redosing teplizumab, a humanised anti-CD3 monoclonal antibody, in individuals with stage 2 and 3 type 1 diabetes. This study aimed to investigate the impact of redosing an anti-CD3 antibody on disease reversal and immune responses in NOD mice.</p> Methods <p>New-onset diabetic NOD mice were treated with a short course (days 0–4) of low-dose anti-CD3 (2.5 µg/day i.v.), followed by a second treatment course administered either early (days 14–18) or late (days 43–47) following the initial course. Diabetes outcomes, anti-drug antibody titres, inflammatory markers and the profiles of peripheral blood and pancreatic immune cells were assessed.</p> Results <p>A single course of anti-CD3 therapy reversed type 1 diabetes in 17 out of 40 treated mice (43%). However, neither early nor late redosing improved therapeutic outcomes in non-responder mice or disrupted re-established tolerance in responder mice. Early redosing, administered at the time of CD3⁺ T cell repopulation, and late redosing, timed when anti-drug antibody titres declined after their peak at 14 days, failed to induce remission in non-responder mice (0/10 and 0/5, respectively). Importantly, redosing did not trigger relapse in mice that had achieved remission following the initial treatment course, with all remaining normoglycaemic (5/5 with early redosing; 23/23 with late redosing). Inflammatory markers increased transiently, regardless of treatment response or regimen. In the pancreas, responder mice had a pronounced shift from an effector (CD62L⁻CD44⁺) to a naive (CD62L⁺CD44⁻) phenotype in both CD4⁺ and CD8⁺ T cells, independent of treatment regimen, indicative of a more regulated immune environment. These mice also exhibited elevated frequencies of CD4⁺ and CD8⁺ T cells with an exhausted (programmed cell death protein 1 [PD1]⁺killer cell lectin-like receptor subfamily G, member 1 [KLRG1]⁺) profile in their pancreas, a trait not observed in non-responder mice. Furthermore, the proportion of natural killer (NK) (NKp46⁺CD3⁻) cells was enriched in the pancreas of non-responder mice.</p> Conclusions/interpretation <p>These findings suggest that while a single course of anti-CD3 therapy can be effective in a subset of mice, redosing does not enhance efficacy yet is well tolerated in previously reversed mice.</p> Graphical Abstract <p></p>

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Redosing of anti-CD3 antibodies in NOD mice with new-onset diabetes does not alter the effect of a single treatment course

  • 期刊论文

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  • 发表日期：

    2025年11月20日

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  • Amber Wouters,
  • Pierre Lemaitre,
  • Laure Degroote,
  • Marijke Viaene,
  • Marc Packbier,
  • Nick Geukens,
  • Chantal Mathieu,
  • Conny Gysemans

摘要

Aims/hypothesis

Uncertainty exists regarding the effectiveness of redosing teplizumab, a humanised anti-CD3 monoclonal antibody, in individuals with stage 2 and 3 type 1 diabetes. This study aimed to investigate the impact of redosing an anti-CD3 antibody on disease reversal and immune responses in NOD mice.

Methods

New-onset diabetic NOD mice were treated with a short course (days 0–4) of low-dose anti-CD3 (2.5 µg/day i.v.), followed by a second treatment course administered either early (days 14–18) or late (days 43–47) following the initial course. Diabetes outcomes, anti-drug antibody titres, inflammatory markers and the profiles of peripheral blood and pancreatic immune cells were assessed.

Results

A single course of anti-CD3 therapy reversed type 1 diabetes in 17 out of 40 treated mice (43%). However, neither early nor late redosing improved therapeutic outcomes in non-responder mice or disrupted re-established tolerance in responder mice. Early redosing, administered at the time of CD3⁺ T cell repopulation, and late redosing, timed when anti-drug antibody titres declined after their peak at 14 days, failed to induce remission in non-responder mice (0/10 and 0/5, respectively). Importantly, redosing did not trigger relapse in mice that had achieved remission following the initial treatment course, with all remaining normoglycaemic (5/5 with early redosing; 23/23 with late redosing). Inflammatory markers increased transiently, regardless of treatment response or regimen. In the pancreas, responder mice had a pronounced shift from an effector (CD62L⁻CD44⁺) to a naive (CD62L⁺CD44⁻) phenotype in both CD4⁺ and CD8⁺ T cells, independent of treatment regimen, indicative of a more regulated immune environment. These mice also exhibited elevated frequencies of CD4⁺ and CD8⁺ T cells with an exhausted (programmed cell death protein 1 [PD1]⁺killer cell lectin-like receptor subfamily G, member 1 [KLRG1]⁺) profile in their pancreas, a trait not observed in non-responder mice. Furthermore, the proportion of natural killer (NK) (NKp46⁺CD3⁻) cells was enriched in the pancreas of non-responder mice.

Conclusions/interpretation

These findings suggest that while a single course of anti-CD3 therapy can be effective in a subset of mice, redosing does not enhance efficacy yet is well tolerated in previously reversed mice.

Graphical Abstract