Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival

AB Adams, N Shirasugi, TR Jones… - The journal of …, 2005 - journals.aai.org
AB Adams, N Shirasugi, TR Jones, MM Durham, EA Strobert, S Cowan, P Rees, R Hendrix…
The journal of immunology, 2005journals.aai.org
In recent years, reagents have been developed that specifically target signals critical for
effective T cell activation and function. Manipulation of the CD28/CD80/86 and CD40/CD154
pathways has exhibited extraordinary efficacy, particularly when the pathways are blocked
simultaneously. Despite the reported efficacy of anti-CD154 in rodents and higher models,
its future clinical use is uncertain due to reported thromboembolic events in clinical trials. To
circumvent this potential complication, we developed and evaluated a chimeric Ab targeting …
Abstract
In recent years, reagents have been developed that specifically target signals critical for effective T cell activation and function. Manipulation of the CD28/CD80/86 and CD40/CD154 pathways has exhibited extraordinary efficacy, particularly when the pathways are blocked simultaneously. Despite the reported efficacy of anti-CD154 in rodents and higher models, its future clinical use is uncertain due to reported thromboembolic events in clinical trials. To circumvent this potential complication, we developed and evaluated a chimeric Ab targeting CD40 (Chi220, BMS-224819) as an alternative to CD154. Although Chi220 blocks CD154 binding, it also possesses partial agonist properties and weak stimulatory potential. The anti-CD40 was tested alone and in combination with a rationally designed, high affinity variant of CTLA4-Ig, LEA29Y (belatacept), in a nonhuman primate model of islet transplantation. Although either agent alone only modestly prolonged islet survival (Chi220 alone: 14, 16, and 84 days; LEA29Y alone: 58 and 60 days), their combination (LEA29Y and Chi220) dramatically facilitated long term survival (237, 237, 220,> 185, and 172 days). We found that the effects of Chi220 treatment were not mediated solely through deletion of CD20-bearing cells and that the combined therapy did not significantly impair established antiviral immunity.
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