Development of a Chimeric Anti-CD40 Monoclonal Antibody That Synergizes with LEA29Y to Prolong Islet Allograft Survival

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.

ASKP1240, a Fully Human Anti-CD40 Monoclonal Antibody, Prolongs Pancreatic Islet Allograft Survival in Nonhuman Primates

“…With regard to the prolongation of islet allograft survival time, ASKP1240 appeared to have a stronger effect than other anti-CD40 mAbs, e.g. Chi220 (17), 2C10 (20) or 3A8 (18,19), but was equivalent to or less potent than anti-CD154 mAbs (12)(13)(14).…”

“…Blockade of this signaling pathway by various approaches has been shown to induce potent immunosuppression against cellular immunity and tolerance to allografts in experimental organ transplantation (46)(47)(48). In PITx, Adams et al (17) demonstrated that Chi220, which is a chimeric IgG1 CD40-specific mAb, dramatically prolonged islet allograft survival to 237, 237, 220, >185 and 172 days when combined with LEA29Y (belatacept). It has been shown that other anti-CD40 mAbs, i.e.…”

“…A histologic examination of islet allografts in the liver revealed that the cellular infiltrate surrounding the rejected islets was strongly positive for CD3 þ T cells but not for CD20 þ B cells, C4d or neutrophils (17,39), which is consistent with recipient T cell alloreactivity assessed in mixed lymphocyte cultures (19). Indeed, immunodepletion or modulation of T cells has emerged as a valuable adjunct treatment after PITx; it has been shown that higher insulin independence can be achieved by utilizing thymoglobulin (40), alemtuzumab (41,42) or alternative nonFc-binding humanized antiCD3mAb teplizumab (hOKT3-ala-ala) induction therapy (43).…”

LFA-1–specific therapy prolongs allograft survival in rhesus macaques

“…Group 5 received single-agent therapy with belatacept. Group 5 also consisted of 1 current and 2 historical controls to minimize the use of primates (42). The hybridoma producing antihuman CD11a, TS-1/22.1.1.13, was obtained from ATCC.…”

“…Three initial recipients (RWi11, RVh11, and RMc11) were dosed at 1,600 mg/m 2 i.v., but observed toxicity in RWi11 and monkeys in other concurrent studies prompted subsequent usage at 1,250 mg/m 2 . Four historical control animals (RQz6, RIb7, RIt7, and RKu7) underwent duodenal-sparing total pancreatectomies for diabetes induction 2-4 weeks prior to transplant, as previously described (41,42).…”