Session Time: 6:00pm-7:00pm
Presentation Time: 6:05pm-6:10pm
*Purpose: Immune intervention with a CD40L specific monoclonal antibody (mAb, Hu5c8, Biogen) has previously been shown to safely and effectively prevent islet allograft (IA) rejection in three nonhuman primate (NHP) models. Clinical development for IA was precluded due to occurrence of thromboembolic complications (TE). AT-1501 (Novus Therapeutics) was engineered to preserve immune modulatory potential while avoiding TE and was shown to be safe in NHP. We tested AT-1501 in a diabetic cynomolgus monkey IA model, alone or in combination with additional agents.
*Methods: A total of 5 groups (n=2 each, recipients MHC mismatched to the islet donor) received 10,000 or more IEQ/kg into the liver. An AT-1501 monotherapy group, with 25 mg/kg given IV on POD -1, 0, 3, 10, 18, 23 and 28 and every 14 days thereafter, was included to verify the previously observed efficacy of anti-CD40L. The other 4 groups incorporated T cell depletion with thymoglobulin (Thy; 5 peri-transplant doses at 5 mg/kg each), with a standard of care (SOC) group also receiving FK506 and rapamycin (target trough levels 8-12 and 4-6 ng/ml, respectively) plus Enbrel (0.8 mg/kg IV on POD 0 and 0.4 mg/kg SC on POD 3, 7, 10). For the remaining 3 groups, AT-1501 was given as described for monotherapy but with additional doses on POD -2, -1 and 7. One group involved immune suppression as for the SOC group but replacing FK506 with AT-1501.
*Results: As compared to recipients in the SOC group, animals in the 4 AT-1501 treated groups had lower fasting blood glucose (FBG, 63 ± 14 vs 97 ± 19 mg/dl; p=0.04) and higher fasting (4.5 ± 0.1 vs 1.7 ± 0.1 ng/mg; p = 0.014) and stimulated (9.0 ± 2.1 vs 2.6 ± 0.4 ng/mg; p = 0.010) C-peptide/FBG. Animals in the AT-1501 groups experienced: greater weight gain, none to minimal CMV viral infection and down-regulation of anti-donor specific CD3/4 and 3/8 central memory T cells (at 2 months post-transplant). No class I or II alloantibody was observed.
*Conclusions: AT-1501 appears to be a safe and effective agent to promote islet engraftment and long-term survival and a promising tool for tolerance induction strategies.
To cite this abstract in AMA style:Berman D, Kenyon N, Willman M, Gill A, Perrin S, Ricordi C. AT-1501, a Novel and Clinically Applicable CD40L Specific Monoclonal Antibody, Promotes Islet Allograft Survival in Nonhuman Primates [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/at-1501-a-novel-and-clinically-applicable-cd40l-specific-monoclonal-antibody-promotes-islet-allograft-survival-in-nonhuman-primates/. Accessed June 13, 2021.
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