B003 - CD6-Targeted Antibody-Drug Conjugate for Preventing Renal Allograft Rejection in Non-Human Primates

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Author Block: N. Bazzi¹, M. Okoreeh¹, K. Krynychka¹, K. Williams², H. Xu², F. Lin³, A. Kirk¹, ¹General Surgery, Duke University Medical Center, Durham, NC, ²Duke University Medical Center, Durham, NC, ³Cleveland Clinic, Cleveland, OH
*Purpose: Depletional induction therapy is known to reduce the risk of acute rejection, but current depletional biologics non-specifically eliminate T cells, increasing infectious risk and disrupting regulatory mechanisms. Here we report the first pilot investigation of a novel CD6 antibody-drug conjugate (CD6-ADC) that combines monomethyl auristatin E (MMAE; a highly potent, anti-mitotic tubulin polymerization inhibitor) with a CD6-specific antibody, designed to specifically target proliferating T cells and potentially offer a selectivity advantage compared to other pan-T-cell depletional therapies.
*Methods: In vitro drug efficacy was initially demonstrated with a one-way mixed lymphocyte reaction (MLR) using PBMCs from two non-human primates (NHPs). Four kidney transplants were then performed between naïve, MHC-mismatched NHPs treated with monotherapy CD6-ADC dosed as indicated in Figure 1. Outcomes were compared to two contemporary untreated NHP kidney recipients.
*Results: Proliferation of CD3⁺ cells in MLR showed a dose-response relationship with a decrease from 15% (untreated) to 13%, 10%, 7%, and 1% in cells treated with 16, 32, 64, and 128 nM of CD6-ADC, respectively. Untreated animals rejected in 7 days. The first treated recipient received 1.25mg/kg on day 0 and 1.76 mg/kg on day 3. Rejection occurred at day 6, prompting a switch to the more aggressive dosing strategy. The following three recipients received a 5 mg/kg loading dose followed by 2 mg/kg doses daily for one week, with doses tapering over time, thereafter (Figure 1). In this cohort, median graft survival was significantly prolonged compared to untreated controls (43 days versus 7 days; P = 0.0455). The drug was discontinued on days 27, 27, and 51. Rejections occurred, after drug discontinuation, on day 41 and 43 in the two animals dosed for <30 days, and the animal with prolonged dosing survived the full 90-day study period (Figure 1). The drug was well tolerated with adverse reactions limited to anemia. Flow cytometric analysis of the T-cell depletional effect of CD6-ADC is ongoing.
*Conclusions: When sufficiently dosed, CD6-ADC monotherapy significantly improved survival in NHPs compared to controls. This may offer a more selective depletional induction therapeutic agent, and we are proceeding with additional experiments combining CD6-ADC with co-stimulatory blockade.
Figure 1: Treatment dose and timing of CD6-ADC monotherapy and graft survival of all animals.