Background/Purpose: ZB004 is a bioengineered cytotoxic T-lymphocyte-associated antigen 4 ‑immunoglobulin (CTLA-4-Ig) fusion protein. Its mechanism of action is selective inhibition of T lymphocyte (T cell) costimulation via binding to cluster of differentiation (CD)80 and CD86, which blocks their interaction with CD28 on T lymphocytes. ZB004 contains two CTLA-4 extracellular domain (ECD) substitutions, for increased binding to CD80 and CD86. The fragment crystallizable (Fc) domain of ZB004 consists of a hybrid immunoglobulin G (IgG) 1/2 constant region containing 2 amino acid substitutions, M428L and N434S, referred to as the Xtend™ Fc domain. This domain is designed to increase affinity to the neonatal Fc receptor (FcRn) and thus increase ZB004 half-life.  The substitutions in the Fc domains are designed to enable reduced frequency of administration. The objectives of this study were to evaluate ZB004 safety and tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) in healthy volunteers (HV).

Methods: This study was a double blind, randomized, placebo-controlled, single ascending dose (SAD) study. Male and female HVs ages 18-55 years were enrolled at a single center (New Zealand Clinical Research). Eight HVs were enrolled into each dosing cohort and randomized in a 3:1 ratio to receive subcutaneous ZB004 or placebo. Dose escalation between cohorts was approved by a Safety Review Committee (SRC). Doses tested were 3 mg, 12.5 mg, 50 mg, 125 mg, and 200 mg. ZB004 PK and anti-drug antibodies (ADA) were analyzed, CD86 receptor occupancy (RO) levels were measured in the whole blood for evaluation of ZB004 target engagement, and PD activity was assessed using ex vivo stimulated whole blood.

Results: No safety signals were identified, with adverse events consistent with expectations in a HV population, and no serious adverse events observed. PK results showed a ZB004 half-life of between 8-18 days. The presence of target mediated drug distribution (TMDD) effect is likely, as evidenced by the nonlinear increase in PK parameters with increase in dose level.  PD analysis in whole blood samples revealed clear target engagement with dose dependent response in %CD86 RO levels, and inhibition of ex vivo stimulated IL-2 in all dose cohorts. Immunogenicity evaluation showed a lowering of both incidence and titer value with increase in dose level, consistent with the immunosuppressive effect of ZB004.  

Conclusion: This study demonstrated that ZB004 was safe and well tolerated at all doses studied. Observed ZB004 PK and target engagement warrants continued clinical development.

References:  

1.   Bernett MJ, Chu SY, Leung I, et al. Immune suppression in cynomolgus monkeys by XPro9523: an improved CTLA4-Ig fusion with enhanced binding to CD80, CD86 and neonatal Fc receptor FcRn. MAbs. May-Jun 2013;5(3):384-96. doi:10.4161/mabs.23976

2.   Martins JP, Kennedy PJ, Santos HA, Barrias C, Sarmento B. A comprehensive review of the neonatal Fc receptor and its application in drug delivery. Pharmacol Ther. May 2016;161:22-39. doi:10.1016/j.pharmthera.2016.03.007

3.   Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T

cell responses. Nat Rev Immunol. Nov 25 2011;11(12):852-63. doi:10.1038/nri3108

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-1-single-ascending-dose-study-to-evaluate-the-safety-and-pharmacokinetics-of-zb004-a-ctla-4-ig-fusion-protein-designed-for-increased-binding-affinity-and-extended-half-life-in-healthy-volunt/