Background/Purpose: ZB002 is a recombinant human monoclonal antibody (mAb) that targets human TNFα with an Fv domain identical in amino acid sequence to adalimumab and was designed to have an extended half-life. Adalimumab has been approved for the treatment of a broad spectrum of autoimmune diseases but has a half-life of only approximately 2 weeks and is dosed either weekly (QW) or every 2 weeks (Q2W)¹. The fragment crystallizable (Fc) domain of ZB002 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 ZB002 half-life, potentially enabling reduced frequency of administration. The objectives of this study were to evaluate ZB002 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 were enrolled at a single center (New Zealand Research Center). Eight HVs were enrolled into each dosing cohort and randomized in a 3:1 ratio to receive subcutaneous ZB002 or placebo. Dose escalation between cohorts was approved by a Safety Review Committee (SRC). Doses tested were 20 mg, 40 mg, 80 mg, 160 mg, and 240 mg. ZB002 PK and anti-drug antibodies (ADA) were analyzed, and PD effects were assessed using ex vivo stimulated whole blood.

Results: No safety signals were identified, with adverse events consistent with expectations for a TNFα antibody. PK results showed a ZB002 half-life of approximately 6-7 weeks. Modelling and simulations indicate that potentially efficacious dosing for indications such as rheumatoid arthritis could be administered every 2 months (Q2M). Given the long dosing interval, administration of a loading dose would help to bring patients to steady state rapidly. Pharmacodynamic analysis revealed approximately 95% inhibition of ex vivo-stimulated TNFα production in samples obtained from the HVs 8 hours post dosing with ZB002.  

Conclusion: This study demonstrated that ZB002 was well tolerated, and the safety profile was consistent with anti-TNF treatment of a HV population at the doses studied. Observed ZB002 half-life and confirmation of target engagement warrants continued clinical development. 

References:   

1.   Humira Full Prescribing Information. US Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125057s406lbl.pdf. Accessed January 11, 2024. 

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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-zb002-an-anti-tnf%ce%b1-mab-designed-for-extended-half-life-in-healthy-volunteers/