Background/Purpose: Dapirolizumab pegol (DZP) is a novel CD40L inhibitor with broad modulatory effects on SLE immunopathology;1,2 it consists of a polyethylene glycol (PEG)-conjugated antigen-binding fragment (Fab’), which lacks an Fc domain. DZP demonstrated efficacy in the phase 3 PHOENYCS GO trial (NCT04294667).3 SLE predominantly affects women of childbearing age, conferring potential maternal and fetal risks.4 Here, DZP reprotoxicity was studied in vivo in non-human primates (NHPs; cynomolgus monkeys), and DZP transfer across human placentas was evaluated ex vivo.

Methods: In an enhanced pre/postnatal development (ePPND) study, pregnant NHPs (N&#3f14) received weekly intravenous DZP 27 or 50 mg/kg from gestation Day 20 to birth. Infant development was monitored for 9 months. Ex vivo dual perfusion of human placentas (N&#3f22) assessed DZP and control IgG full monoclonal antibody transfer over up to 6 hours.

Results: In the ePPND study, pregnancy outcomes, embryofetal development, and infant postnatal development to 9 months post-birth were not affected by DZP. DZP induced expected decreases in B cells, IgG, and IgM in pregnant mothers, with no evidence of these effects in infants, nor altered development of infant immune systems to 9 months post-birth. Post-birth, DZP transfer from mother to infant (< 0.3% infant:mother plasma ratio) and mother plasma to milk (< 0.08% mother milk:plasma ratio) were very low. In the human ex vivo placental model, DZP was below quantification (minimal to none) in human placental fetal perfusate, in contrast to IgG full antibody control.

Conclusion: DZP showed no adverse outcomes on pregnancy or infant development post-birth in NHPs. In the ex vivo human placental model, DZP transfer was below the level of detection. These data align with lack of active placental transfer via the neonatal Fc receptor, causing minimal to no DZP transfer from mother to fetus, and suggest DZP may not be anticipated to cross the placenta to significant levels. These findings support further investigation of DZP in the setting of human pregnancy.References: 1. Cutcutache I. Arthritis Rheumatol 2023;75 (suppl 9); 2. Powlesland AS. Annals Rheum Dis 2024;83 (suppl 1):261; 3. Clowse M. Arthritis Rheumatol 2024;76 (suppl 9); 4. Gamba A. J Clin Med 2024;13(12):3454.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dapirolizumab-pegol-a-novel-cd40l-inhibitor-showed-no-adverse-outcomes-in-an-in-vivo-non-human-primate-reprotoxicity-study-and-displayed-minimal-to-no-human-placental-transfer-in-an-ex-vivo-study/