Zinpentraxin alfa is a recombinant human pentraxin-2 (PTX-2) developed for the treatment of various fibrotic diseases with the hypothesis that supplementing endogenous PTX-2 levels through intravenous administration should increase its regulatory capacity in circulation and at the site of disease, thereby promoting healing and reducing fibrosis. Zinpentraxin alfa has been studied in various clinical trials, particularly in patients with idiopathic pulmonary fibrosis, where it has demonstrated efficacy in slowing decline in lung function in a phase 2 study. In the present investigation, we summarize findings from 14-day repeat-dose toxicity studies in rats and cynomolgus monkeys supporting early clinical development of zinpentraxin alfa. In addition, we also describe the findings from the embryo-fetal developmental (EFD) studies conducted in rats and rabbits, since the intended fibrosis patient population may include patients of childbearing potential. Zinpentraxin alfa was well tolerated by rats and monkeys in general toxicity studies with no treatment-related adverse effects, as well as by pregnant rats over the same dose range in a definitive EFD study. In contrast, substantial toxicity was observed in a rabbit dose-range-finder EFD study. Zinpentraxin alfa was poorly tolerated by pregnant rabbits and effects on the dams correlated with post-implantation fetal losses. The disparate effects of zinpentraxin alfa on embryo-fetal development between the two species suggests a potential unknown biological function of PTX-2 in pregnancy in the rabbit, which may be relevant to humans. Our findings warrant the consideration for highly effective contraceptive measures to avoid pregnancy in patients enrolled in clinical studies with zinpentraxin alfa.

Zinpentraxin alfa 是一种重组人 pentraxin-2 (PTX-2)，开发用于治疗各种纤维化疾病，其假设是通过静脉注射补充内源性 PTX-2 水平应增加其在循环中和疾病部位的调节能力，从而促进愈合并减少纤维化。Zinpentraxin alfa 已在各种临床试验中进行了研究，特别是在特发性肺纤维化患者中，在一项 2 期研究中，它证明了它可以减缓肺功能下降的功效。在本研究中，我们总结了在大鼠和食蟹猴中进行的 14 天重复剂量毒性研究的结果，支持 zinpentraxin alfa 的早期临床开发。此外，我们还描述了在大鼠和兔子中进行的胚胎-胎儿发育（EFD）研究的结果，因为预期的纤维化患者群体可能包括有生育潜力的患者。在一般毒性研究中，大鼠和猴子对 Zinpentraxin alfa 具有良好的耐受性，没有与治疗相关的不良反应，在一项明确的 EFD 研究中，相同剂量范围内的怀孕大鼠也对 Zinpentraxin alfa 具有良好的耐受性。相比之下，在兔子剂量范围探测器 EFD 研究中观察到了显着的毒性。怀孕兔对 Zinpentraxin alfa 的耐受性较差，对母兔的影响与着床后胎儿丢失相关。zinpentraxin alfa 对两个物种胚胎-胎儿发育的不同影响表明 PTX-2 在兔子妊娠过程中具有潜在的未知生物学功能，这可能与人类有关。我们的研究结果值得考虑采取高效的避孕措施，以避免参加 zinpentraxin alfa 临床研究的患者怀孕。