Mistry Hitesh B, Hodson David, Battula Sailaja, Schmidt Michael M, Tighe Robert, Kaufman Howard L, Chassagnole Christophe
Physiomics Plc, Abingdon, United Kingdom.
Ankyra Therapeutics, Cambridge, Massachusetts, United States.
Mol Cancer Ther. 2025 Mar 13. doi: 10.1158/1535-7163.MCT-24-1051.
Interleukin-12 (IL-12) mediates innate and adaptive immune responses and has demonstrated therapeutic anti-tumor activity but clinical development has been hindered by a narrow therapeutic window. We generated a novel IL-12 anchored-drug conjugate by physiochemical linking of murine IL-12 to aluminum hydroxide (alum). The complex was designed to utilize alum as a scaffolding for durable retention of IL-12 within the tumor microenvironment as a strategy to increase the therapeutic window. To better define the systemic PK profile of the anchored IL-12 (mANK-101), a model-based assessment tool was developed to describe the systemic PK profile and downstream signaling factors following intratumoral (IT) injection of mANK-101. When compared to non-anchored IL-12, mANK-101 exhibited a distinct PK profile. Specifically, mANK-101 treatment was associated with a significant 9-fold increase in the systemic terminal volume of distribution (Vd). Furthermore, linear mixed-effects models provided evidence that CD8+ T cell infiltration and increased serum interferon gamma (IFNG) levels were correlated with tumor regression after a single dose of mANK-101. In addition, PK/PD modeling confirmed a link between systemic IL-12 and serum IFNG. The model also suggests that anchored IL-12 drug conjugate is expected to prolong the absorption half-life (115 h vs 8 h for the unanchored drug) with durable local retention and limited systemic absorption. In addition, serum IFNG may be a surrogate marker for drug activity. The PK modeling predictions may also contribute to determining the optimal clinical dose and schedule of ANK-101 and other anchored drug conjugates in patients with solid tumors.
白细胞介素-12（IL-12）介导先天性和适应性免疫反应，并已显示出治疗性抗肿瘤活性，但临床开发受到狭窄治疗窗的阻碍。我们通过将小鼠IL-12与氢氧化铝（明矾）进行物理化学连接，生成了一种新型的IL-12锚定药物偶联物。该复合物旨在利用明矾作为支架，使IL-12在肿瘤微环境中持久保留，作为扩大治疗窗的一种策略。为了更好地定义锚定IL-12（mANK-101）的全身药代动力学特征，开发了一种基于模型的评估工具，以描述瘤内（IT）注射mANK-101后的全身药代动力学特征和下游信号因子。与未锚定的IL-12相比，mANK-101表现出独特的药代动力学特征。具体而言，mANK-101治疗与全身终末分布容积（Vd）显著增加9倍相关。此外，线性混合效应模型提供的证据表明，单剂量mANK-101后，CD8 + T细胞浸润和血清干扰素γ（IFNG）水平升高与肿瘤消退相关。此外，药代动力学/药效学建模证实了全身IL-12与血清IFNG之间的联系。该模型还表明，锚定的IL-12药物偶联物有望延长吸收半衰期（未锚定药物为8小时，锚定药物为115小时），具有持久的局部保留和有限的全身吸收。此外，血清IFNG可能是药物活性的替代标志物。药代动力学建模预测也可能有助于确定实体瘤患者中ANK-101和其他锚定药物偶联物的最佳临床剂量和给药方案。
