Data Sheet 1_SON-1010: an albumin-binding IL-12 fusion protein that improves cytokine half-life, targets tumors, and enhances therapeutic efficacy.pdf

BackgroundCytokines have been promising cancer immunotherapeutics for decades, yet only two are licensed to date. Interleukin-12 (IL-12) is a potent regulator of cell-mediated immunity that activates NK cells and interferon-γ (IFNγ) production. It plays a central role in multiple pathways that can enhance cancer cell death and modify the tumor microenvironment (TME). Attempts to dose rIL-12 were initially successful but IFNγ toxicity in Phase 2 complicated further development in the late 1990s. Since then, better dosing strategies have been developed, but none have achieved the level of cancer control seen in preclinical models. We set out to develop a novel strategy to deliver fully functional IL-12 and other biologics to the TME by binding albumin, taking advantage of its ability to be concentrated and retained in the tumor.
MethodsSingle-chain variable fragments (scFv) were identified from a human phage display library that bound human, mouse, and cynomolgus macaque serum albumin, both at physiologic and acidic conditions. These were taken through a series of steps to identify strongly binding molecules that don’t interfere with the normal physiology of albumin to bind FcRn, giving it prolonged half-life in serum, along with SPARC/GP60, which allows albumin to target the TME. A final molecule was chosen and a single mutation was made that minimizes the potential for immunogenicity. This fully human albumin-binding (FHAB®) domain was characterized and manufacturing processes were developed to bring the first drug candidate into the clinic.
ResultsOnce identified, the murine form of mIL12-FHAB was studied preclinically to understand its mechanism of action and biodistribution. It was found to be much more efficient at blocking tumor growth compared to murine IL-12, while stimulating significant IFNγ production with minimal toxicity. SON-1010, which uses the human IL-12 sequence, passed through all of the characterization and required toxicology and is currently being studied in the clinic.
ConclusionsWe identified and developed a platform technology with prolonged half-life that can target IL-12 and other immune modulators to the TME. Safety and efficacy are being studied using SON-1010 as monotherapy and in combination with checkpoint blockade strategies.

背景
数十年来，细胞因子（cytokines）一直是颇具前景的癌症免疫治疗候选手段，但截至目前仅有两款获得上市许可。白细胞介素-12（Interleukin-12，IL-12）是细胞介导免疫的强效调控因子，可激活自然杀伤细胞（natural killer cell，NK）并诱导干扰素-γ（interferon-γ，IFNγ）的产生。其在多条信号通路中发挥核心作用，可促进癌细胞死亡并重塑肿瘤微环境（tumor microenvironment，TME）。早期重组白细胞介素-12（recombinant IL-12，rIL-12）的给药尝试曾取得初步成效，但在20世纪90年代末的II期临床试验中出现的IFNγ毒性反应阻碍了其后续开发进程。自彼时起，学界已开发出更优化的给药策略，但均未达到临床前模型中观测到的癌症控制效果。本研究旨在开发一种全新策略，通过结合白蛋白将功能完整的IL-12及其他生物制剂递送至肿瘤微环境，利用白蛋白在肿瘤组织内富集并滞留的特性。

方法
研究人员从人源噬菌体展示文库中筛选出可在生理及酸性条件下结合人、小鼠及食蟹猴血清白蛋白的单链可变片段（single-chain variable fragment，scFv）。通过一系列筛选流程，最终获得结合能力强且不干扰白蛋白结合新生儿Fc受体（Fc neonatal receptor，FcRn）的分子——该结合可延长白蛋白在血清中的半衰期——同时保留其结合SPARC/GP60的能力，使白蛋白能够靶向肿瘤微环境。最终筛选得到一款最优分子，并通过单点突变最大限度降低其免疫原性风险。该全人源白蛋白结合结构域（FHAB®）已完成全面表征，同时开发了规模化生产工艺，将首款候选药物推进至临床研究阶段。

结果
研究人员对鼠源形式的mIL12-FHAB开展了临床前研究，以阐明其作用机制与生物分布特性。结果显示，相较于鼠源IL-12，该分子在抑制肿瘤生长方面效率显著提升，同时可诱导显著的IFNγ产生且毒性极低。采用人源IL-12序列的SON-1010已完成全部表征及必要的毒理学研究，目前正处于临床阶段。

结论
本研究筛选并开发了一款可延长半衰期的平台技术，能够将IL-12及其他免疫调节剂靶向递送至肿瘤微环境。目前正在开展SON-1010单药治疗及联合免疫检查点阻断策略的安全性与有效性研究。